Use of Dietary Supplements by Military Personnel

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Use of Dietary Supplements by Military Personnel

Committee on Dietary Supplement Use by Military Personnel Food and Nutrition Board M.R.C. Greenwood and Maria Oria, Editors

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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. W911QY-06-C-0095 between the National Academy of Sciences and the Department of Defense; Contract No. DAMD27-99-1-9478 between the National Academy of Sciences and the United States Army; Contract No. N01-OD-4-2139 TO #177 between the National Academy of Sciences and the National Institutes of Health, U.S. Department of Health and Human Services; Contract No. HHSF223200710832P between the National Academy of Sciences and the Food and Drug Administration, U.S. Department of Health and Human Services; and Letter of Agreement No. OFED-7819 between the National Academy of Sciences and Samueli Institute. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-XXXXX-X (Book) International Standard Book Number 0-309- XXXXX -X (PDF) Library of Congress Control Number: 00 XXXXXX

Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2008 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2008. Use of Dietary Supplements by Military Personnel. Washington, DC: The National Academies Press.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL M.R.C. GREENWOOD (Chair), University of California, Davis CHERYL ANDERSON, Department of Epidemiology, Johns Hopkins University, Baltimore BRUCE BISTRIAN, Harvard Medical School, Boston JOHN W. ERDMAN, Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign WILLIAM C. FRANKE, Center for Advanced Food Technology, Rutgers, The State University of New Jersey, New Brunswick ELIZABETH JEFFERY, Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign ROBIN B. KANAREK, Department of Psychology, Tufts University, Medford, MA CARL L. KEEN, Department of Nutrition, University of California, Davis GAIL B. MAHADY, UIC/NIH Center for Botanical Dietary Supplements Research for Women’s Health, Chicago SANFORD A. MILLER, Center for Food, Nutrition, and Agriculture Policy, University of Maryland, College Park ESTHER F. MYERS, Research and Scientific Affairs, American Dietetic Association, Chicago JANET WALBERG RANKIN, Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University

Consultant DAVID F. DINGES, Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia

Staff MARIA P. ORIA, Study Director SHANNON L. WISHAM, Research Associate (until April 2008) ALICE VOROSMARTI, Research Associate (from April 2008) SANDRA AMAMOO-KAKRA, Program Associate HILARY RAY, Editor

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STANDING COMMITTEE ON MILITARY NUTRITION RESEARCH JOHN W. ERDMAN (Chair), Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign ELDON WAYNE ASKEW, Division of Nutrition, University of Utah, Salt Lake City BRUCE R. BISTRIAN, Harvard Medical School, Boston JOSEPH G. CANNON, School of Allied Health Sciences Health Research, Medical College of Georgia JOHANNA DWYER, Frances Stern Nutrition Center, Tufts University, Office of Dietary Supplements, National Institutes of Health WILLIAM C. FRANKE, Center for Advanced Food Technology, Rutgers, The State University of New Jersey, New Brunswick RONALD GLASER, Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus ROBIN B. KANAREK, Department of Psychology, Tufts University, Medford, MA ESTHER F. MYERS, Research and Scientific Affairs, American Dietetic Association, Chicago Staff MARIA P. ORIA, Study Director SANDRA AMAMOO-KAKRA, Program Associate

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FOOD AND NUTRITION BOARD* DENNIS M. BIER (Chair), Children’s Nutrition Research Center, Houston, TX MICHAEL P. DOYLE (Vice Chair), Center for Food Safety, University of Georgia, Griffin DIANE BIRT, Department of Food Science and Human Nutrition, Iowa State University, Ames YVONNE BRONNER, School of Public Health and Policy, Morgan State University, Baltimore FERGUS M. CLYDESDALE, Department of Food Science, University of Massachusetts, Amherst GORDON L. JENSEN, Department of Nutritional Sciences, Pennsylvania State University, University Park REYNALDO MARTORELL, Department of Global Health, Emory University, Atlanta SUSAN T. MAYNE, Division of Chronic Disease Epidemiology, Yale University School of Medicine, New Haven, CT SANFORD A. MILLER, Center for Food, Nutrition, and Agriculture Policy, University of Maryland, College Park J. GLENN MORRIS, JR., Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore SUZANNE P. MURPHY, Cancer Research Center of Hawaii, University of Hawaii, Honolulu JOSE M. ORDOVAS, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston MARTIN A. PHILBERT, School of Public Health, University of Michigan, Ann Arbor JIM E. RIVIERE, Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, Raleigh REBECCA J. STOLTZFUS, Division of Nutritional Sciences, Cornell University, Ithaca, NY PATRICK J. STOVER, Division of Nutritional Sciences, Cornell University, Ithaca, NY WALTER C. WILLETT, Department of Nutrition, Harvard School of Public Health, Boston Staff LINDA D. MEYERS, Director GERALDINE KENNEDO, Administrative Assistant ANTON L. BANDY, Financial Associate

*IOM Boards and Standing Committees do not review or approve individual reports and are not asked to endorse conclusions and recommendations. The responsibility for the content of the report rests with the authoring committee and the institution.

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REVIEWERS This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Eldon Wayne Askew, Division of Nutrition, University of Utah, Salt Lake City Diane Birt, Center for Research on Dietary Botanical Supplements, Department of Food Science and Human Nutrition, Iowa State University, Ames Graham A. Colditz, Department of Surgery, Washington University School of Medicine, St Louis, MO Harry S. Fong, Department of Medicinal Chemistry and Pharmacognosy, Professor Emeritus, University of Illinois at Chicago, IL David W. Kaufman, Slone Epidemiology Center and School of Public Health, Boston University, MA Rick Kingston, SafetyCall(tm) International and College of Pharmacy, University of Minnesota, Bloomington Melinda M. Manore, Department of Nutrition, Oregon State University, Corvallis Mohsen Meydani, Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging and Dorothy R. Friedman School of Nutrition Science, Tufts University, Boston, MA Simin Nikbin Meydani, Nutritional Immunology Laboratory, School of Nutrition Science and Policy and Sackler Graduate School, Tufts University, Boston, MA Joseph V. Rodricks, Environ, Institute for Health Risk Sciences, Arlington VA A.P. Smith, Centre for Occupational and Health Psychology, Cardiff University, Cardiff, UK Judith S. Stern, Department of Nutrition, University of California at Davis Matthew Vukovich, Applied Physiology Laboratory, Department of Health Physical Education and Recreation, South Dakota State University, Brookings Thomas R. Ziegler, Clinical Research Center, Emory University Hospital, Atlanta, GA Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by John C. Bailar III, The University of Chicago and Robert J. Cousins, Food Science and Human Nutrition Department, University of Florida. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Preface

This report, titled Use of Dietary Supplements by Military Personnel, is the product of the work of an ad hoc committee under the auspices of the Standing Committee on Military Nutrition Research (CMNR). The CMNR, a standing committee of the Food and Nutrition Board (FNB), was established in 1982 to advise the U.S. Department of Defense (DOD) on the need for and conduct of nutrition research and related issues. This report was produced in response to a request by the Military Nutrition Division of the U.S. Army Research Institute of Environmental Medicine (USARIEM) to the Institute of Medicine (IOM) to convene a committee to review the use of dietary supplements by military personnel and recommend an approach to determine which dietary supplements need active management. Initial sponsors of the study were USARIEM, the U.S. Army Medical Research and Materiel Command, the Samueli Institute and the National Institute of Health’s Office of Dietary Supplements. Their representatives helped with the formulation of the specific questions in consultation with the CMNR. As the project was initiated, the Food and Drug Administration’s (FDA’s) Center for Food Safety and Applied Nutrition (CFSAN) became a sponsor of the study. A 12-member committee was formed that had expertise in micronutrients, protein, energy balance and sports nutrition, gastroenterology, clinical medicine, food processing and technology, eating behavior and intake regulation, clinical nutrition, dietetics, and psychology. Dietary supplements are widely available through a rapidly expanding market of products that are commonly advertised as being beneficial for health, performance enhancement, and disease prevention. These claims may influence the use of dietary supplements by military personnel, given the importance and frequent evaluation of physical performance and health as criteria to join and remain in the military. The increase in use of these products has raised some concern regarding their overall and long-term efficacy and safety. The evaluation of such products is especially difficult since many contain multiple ingredients, have a changing composition over time, or are used intermittently at doses difficult to measure. Because of these difficulties, it may take a long time for the current system of voluntary adverse events reporting to detect problems. Although the vast majority of military personnel are assumed to be at the same general risk as the overall U.S. population, the specific requirements of some military personnel require that additional due diligence be exercised both with respect to possible benefits and to the possible risks when these products are used by military personnel in particular job classifications and/or environments. For special military subpopulations, relatively minor adverse effects could seriously affect the unit’s ability to perform its mission. It is clear then that these subpopulations within the military are different from the general civilian population, and guidance on managing their use of dietary supplements needs to be tailored to address their specific needs. This expert committee analyzed the patterns of dietary supplement use among military personnel, and by examining published reviews of the scientific evidence, the committee identified those dietary supplements that are beneficial and/or warrant concern due to risks to health or performance. The committee also developed a system to monitor adverse health effects and PREPUBLICATION COPY: UNCORRECTED PROOFS xi

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recommended a framework to identify the need for active management of dietary supplement use by military personnel. Specifically, the committee: 1. Reviewed survey data and findings made available to the committee related to supplement use by military personnel to identify: (a) which dietary supplements are of most prevalent use, with consideration of differences according to demographic factors such as age, rank, sex, deployment status, military occupational specialty, organization, and unit; and (b) expectations of benefits and reasons for use of dietary supplements by military personnel. 2. Identified information gaps regarding dietary supplement use by military personnel and recommended processes and designs by which current and future usage of supplements (including dosages, quality, and forms of supplement) should be monitored, surveyed, analyzed, reported, and the resultant data shared. 3. Selected a limited number of dietary supplements from those identified as commonly used. On the basis of already published reports that review the available scientific evidence, the committee identified those supplements that may be of benefit and/or pose serious hazards to the health and/or physical and cognitive performance capability of military personnel and determined whether further examination and integrative evaluation or research on each is warranted. The committee considered potential effects of supplement withdrawal and interactions. 4. Considered existing military policies for managing dietary supplements, and assessed the applicability to a military setting of the framework outlined in the 2005 IOM report Dietary Supplements: A Framework for Evaluating Safety and determined how it could it be modified to determine which supplements need active management by the military. 5. Proposed an approach that could be followed to monitor military personnel for adverse health effects that might indicate a concern associated with consumption of dietary supplements. The DOD has provided many policies and regulations on nutrition for military personnel in many different settings; however, there is currently no systematic approach by which the risks and benefits of the use of dietary supplements by the military are evaluated and whereby parallel servicewide policies address their management. In the absence of those policies, the DOD relies on the monitoring of dietary supplement safety through the FDA. This approach might be adequate for the general public and for those in the military service that perform tasks similar to those of civilians; however, a different approach is needed for specific military subpopulations so that risks that might compromise the success of military operations are not overlooked, and potential benefits in performance or health from use of dietary supplements by military personnel are realized. The committee carried out its work over 18 months and held three meetings and numerous teleconferences. The first meeting of the committee was held in conjunction with a 2-day workshop. Speakers addressed the issues related to dietary supplement use in the military and included original data on recent military survey instruments. These presentations were useful for the committee’s deliberations and recommendations and are included in this report as individually authored papers in Appendix B. The committee expresses its appreciation to Andrew Young, Chief of the Military Nutrition Division and representative from the DOD for this task, for generously giving his time and help and for being available to clarify the task of the committee. Special thanks are extended to Rebecca Costello of the Office of Dietary Supplements (ODS); Wayne B. Jonas, Joan Walter, Christine Choate, and Deborah Ader from the Samueli Institute; and Patricia Deuster from the Uniformed Services University of the Health Sciences who helped delineate the task, and to Jean Louis Belard PREPUBLICATION COPY: UNCORRECTED PROOFS xii

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from the Telemedicine and Advanced Technology Research Center (TATRC) for his invaluable input during the first committee meeting. In addition, the committee thanks COL Karl Friedl, Director of TATRC, who continues to support the work of the CMNR and was readily available to provide the appropriate contacts needed to gather information for the committee On behalf of the committee, I sincerely thank the workshop participants and speakers for addressing topics critical to the completion of the committee's work. These presentations were important reference sources for the committee. Each speaker provided an excellent presentation, prepared a manuscript of the presentation (see Appendix B), and worked with IOM staff throughout the revision process. Presenters of military surveys on dietary supplements deserve special thanks for going the extra mile in answering questions and analyzing data throughout the study at the committee’s request. Further, the committee wants to express its deepest gratitude to David Dinges for his effort and committed participation as a consultant to the committee who helped with drafts of the report and valuable comments. The quality of the report was significantly improved by the comments of external reviewers, and the diligent oversight of the National Research Council monitor, John Bailer and the coordinator, Robert Cousins. The committee expresses its gratitude to them as well. The committee owes a strong debt of gratitude to the FNB staff for their professionalism and effectiveness in ensuring that our committee adhered to its task statement, for providing discipline and experience in helping to assemble the report and effectively respond to reviewers, and for providing background research support and organizing our meetings. In particular, we thank Senior Program Officer Maria Oria, who worked on numerous drafts and revisions. Ably assisting Dr. Oria in her efforts were Program Associate Sandra Amamoo-Kakra and Research Associates Shannon Wisham and Alice Vorosmarti. The committee also wants to acknowledge the excellent work of Hilary Ray who edited numerous versions of the report. The committee is also grateful to the overall guidance and continuous support of Linda Meyers, FNB Director. And finally I want to thank the members of this committee for their diligent and collegial work. I have worked with many committees over the years, and the members of this committee will always have my deepest respect and admiration for their individual accomplishments and their ability to work as a group on these important issues. I hope our readers will find this report informative and useful. M.R.C. Greenwood, Chair Committee on Dietary Supplement Use by Military Personnel

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Contents

SUMMARY

S-1

1

INTRODUCTION

1-1

2

RECENT SURVEY FINDINGS AND IMPLICATIONS FOR FUTURE SURVEYS OF DIETARY SUPPLEMENT USE 2-1

3 VITAMINS AND ESSENTIAL MINERALS FOR MILITARY PERSONNEL

3-1

4

OTHER DIETARY SUPPLEMENTS FOR MILITARY PERSONNEL

4-1

5

FRAMEWORK TO REVIEW THE SAFETY OF DIETARY SUPPLEMENTS FOR USE BY MILITARY PERSONNEL 5-1

6

MONITORING ADVERSE HEALTH EFFECTS ASSOCIATED WITH DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

6-1

RESEARCH NEEDS

7-1

7

APPENDICES

A Workshop Agenda A-1 B Workshop Papers B-1 C Findings from Recent Surveys on Dietary Supplement Use by Military Personnel and the General Population C-1 D Case Studies D-1 E Adverse Event Reporting Forms E-1 F Biographical Sketches of Workshop Speakers F-1 G Biographical Sketches of Committee Members G-1 H Acronyms and Abbreviations H-1 I Glossary I-1

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Summary

To achieve and maintain optimal readiness and mission performance goals, the military has the responsibility of guiding its service members in making choices that best enhance their health, including nutrition. As with other sectors of the population, the use of dietary supplements to promote health has become increasingly popular among members of the military, which faces a paradox in managing their use. Supplements available to service members range from those that might impart beneficial effects to health and performance with negligible side effects to others that have uncertain benefits and might be potentially harmful to health and performance. Furthermore, the military, cognizant of the potential benefits of dietary supplements, is conducting research on some promising supplements; in these cases, the potential for adverse effects should also not be underestimated. Without appropriate guidance on their use, military service members might not only compromise their own performance or health and the success of military operations, but might also forego dietary supplements with potential to improve performance or health. There are no servicewide military policies (e.g., education or regulations) to guide commanders in management practices for safe use of dietary supplements; furthermore, there is no formal military pathway to report adverse events potentially associated with dietary supplements. The lack of consistent policies for the safe use of dietary supplements has raised concerns owing to the vulnerabilities of some military subpopulations. Previous Institute of Medicine (IOM) reports prepared under the auspices of the Committee on Military Nutrition Research (CMNR) have found that nutritional needs of military service members differ from those of civilians, depending on the specific subpopulation, the mission, and the environmental circumstances. Thus, the effects of dietary supplements, whether beneficial or detrimental, might be different for military service members, specifically for some subpopulations facing heightened risks (e.g., Special Forces, Rangers, aviators). Perhaps more importantly, even minor detriments to health that represent simply discomfort or inconvenience to a civilian (e.g., mild dehydration or mild diarrhea) might compromise a service member’s performance or health and, thus, the success of the military operation. The regulatory responsibility of the U.S. Food and Drug Administration (FDA) for the safety of dietary supplements is designated by the 1994 Dietary Supplement Health and Education Act (DSHEA). Actions to restrict the availability of a dietary supplement must proceed from a demonstration by the FDA of a significant or unreasonable risk of illness or injury to consumers under conditions of recommended use. Manufacturers are responsible for ensuring the safety of the ingredient, but FDA is not authorized by statute to require data supporting safety, as it is the case for food additives or drugs. This approach may not be sufficient to ensure the safe use of dietary supplements in some military contexts, which inherently present considerable risk to individuals. Based on the heightened risks, potential for benefits, frequency of use among military service members, the lack of consistent policies, and the absence of a process to report adverse events as they occur in military settings, the Department of Defense (DoD), Samueli Institute, and PREPUBLICATION COPY: UNCORRECTED PROOFS S-1

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S-2

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

National Institutes of Health, with additional support from the FDA, requested that the IOM convene an ad hoc committee under the oversight of the CMNR. The Committee on Dietary Supplement Use by Military Personnel was asked to review the patterns of dietary supplement use among military personnel, to recommend a framework to identify the need for active management of dietary supplement use by military personnel, and to develop an approach system to monitor adverse health effects. The committee was further tasked with selecting a subset of dietary supplements and, by examining published reviews of the scientific evidence, identifying those that are beneficial and/or warrant concern (see full Statement of Task in Chapter 1). The committee held a public workshop on February 12–13, 2007, in Washington, D.C., to gather results from military surveys on the use of dietary supplements, and current approaches and innovative ideas on monitoring adverse effects; this information was of primary consideration in the preparation of this report. The committee also reviewed the 2005 IOM report Dietary Supplements: A Framework for Evaluating Safety as a starting point for its deliberations. The 2005 IOM report framework was prepared to assist the FDA in evaluating scientific information to determine the level of concern prompted by use of a given dietary supplement. In developing its approach, the committee considered the special demands facing military subpopulations that set them apart from the general population. The committee further recognized that the military is able to make policy decisions (e.g., prohibit the use of a dietary supplement) based on criteria related to the needs of military subpopulations and the demands of their missions. Although the development of a detailed process to establish a dietary supplement’s level of efficacy was not within the scope of the current task, the committee did consider the importance of efficacy in developing policy on the use of dietary supplements in a military context. This summary presents the committee’s recommendations for an approach to management by military leadership of the use of dietary supplements and identifies general areas of research needs. Because the U.S. Army Medical Command has the official responsibility to make decisions regarding nutrition for all military services, many of the studies or policies refer to the U.S. Army. However, the recommended approach applies to all branches of the military. APPROACH TO MANAGE THE USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL The committee’s reviews of selected dietary supplements showed that some popular dietary supplements among military personnel might result in health and performance detriments if misused, particularly for those subpopulations facing demanding tasks. For example, Ginkgo biloba and garlic have anticoagulant effects, valerian and melatonin are sedative, and ephedrinelike substances may cause harmful cardiac effects. The use of multi-ingredient dietary supplements is of concern because of the unknown interactions among ingredients. Based on these, the committee concluded that a separate system to monitor and evaluate adverse effects is needed. This system will be one component of the committee’s recommended approach to managing dietary supplements in a military context, which comprises four related components: (1) improving monitoring of the use of dietary supplements by military personnel, (2) using a framework to determine the level of concern for dietary supplements in a military context, (3) implementing a system to report adverse events associated with dietary supplements, and (4) expanding education on dietary supplements. To demonstrate application of the framework recommended in the second component, the committee reviewed a number of dietary supplements (Chapter 4) and identified those that might pose concerns or be beneficial (Table 5-3). In addition, the overall approach (i.e., PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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S-3

SUMMARY

recommendations for action) was applied to a subset of those dietary supplements in Appendix D. It was outside the committee’s task to provide a review of all dietary supplements. These monographs and case studies should be considered examples, and determination of the specific actions to take in response to a dietary supplement review should be the prerogative of military leadership. The committee considered organizational resources needed to follow its approach including existing military infrastructure, policies, and organizational units and their responsibilities. For the approach to succeed, it is crucial that a military committee or entity (hereafter referred to as the designated oversight committee) has the responsibility for coordination and oversight of various dietary supplement activities (Recommendation 8). Creation of a new entity may not be feasible and, instead, the tasks of an existing one could be expanded to include the oversight of dietary supplement-related activities. The actual operational and data collection activities would rest with other existing military organizations, such as the U.S. Army Research Institute of Environmental Medicine, Center for Health Promotion and Preventive Medicine, or Office of the Assistant Secretary of Defense (Health Affairs). Improving Monitoring of the Use of Dietary Supplements by Military Personnel Data from these surveys on dietary supplement use are a key component of the committee’s approach, serving as a signal to apply the recommended framework and determine the level of concern. For example, increased use will serve as a signal to initiate a review. The committee reviewed questionnaire designs and results from eight surveys (conducted in groups of active duty military personnel; active duty, National Guard, and reserve military personnel; U.S. Army personnel; U.S. Army personnel deployed in Germany; U.S. Army Rangers; Special Forces members; U.S. Air Force personnel; U.S. Army physicians). The surveys provide extensive data in some areas (e.g., demographics, frequency of use) but inadequate data in others (e.g., dose, association with beneficial or adverse outcomes). Within these limitations, the committee found a high use of dietary supplements (e.g., in one survey, 60 percent of respondents reported using at least one dietary supplement), especially vitamins and minerals, but also others. Vitamins and minerals were used by about 45 percent of service members on active duty; other popular dietary supplements were “bodybuilding” supplements ( 21 percent), and “weight-loss products” (18 percent) (see Appendix C). Recommendations 1, 2, and 3 are meant to improve the quantity and quality of data collected. Recommendation 1. Surveys to collect data on the use of dietary supplements need to continue. The committee recommends that DoD continue to exploit a large, generic survey by expanding the DoD Survey of Health-Related Behaviors managed by the Office of the Assistant Secretary of Defense (Health Affairs) with questions related to adverse events and beneficial outcomes as well as the use of specific dietary supplements that might be of concern. Recommendation 2. More comprehensive data collection is needed from select populations. The committee recommends that in-depth, anonymous surveys about dietary supplement use be administered at select military installations. These select sites would be chosen because their military populations (e.g., Special Forces or Rangers) would be more likely to use dietary supplements and face higher or

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S-4

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

unknown risks due to greater mission demands and harsher environments (e.g., high altitude, extreme temperature) than most military personnel. For example, the in-depth surveys should capture data during intense military operations that are similar to combat (e.g., Special Forces training or situations of deployment) when data collection will not interfere with mission completion. Recommendation 3: Data quality needs to be improved. Surveys should be designed in consultation with the proposed designated oversight committee, which could oversee many aspects of dietary supplement management including adverse event reporting, as described below. The system of surveillance needs to be comprehensive and include the collection of data as described in Box S-1. To obtain a more complete picture of use, survey data (from self-reported questionnaires and interviews) should be complemented with information from other sources, such as electronic health records and sales data from military installations. Professional expertise should be consulted extensively in the design, administration, and use of surveys. BOX S-1 Improving Survey Designs The committee recommends that researchers implement the following additions and modifications to the surveys on dietary supplement use in order to improve their value: x

Frame appropriate questions, with unambiguous terminology (e.g., clarify terms such as antioxidant) and attending to the order of the questions.

x

Design questions that expressly define a dietary supplement user (e.g., an individual consuming a dietary supplement at least once a week).

x

Complement exposure data on dietary supplement ingredients with data from questions on consumption from other dietary sources (e.g., foods and beverages).

x

Include questions that allow the analysis of associations of dietary supplement use with health and performance outcomes, whether adverse or beneficial.

x

Collect data on various demographic characteristics.

x

Collect data on the environment and conditions under which respondents use supplements (e.g., special operations).

x

Include questions about sources of information used by military service members to determine the most effective methods of dissemination of information.

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SUMMARY

Using a Framework to Characterize Concern Level for Dietary Supplements in a Military Context The committee adapted the framework developed in the 2005 IOM report Dietary Supplement Use: A Framework for Evaluating Safety to characterize concern levels for dietary supplements in a military context. The 2005 IOM report framework (developed to assist the FDA in determining the level of concern from using a dietary supplement), is meant for the general population, although the report recognizes that some subpopulations may have special vulnerabilities. The committee’s adapted framework is intended to evaluate concerns about use of dietary supplements, specifically considering the vulnerabilities and needs of military subpopulations (Recommendations 4, 5, and 6). For example, the criteria that categorize adverse effects differs: effects that would not be considered serious in the civilian population (e.g., drowsiness) might compromise the performance of a military service member and therefore initiate a review. Also, in contrast to the IOM framework, the review of dietary supplements and corresponding management actions attends to the specific environment, missions, and military subpopulations. Furthermore, because of the military’s emphasis on individual readiness and performance, management of dietary supplements needs to weigh the potential for risks against benefits, rather than predicate action solely on risk. The general steps in the adapted framework—signal detection, initial review of signals, and integrated safety evaluation—are depicted in Figure S-1. The committee recognizes three challenges in applying its framework to determine level of concern: insufficient data on safety and efficacy, dietary supplements that contain multiple ingredients, and the presence of contaminants (Box S-2). When addressing these challenges, the military might need to apply temporary policies until a definitive conclusion is reached. Recommendation 4: The decision to initiate a review of a dietary supplement should be based on two criteria: severity and number of adverse events, and prevalence of use. The selection of dietary supplements for review should consider the particular vulnerabilities of the military subpopulation, which would depend on their missions and mission environments. Summaries of adverse events reported in military and nonmilitary settings and data on use will be evaluated by the designated oversight committee, which will provide guidance to military leadership about the need to review a dietary supplement. For example, if the surveys indicate frequent use, or if adverse events reported are of moderate concern, use of the framework by a review panel to evaluate published science-based safety reviews might be recommended. If summaries indicate serious adverse events, generating a high risk of concern, then a more immediate action might also be recommended (e.g., restriction of use) (Figure S-1). The committee recommended that the evidence (e.g., how many adverse events were associated with the dietary supplements, how strong the association, level of intake, intake of other medications/supplements, actual circumstances, characteristics of the individual) for an adverse event be reviewed and that the level of concern be determined by taking into consideration not only the the strength of the evidence but also the tasks of the specific military subpopulation and the environment in which these tasks will be conducted.

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BOX S-2 Potential Challenges When Applying the Recommended Framework Insufficient scientific data. Acquisition of sufficient scientific data from literature searches to support an informed decision about the safety and efficacy of a dietary supplement within the military will be a challenge. The committee emphasizes that absence of evidence of risk, a frequent reality, does not necessarily indicate that there is no risk, but might reflect inadequacy of the study design to identify risk. In areas of notable concern where significant data gaps exist, the military should perform research as recommended below. Multi-ingredient dietary supplements. Dietary supplements commonly contain multiple ingredients, which are often reformulated with different ratios, amounts, and even constituents. Finding data on the safety of the multi-ingredient products in the market is a yet greater challenge than finding data for single-ingredient products. There are two potential approaches to determining the safety or efficacy of these products; both offer pros and cons. In one approach, the military could conduct research on the composite dietary supplement product using military subpopulations under performance environments of interest. This approach would more accurately reflect usage, but would be costly, time consuming, and given the rapid turnover of products in the market, impractical. Another approach would be to review the safety of each individual ingredient. Here, limitations are twofold and relate not only to the possible dearth of data for the effects of the ingredients themselves, but for the interactions among ingredients. The committee concluded that these products merit special consideration and should be frequently monitored for use, sales, and adverse event reports. Presence of contaminants. The linking of an adverse event to the use of a dietary supplement ingredient might be confounded if the product contains adulterants or contaminants. If contamination occurs, then attribution of the source of the adverse event becomes a formidable task. If enforced, the newly adopted cGMPs (current Good Manufacturing Practices) rule should minimize the potential for inclusion of adulterants or contaminants.

Recommendation 5: The military should use the framework (Figure 5-1) to review the dietary supplements that raise safety concerns (per criteria above). The framework consists of the integrated evaluation of results from current, authoritative reviews (or, if no reviews are available, original research conducted over the previous 10 years) analyzing bioactivity and potential for drug interactions. When evaluating the safety of a dietary supplement, the military should follow the criteria on which to determine the level of concern (i.e., high, moderate, low, and minimal) and the principles in the 2005 IOM report, but with heightened attention to optimal performance and to the risks to survivability of military service members under the environmental conditions and demands of military operations. For example, if a product significantly contributes to hypoxia, its use may be of high concern for aviators (see Box S-3). A review panel that includes nutritionists, epidemiologists, toxicologists, clinicians, and pharmacognosists should conduct the reviews and determine the level of concern. Recommendation 6: The military’s decisions on dietary supplement policy (e.g., rules, education, monitoring of use) should be based on conclusions about both safety and efficacy derived from the available published, authoritative scientific PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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SUMMARY

literature and considering conditions associated with a specific type of mission, location, and environment. Determining the specific actions to take in response to a dietary supplement review should be the prerogative of military leadership. In some cases, the policies may apply to all services and therefore be established by the DoD Health Affairs; in other cases, policies may be established by each service or by individual commanders who are knowledgeable about the tasks and circumstances of a particular military subpopulation. Policy decisions based on scientific reviews should use a model similar to the risk analysis model. Determinations about the level of concern and benefit should be made by a review panel (parallel to the “risk assessment” concept in a risk analysis model), whereas the decisions about implementing military policy should be made by military leadership (e.g., DoD Health Affairs in consultation with the designated oversight committee, which has an advisory role; or military commanders in consultation with the local Medical Treatment Facilities’ Pharmacy and Therapeutics Committees [P&TC] and the designated oversight committee), paralleling the “risk management” concept in a risk analysis model. This model can be useful in making policy only when scientists work in consultation with military leadership, so that technical questions arising from reviews or other data and questions on the circumstances of military subpopulations can be clarified. Implementing an Adverse Event Surveillance System The military lacks a systematic process by which adverse events linked to dietary supplement use are reported, analyzed, and used as the basis for making management decisions. Implementing such a system is justified, especially considering the dangerous tasks and extreme environments faced by some military populations. This system, the third component of the committee’s approach, will serve as a signal to initiate a review of a dietary supplement or implement policy (e.g., restrict the use of a dietary supplement). Recommendations are provided in three areas: (1) the implementation of an adverse event reporting system for military personnel (Recommendations 7, 8, and 9); (2) the establishment of a forum or coalition to share data and information related to dietary supplements (Recommendation 10); and (3) increasing the reporting of adverse events by broadening outreach activities and educational programs (Recommendations 11 and 12). To the extent possible, the adverse event reporting system currently in use for medications could be expanded to include dietary supplements. Recommendation 7: The military should use a centralized monitoring system for reporting dietary supplement adverse events (and data on use), in which data are recorded through the integrated electronic health record system already being implemented in the military. DoD should ensure that future electronic health records adequately capture dietary supplement use and adverse event data by soliciting this information during medical visits. For instance, it would be appropriate during medical visits to add a standard assessment question(s) as part of the routine office check-in. In addition, future electronic health records should be capable of generating standard reports on frequency of use and adverse event data that can be aggregated for analysis; and automated alerts to signal a significant change in usage or adverse event reporting, or to signal a risk of interaction with a medication or other treatment.

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Recommendation 8: The military should designate a committee or military entity to be responsible for the oversight and coordination of dietary supplement-related activities, such as overseeing the adverse event surveillance system and parallel educational components. This designated committee will have an advisory role; it should provide input to the DoD leadership on military policies in matters addressing the safety and efficacy of dietary supplements. These include recommendations on when to initiate a safety review, where to focus research, and the design of educational programs and materials for military service members as well as for health care professionals that highlight the benefits and risks of dietary supplement use. The committee should: x

Advise DoD on the mechanisms for submission of adverse event reports and a process for provision of summaries to those with leadership or educational roles.

x

Identify relevant databases and efforts related to surveillance of adverse events associated with dietary supplement use by military and nonmilitary groups.

x

Participate in a coalition or forum to exchange and share data and information related to dietary supplements (Box S-3).

Recommendation 9: The responsibilities of the local Medical Treatment Facilities’ Pharmacy and Therapeutics Committees should be extended to reviewing and summarizing the adverse event reports as submitted by health care providers or service members, and preparing and providing summaries via a process recommended by the designated oversight committee.

x x x x x x x x x x x x x x

BOX S-3 Suggested Partners of a Forum or Coalition to Share Data on Dietary Supplements Designated military committee to oversee dietary supplements Registered dietitians from U.S. Air Force, U.S. Army, and U.S. Navy (DoD Nutrition Committee) USARIEM Pharmacist from DoD Pharmacoeconomic Center, U.S. Air Force, U.S. Army, and U.S. Navy Medical representative from U.S. Air Force, U.S. Army, and U.S Navy FDA’s Center for Food Safety and Applied Nutrition Federal Trade Comission NIH’s Office of Dietary Supplements Army and Air Force Exchange Service, Navy Exchange Service (AAFEX/NEX) Supplement sales outlets located on military installations Industry trade associations Health and Wellness and Health Promotion Centers from U.S. Air Force, U.S. Army, and U.S. Navy Fitness centers or unit trainers from U.S. Air Force, U.S. Army, and U.S. Navy Optional additional representatives PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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To conduct these tasks, P&TCs should not only have appropriate scientific expertise, but should be familiar with the demands and conditions unique to military operations and be experienced in identifying serious or unexpected adverse effects, especially when relevant to military performance. Sharing Data and Information Recommendation 10: The committee recommends that a coalition or forum be established for the exchange of data and information related to dietary supplements, such as data from surveillance of dietary supplement use and adverse events. The members of this forum (military and nonmilitary government organizations, nongovernmental organizations, and industry) would share data on adverse event summaries and reports as well as educational and outreach materials and activities. Members would also share data related to sales and use of dietary supplements and associated adverse events (or beneficial effects) in the military and civilian populations. Participants of the forum should include, among others, experts in toxicology and safety evaluation of natural products. Expanding Education: Training and Outreach The committee recognizes the importance of expanding educational programs and outreach activities to increase awareness about the effects of dietary supplements. These educational elements are key to supporting an effective, centralized adverse event monitoring system. Recommendation 11: Military service members and commanders should be educated to recognize both the potential adverse effects and benefits from using specific dietary supplements and the importance (and the process) of reporting an adverse event. The designated oversight committee should oversee the development of and recommend educational materials to be disseminated for this purpose (e.g., point-of-sale brochures, posters, or websites). Recommendation 12: Health care personnel should be trained in evaluating dietary supplement use, informing and obtaining information from their patients, and appropriately reporting adverse events. Education should be included in existing programs (e.g., Uniformed Services University of Health Sciences, internships and residencies, aerospace medicine training, independent duty medical technician training, and mandatory continuing education at medical staff meetings).

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High Concern

Safety Review

Moderate Concern

Low Concern

Integrate Data from A, B, C and Decide on Lev el of Concern (See Box 5-1)

B. Review of Original Research Pertaining to Specific Military Concerns1

Adverse Effects, not severe

A. Review of Safety Using Reviews or Original Research if Reviews are Nonexistant

Severe AdverseEffects

Signal Detection-Adverse Effects

Minimal Concern

C. Review of Interactions with Medications

Proactive Initiative

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

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FIGURE S-1 Framework to review the safety of dietary supplements

Footnote: 1High Physical Activity; Calorie Restriction; Hydration; GI Tract (diarrhea/nausea); Liver Health/Function (xenobiotic clearance); Cardiovascular Health; Mood/Behavior Altering; Alertness/Drowsiness; Extreme Heat/Cold; Injury/Bleeding

S-10

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RESEARCH NEEDS The committee was requested to select a limited number of dietary supplements to review and then determine whether further examination and integrative evaluation or research on each is warranted. Consequently, the committee did not attempt to provide an exhaustive listing of research needs and instead, presents key considerations for conducting dietary supplement research in a military context and an approach to prioritize research needs according to the special needs of military subpopulations. Key Considerations for Conducting Military Nutrition Research Study Designs Studies to investigate the safety and efficacy of dietary supplements in a military context should be performed using the existing military human models that mimic the physical stresses and environments that accompany military missions and training programs (e.g. a predefined course). The selection of subjects should take into consideration physiological differences and reflect demographic factors of the military population that might result in different effects of dietary supplement use. Research populations should particularly represent those participating in garrison training, serving in combat, or both and should be selected accordding to a welldesigned research plans that permits generalizations to the target populations. Access to analytical capabilities is a vital element of those studies designed to assess the identity and integrity of dietary supplement products associated with reported adverse events, possibly by contracting with appropriate research facilities. Animal Models Human models that simulate severe mental and emotional stresses and some toxicological tests present practical and ethical limitations. The military should continue the development of animal model systems that mimic the stresses of military personnel, particularly those facing demanding tasks and environments such as those in garrison training and combat, to allow screening for physiological effects of dietary supplements used under extreme conditions. Screening with well-designed and ethical animal studies could be followed with more focused human studies, possibly in collaboration with civilian researchers. Approaches to Identifying Research Needs Future studies on dietary supplement use in the military should be approached from an etiological or mechanistic perspective. To prioritize research needs, the military should include input from all the services. The designated oversight committee should be tasked with providing recommendations to the DoD on research to be pursued or funded. Gaps in data should be identified based on the following elements of the recommended approach: (1) results of the surveillance system on the use of dietary supplements, (2) gaps identified in the reviews conducted for specific dietary supplements, and (3) occurrence of adverse events of military importance associated with the use of specific dietary supplements. In addition, research conducted in the civilian population should be monitored for potential military

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implications. Following a similar approach, the committee provides a list of potential, general research topics and activities in Box S-4; however, as mentioned above, to increase the value of this exercise, the identification of research gaps should include coordinated input from all military services. Safety The military should develop a list of adverse effects of particular concern (see Box 5-1 in Chapter 5). The military might generate requests for proposals for methods to evaluate safety in these areas, or of any classes of compounds that could be expected to cause such safety issues. Benefit The committee recommends that the military identify physical and mental performance areas where improvement is of interest. In addition, the military should consider a future study to develop a framework approach to determine whether a dietary supplement is efficacious. Concomitantly, the military could take a similar approach as that suggested for safety, that is, to issue requests for proposals that cover both methods for evaluation and the particular class of compound that might be expected to confer these benefits. Studies on beneficial effects should be designed so that adverse effects can be identified.

Box S-4 Potential Research Topics and Activities x x

x x x x x x x x x

Continue to gather data on ration nutrient composition and total dietary intake of vitamins and minerals by military personnel. Consider establishing Tolerable Upper Intake Levels (ULs) for the military in special conditions (e.g., during combat when the risk of injury is high, the intake of vitamin E [or other compounds with thrombolytic potential] might need to be restricted); follow the ULs for the general population and include them in Military Dietary Reference Intakes. Continue collecting and analyzing data on dietary supplement use. Monitor the frequency and severity of adverse events associated with popular or potentially beneficial dietary supplements. Develop methodologies to assess safety (and efficacy) of multi-ingredient dietary supplements. Study the effects of interactions with other supplements, foods, or medications. Consider study designs that allow for identification of tolerance and withdrawal effects associated with popular or potentially beneficial dietary supplements. Validate the recommended approach to manage dietary supplements. Evaluate the efficacy of education methods. Investigate the potential beneficial effects of dietary supplements to mitigate or recover from stress. Explore the use of dietary supplements for the prevention or treatment of injuries (e.g., wound healing, traumatic brain injury or post-traumatic stress disorder).

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1 Introduction

For several decades, interest in optimizing performance and health in many segments of the U.S. population has increased, and the corresponding use of dietary supplements and performance-enhancing substances has grown substantially. The increase in use of these products has raised concern regarding their immediate and long-term efficacy and safety. The evaluation of such products is especially difficult as many are used intermittently at doses difficult to measure or contain multiple ingredients, and manufacturers may change their formulation. Because of these difficulties, it may take a long time for the current system of reporting adverse events to help detect problems. While the vast majority of military personnel are assumed to be at the same general risk of adverse effects as the overall U.S. population, additional diligence should be exercised both with respect to possible benefits and to the possible risks when these products are used by military personnel in particular job classifications and/or environments. For special military subpopulations, relatively minor adverse effects could seriously impair the ability of the individual or the unit to perform its mission. It is clear that these subpopulations within the military are different from the general civilian population, and guidance on managing their use of dietary supplements needs to be tailored to address their specific needs. COMMITTEE’S TASK AND APPROACH Statement of Task For the reasons stated above, the Institute of Medicine (IOM) was requested to convene an ad hoc expert committee under the oversight of the Committee on Military Nutrition Research to provide recommendations on an approach to manage the use of dietary supplements by military personnel. This expert committee analyzed the patterns of dietary supplement use among military personnel, and selected a subset of dietary supplements to evaluate; for these, by examining published reviews of the scientific evidence, the committee identified those dietary supplements that are beneficial and/or warrant concern due to risks to health or performance. The committee also developed a system to monitor adverse health effects and recommended a framework to identify the need for active management of dietary supplement use by military personnel. Specifically, the committee: 1. Reviewed survey data and findings made available to the committee related to supplement use by military personnel to identify: (a) which dietary supplements are of most prevalent use, with consideration of differences according to demographic factors such as age, rank, PREPUBLICATION COPY: UNCORRECTED PROOFS 1-1

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sex, deployment status, military occupational specialty, organization and unit; and (b) expectations of benefits and reasons for use of dietary supplements by military personnel. 2. Identified information gaps regarding dietary supplement use by military personnel and recommended processes and designs by which current and future usage of supplements (including dosages, quality, and forms of supplement) should be monitored, surveyed, analyzed, reported, and the resultant data shared. 3. Selected a limited number of dietary supplements from those identified as commonly used. On the basis of already published reports that review the available scientific evidence, the committee identified those supplements that may be of benefit and/or pose serious hazards to the health and/or physical and cognitive performance capability of military personnel and determined whether further examination and integrative evaluation or research on each is warranted. The committee considered potential effects of supplement withdrawal and interactions. 4. Considered existing military policies for managing dietary supplements, and assessed the applicability to a military setting of the framework outlined in the 2005 IOM report Dietary Supplements: A Framework for Evaluating Safety and determined how it could it be modified to determine which supplements need active management by the military. 5. Proposed an approach to monitor military personnel for adverse health effects that might indicate a concern associated with consumption of dietary supplements. Approach of the Committee: Definitions and Collection and Analysis of Data The committee defined dietary supplements and reviewed the safety assessment procedures in place for those products in the United States. In particular, the committee explored the legal definitions of medications, food, food additives, and dietary supplements (Box 1-1) and mechanisms that are in place to protect the public. The federally approved definition of a dietary supplement determines the procedures used to ensure its safety; however, in informal usage, the term dietary supplement applies to a broader range of products that, while not meeting the legal definition of a dietary supplement, are used in similar ways as dietary supplements and which include ingredients with similar risks and benefits. For the purposes of this report, dietary supplements included those that meet the legal definition as well as some products that are commonly perceived as nutritionally enhanced with ingredients such as botanicals, vitamins, and minerals (e.g., sports drinks and sports bars). The first and second parts of the committee’s statement of task refer to a description of the use of dietary supplements by military personnel (i.e., identifying which dietary supplements are used by whom and under what circumstances). Such usage information was identified or inferred from the results of surveys of military personnel from both published and unpublished sources. Unfortunately, many questionnaires from published sources, which are valuable because the publications have been peer reviewed, were not available to the committee. On the other hand, more recent surveys, though not peer reviewed, offer the advantage that the questionnaires themselves were available for review. Because the focus of the report was the recent military surveys (for which the committee had the actual questionnaires), the committee decided not to contact the authors of the published papers to obtain the questionnaires. The findings from the

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BOX 1-1 Legal Definitions of Drug, Food, Food Additives, and Dietary Supplements Drug: Section 201(g) of the Federal Food, Drug, and Cosmetic Act states: (1) The term drug means (A) articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any articles specified in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to sections 403(r)(1)(B) and 403(r)(3) or sections 403(r)(1)(B) and 403(r)(5)(D), is made in accordance with the requirements of section 403(r) is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 403(r)(6) is not a drug under clause (C) solely because the label or the labeling contains such a statement (FDA, 2004). Food: Section 201(f) of the Federal Food, Drug and Cosmetics Act states: the term food means (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article (FDA, 2004). Food additive: Section 201(s) of the Federal Food, Drug and Cosmetics Act states: The term food additive is defined as any substance the intended use of which results or may reasonably be expected to result—directly or indirectly—in its becoming a component or otherwise affecting the characteristics of any food (FDA, 2004). This definition includes any substance used in the production, processing, treatment, packaging, transportation, or storage of food. The purpose of the legal definition, however, is to impose a premarket approval requirement. Therefore, this definition excludes ingredients whose use is generally recognized as safe (where government approval is not needed), those ingredients approved for use by the U.S. Food and Drug Administration or the U.S. Department of Agriculture prior to the food additives provisions of law, and color additives and pesticides where other legal premarket approval requirements apply (FDA, 2004). Dietary supplement: Section 201(ff) of the Federal Food, Drug and Cosmetics Act defines the term dietary supplement as a product (other than tobacco) that is intended to supplement the diet; contains one or more dietary ingredients (including vitamins; minerals; herbs or other botanicals; amino acids and other substances) or their constituents; is intended to be taken by mouth as a pill, capsule, tablet, or liquid; and is labeled in the front panel as being a dietary supplement (FDA, 2004).

surveys provided useful background information to help the committee select the elements of a system to help ensure safety and to assess the efficacy of dietary supplements used by military personnel. Because the U.S. Army Medical Command has the official responsibility to make decisions regarding nutrition for all military services, many of the studies or policies refer to them. However, the approach of the committee applies to all branches of the military. To develop an approach to managing the use of dietary supplements in military settings, the committee drew from experience with other consumer products. Mechanisms intended to protect the public health vary among the various categories of products (e.g., can include premarket PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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safety and benefit assessments as well as postmarket surveillance). The main basis for the differences in mechanisms appears to be differences in perceptions about the safety and expected outcome of use of each category; that is, food is perceived as natural and intended to nourish, while drugs are perceived as artificial and intended to cure or treat diseases. Society and individuals are generally willing to take higher risks (e.g., adverse neurological effects) when the potential benefits are substantial (e.g., to guard against heart disease). The underlying assumptions for each type of product inform the rationale for the protective mechanisms that have been established and were also the basis for the approach recommended by this committee. These mechanisms are further explained later in the report. As an example, medications (drugs) require extensive premarket studies in animals and humans to demonstrate their benefit as well as document the level and type of side effects that can be expected. In this way, the relative benefits and risks are both addressed prior to a product’s release to the marketplace. These premarket studies also provide the scientific basis for determining an association with an unexpected adverse event as reported through a postmarket surveillance system. Food additives are also subject to a premarket petition for a safety assessment and routinely undergo research studies that document adverse events and establish the potential for risk to public health prior to their introduction to the marketplace. There is no established postmarket surveillance system for foods or food ingredients, but the U.S. Food and Drug Administration (FDA), the federal agency responsible for regulating foods and drugs, can informally ask a manufacturer to conduct postmarket monitoring of adverse events when a new ingredient is marketed. If there are postmarket problems reported, FDA can ask the company to recall a product and remove it from the marketplace. There is, however, no premarket assessment required for foods. Under current law, dietary supplements are regulated as foods, not as drugs. As foods, dietary supplements are not subject to the rigorous premarket safety assessments required for drugs. Postmarket surveillance systems for dietary supplements have therefore been voluntary until now, and less well developed than for drugs. The 1994 Dietary Supplement Health and Education Act (DSHEA) amended the Federal Food, Drug and Cosmetic Act (FFD&C Act) and established a new regulatory framework for FDA’s regulation of dietary supplements (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress, October 25, 1994). The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act amended the FFD&C Act to require, among other things, the mandatory reporting by manufacturers of serious adverse events associated with the use of dietary supplements to the FDA, an improvement in the postmarket monitoring of dietary supplements (Dietary Supplement and Nonprescription Drug Consumer Protection Act. Public Law 109-462. 109th Congress. December 22, 2006). The act also requires the collection, documenting, and archiving of non-serious adverse events reported to the manufacturer by consumers. The general public appears to regard dietary supplements as natural alternatives to traditional Western medicines for the reduction of risk or treatment of disease or the optimization of performance. The recent increase in market sales (Figure 1-1) has generated growing concern about how to appropriately ensure the safety of dietary supplements. [Unfortunately, the source of the information does not explain if the increases in value of market sales are due to sales increases alone or also to rising prices. However, it is unlikely that the increases of more than 10 percent market sales per year are due only to rising prices, especially given the increase in prevalence of use indicated by surveys mentioned above.] Because they are a unique class of products, typically consumed to sustain health but considered neither foods nor medications, the

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current models for evaluation of safety or efficacy of foods or medications are not entirely appropriate for dietary supplements. Implementing the DSHEA has been a challenge for various reasons; unlike regulations for medication, the DSHEA mandates that the FDA itself is responsible for making the determination that a dietary supplement is unsafe. This determination is not easy to make in the absence of any requirement for premarket safety assessments. To help with this challenging implementation, the FDA asked the IOM to prepare the report Dietary Supplements: A Framework for Evaluating Safety (IOM, 2005), including a cost-effective approach for evaluating the safety of dietary supplements under the DSHEA. This proposed framework formed the foundation of this committee’s exploration options and examined potential adaptations for use by the military. The committee considered that for the majority of military personnel whose jobs are administrative in nature and whose work environment is otherwise similar to a civilian setting (e.g., members of Special Forces Operations constitute only about 3 percent of U.S. Army personnel [DoD, 2007a]), the risks and benefits of the use of dietary supplements would be the same as for the general population (see below for a description of the differences between the environment of the general civilian population and that of specific military subpopulations). The 2005 IOM report framework to determine the safety of dietary supplements could therefore apply for this general population. The adapted safety framework recommended by the committee for military use was based on lessons learned from implementing safety systems for drugs, foods, and dietary supplements for the general population as well as consideration of the heightened demands and risks faced by some military subpopulations, and is targeted at these military subpopulations. Although the development of a detailed process to establish a dietary supplement’s level of efficacy was not within the scope of the current task and this committee

FIGURE 1-1 Dietary supplement sales, years 1994 through 2000.* *The sales figure for 2005 is estimated as $21 billion (Saldanha, 2007). SOURCE: Center for Food Safety and Applied Nutrition (CFSAN), 2002.

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was not constituted to address the question of efficacy, the committee did consider the importance of efficacy in developing policy on the use of dietary supplements in a military context. The committee also recommends specific responsibilities for military organizational units and committees; in making these recommendations, the committee considered existing military infrastructure, policy, and organizational units and their responsibilities. ORGANIZATION OF THE REPORT This report has been organized into the following sections: Chapter 2 describes the survey methodology to monitor the use of dietary supplements and describes the results from available surveys. Chapter 2 also describes improvements to the current surveillance methodology, that is, the addition of targeted survey designs as well as surveillance methods that may be necessary for special military populations and improvements in the questions to be used. Chapters 3 and 4 summarize current knowledge about multivitamin and mineral supplement risk and benefits (Chapter 3) and provide monographs on selected dietary supplements that are of interest to the military or in highest use as of February 2006 (Chapter 4). Although minerals and vitamins are classed as dietary supplements, they were addressed as a separate category in Chapter 3 because they are essential nutrients, and their safety as well as their necessity in the human diet have been assessed numerous times (IOM, 1997, 1998, 2000, 2001, 2002/2005, 2004). Chapter 5 describes elements of the IOM framework developed to evaluate dietary supplement safety in the general population. A modified framework that considers special military environments and performance demands is recommended; the chapter also describes when and what type of safety review would be needed and provides a decision-making rubric so that educational materials are designed for and targeted to commanders, educators, health care personnel, and physical trainers. Chapter 6 describes the current civilian adverse-event monitoring system and describes a system that would meet the need for timeliness and other special military needs. Chapter 7 presents an approach to identify research needs. Tables and appendixes provide workshop agendas; summary data from results of current surveys of dietary supplement use; key elements from the initial safety monographs from dietary supplements of high usage; adverse-event reporting forms; biographical sketches of committee members, speakers, and IOM staff; and a glossary of terms. USE AND MANAGEMENT OF DIETARY SUPPLEMENTS IN THE UNITED STATES The prevalence of usage of dietary supplements has been estimated in national dietary surveys (e.g., the National Health and Nutrition Examination Survey [NHANES] I, II, III) as well as other national and local surveys. These surveys indicate that the percentage of individuals reporting the use of dietary supplements rose from 23 percent in 1971 to 37 percent in 2002 (Gardiner, 2007; Radimer et al., 2004). There is a greater tendency to use alternative medicine, including dietary supplements, to optimize performance and health, demonstrating a shift in the public’s perceptions about health self-care. The range of products in the marketplace has expanded from traditional vitamin and mineral once-daily supplements to a plethora of herbals, botanicals, and combination products with a variety of bioactive ingredients, marketed in a manner that implies they will improve some aspect of health or performance. For example, the Sloan Survey, a telephone survey of a random representative (compared with 2000 U.S. Census data) sample of the U.S. population (at least 18 years of age), reports an increase from 14.2 to 18.8 percent in the use of nonvitamin/nonmineral dietary supplements from 1998 to 2002 (Figure

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1-2) (Kelly et al., 2005). As mentioned above, the increase in dietary supplement use is also shown in earlier survey results (e.g. from 23 percent to 37 percent from 1971 to 2002). In response to this rise in dietary supplement consumption, the 1994 DSHEA was implemented to govern their safe use in the U.S. population. However, with the absence of any requirement for a premarket safety assessment, many products reach the market despite a lack of clinical studies proving their safety. In 2007, one regulation was adopted, and one Act was enacted to protect the general population from health risks before and after dietary supplements reach the consumer. The FDA issued a final rule regarding current good manufacturing practices (cGMP) for dietary supplement quality (Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. Final Rule. 21 CFR Part 111). The final rule establishes the minimum cGMPs necessary for activities related to manufacturing, packaging, labeling, or holding dietary supplements to ensure that quality standards are met. This rule will give FDA the necessary tools to enforce rigorous manufacturing standards across the industry, which is to comply by 2008 or 2010, depending on the size of the manufacturing company. The United States Pharmacopeia (USP) developed voluntary dietary

FIGURE 1-2 Use of dietary supplements in the U.S. by age group and gender from 1999 to 2002. SOURCE: Reprinted with permission from Kelly et al., 2005. Copyright © 2005, American Medical Association. All rights reserved.

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standards that companies can use to differentiate their products from others for marketing purposes (Box 1-2). The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act (Dietary Supplement and Nonprescription Drug Consumer Protection Act. Public Law 109-462. 109th Congress. December 22, 2006) serves as an additional safety measure by mandating that manufacturers forward to FDA reports of life-threatening events associated with dietary supplements that are submitted voluntarily by consumers. In addition, the FDA continues to obtain adverse event reports on a voluntary basis from consumers, health care providers, food manufacturers, and others. Prior to 2007, there was no required standardization of quality of dietary supplements, and there was no mandatory system of adverse events reporting. Further complicating the assessment of dietary supplement safety is the lack of a national or standardized database listing products and ingredients. Thus, establishing an association between an adverse event and a product or ingredient is often difficult. Some product marketing claims have been questioned and then modified, and a few dietary supplement products have been removed from the marketplace after reports of safety issues were documented. One example of particular concern to the military was the recall of ephedra. In this case, there were reports of adverse events including a death, and public testimony on deaths that were associated with intake of ephedra by military personnel was given at a senate hearing (U.S. Senate, 2002). The FDA finalized the ban on ephedra on February 6, 2004, and the sale of dietary supplements containing ephedra became illegal on April 12, 2004 (Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk. Final Rule. 21 CFR Part 119). Although there has been concern over the safety of dietary supplements, there has also been considerable interest in documenting their potential benefits. The National Institutes of Health’s Office of Dietary Supplements (ODS) has embarked on a research agenda to address the efficacy as well as the safety of dietary supplements, and several systematic reviews have been commissioned to determine research gaps (ODS, 2007). The ODS has also established and continues to update an extensive database that documents federally funded research on dietary supplements (ODS, 2006).

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BOX 1-2 United States Pharmacopeia’s Role in Certification of Dietary Supplements The United States Pharmacopeia (USP) is a nonprofit, standards-setting organization for foods, drugs, and dietary supplements. The USP has served as an independent, science-based public health organization since its foundation by an independent group of practitioners in 1820. Two of its principal publications, the US Pharmacopeia (USP) and the National Formulary (NF), are recognized in the Federal Food, Drug, and Cosmetic Act (FFDCA) as official compendia of the United States (Bhattacharyya et al., 2004; Schiff et al., 2006). USP documentary standards and reference materials (RMs, also termed official USP Reference Standards) are recognized not only in the United States but also in approximately 130 nations worldwide. USP’s voluntary standards-setting body is the Council of Experts, which has five expert committees devoted to creation of official standards for dietary supplements. These are the Dietary Supplement Information; Bioavailability; Botanicals; General Chapters; and Nonbotanicals, Nutrition, and Electrolytes expert committees (USP, 2007). Beyond USP’s documentary standards and RMs, USP has established a dietary supplement verification program (DSVP), which includes audit, review, and testing components to assist manufacturers in assuring the public that they are making dietary supplements and dietary supplement ingredients of good quality (Atwater et al., 2005). The current edition of the USP and NF (USP30-NF25) includes several quality monographs for dietary supplement ingredients. In addition, the USP provides several general chapters as guidance (such as 2021, Microbial enumeration tests; 2022, Microbiological procedures; 2030, Supplemental information for articles of botanical origin; 2040, Disintegration and dissolution of dietary supplements [USP, 2008a]). The USP general chapters includes recommended good manufacturing practices and the methods to be used in, and the facilities and controls to be used for, the manufacturing of a dietary supplement to assure that such a product meets the requirements of safety, meets the quality and purity characteristics, and has the identity and strength that it is represented to possess. The USP’s DSVP performs a comprehensive verification process on specific dietary supplements. Supplements that pass this process are given the USP verified dietary supplement mark. Manufacturers can display this mark on the label of USP-verified products. The mark indicates that USP has rigorously tested and verified the supplement to assure that all the listed ingredients are present in the declared amount; that the supplement does not contain harmful levels of contaminants; that the supplement will break down and release ingredients in the body; and that the supplement has been made under good manufacturing practices that ensure safe, sanitary, well-controlled, and well-documented manufacturing facilities (USP, 2008b).

MILITARY’S INTEREST IN MANAGING DIETARY SUPPLEMENT USE Reports from the IOM’s Committee on Military Nutrition Research have concluded that some military populations differ sufficiently from the general civilian population in terms of their dietary needs and health considerations to warrant special guidance or recommendations. For example, the IOM report Nutrient Composition of Rations for Short-Term, High-Intensity Combat Operations recommended higher protein intake for soldiers on sustained operations to ensure nitrogen balance and minimize muscle loss in situations of high energy expenditure (IOM, 2007). Also, a previous IOM report, Military Strategies for Sustainment of Nutrition and PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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Immune Function in the Field, recommended that “Soldiers should be cautioned regarding the indiscriminate use of individual supplements” and stated that the preferred method of providing supplemental nutrients in the field environment was through a ration component (IOM, 1999, p. 131). A specific framework to manage dietary supplements is warranted because of the following military demands and cultural factors (described below): (1) heightened performance requirements; (2) strict weight standards; (3) service members’ perceptions of military endorsement of the safety of dietary supplement products as a result of their sale on base; (4) risks, demands, and environments faced by specific subpopulations within the military; and (5) the insufficiency of current military policies to manage dietary supplement use. Heightened Performance Requirements While the general civilian population has an interest in maintaining health and preventing disease, the mission of the military forces makes health a key concern of the Department of Defense (DoD) (DoD, 2007b). Protecting the health of service members and ensuring that they are medically ready for duty are important institutional concerns in the military. Therefore, the DoD therefore emphasizes force health protection (defined as establishing, sustaining, restoring, and improving the health of the active and reserve military forces [DoD Directive 6200.04]) and readiness (defined as a healthy and fit fighting force medically ready to deploy at all times [DoD Instruction, 6025.19]). With this emphasis on readiness and optimal performance, both mental and physical, military personnel have an additional interest in using products that might extend the benefits of a healthy diet. For that reason, it is expected that dietary supplements intended to enhance performance would be much more widely used in certain segments of the military population than in the general civilian population. Soldiers are likely to be involved in demanding physical tasks requiring strength and endurance; most require lifting and carrying heavy loads. Combat activities can include patrolling, mountaineering, attacking, ambushing, and raiding. Significant mental demands accompany the increased speed, complexity, and lethality of modern warfare; in this regard, every individual soldier may be called upon to make rapid decisions and judgment calls, may require fine psychomotor performance (e.g., marksmanship), spatial mapping ability, pattern recognition, and so on. It is also important to maintain mood and motivation as the foundation of all their exertions. In addition to physical and cognitive abilities, a fully responsive immune system is critical for protection against endemic and deliberate infectious threats that may endanger the success of a mission. The various military services continuously seek to achieve optimal diets for the health and performance of their troops, especially for those with unique tasks (see Box 1-3). The military emphasizes human performance optimization through improved physical training regimens, acclimation techniques, and nutritional and pharmacological supplements. Products that benefit physical capacity (e.g., may help build muscle, relieve or retard fatigue, or improve endurance) or mental capacity (e.g., diminish sleep disturbance; increase memory, attention or alertness; or decrease stress) are of special interest for the military. Because extrapolating results from the general population might not be appropriate, research is often conducted by the military services themselves. For example, the U.S. Air Force is currently testing protein powders for pilots; this dietary supplement is already very popular among military recruits, who expect that it may increase their endurance while carrying heavy packs or at high elevations. Other supplements that are under study are the herb Rhodiola rosea, or roseroot, and citrulline malate. The U.S.

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Army, which has been developing nutritionally rich foods for years, has considered adding more protein to the troops' diet; to maintain muscle mass, it is currently considering adding more protein through beverages. Soldiers may already carry nutritional products such as First Strike energy bars, a drink known as ERGO (Energy Rich, Glucose Optimized), or caffeine-packed Stay Alert chewing gum. The U.S. Army Research Institute of Environmental Medicine (USARIEM) in Natick, Massachusetts, has been evaluating drinks rich in carbohydrates and protein similar to those used by athletes. Strict Weight Standards Another difference between the military and the general civilian population is the emphasis on maintaining weight within established military standards. Like the general population, the military has experienced a rise in overweight and obesity.1 (The rate of overweight within the military is 60 percent compared to 66 percent for all civilians; 12 percent of service members are obese, compared to 31 percent of civilians (DoD, 2006). Because failure to maintain established weight standards (maximum allowable body fat percentage is 20 and 30 percent for 17–20 year old males and females, respectively [U.S. Army, 2006]) can lead to discharge from the military and the end of a potential military career, there is high interest in dietary supplement products that are linked to weight control, especially those that promise faster results than a diet or exercise program. For example, the review of data from sales of dietary supplements to military personnel indicates that one of the biggest sellers (second only to multivitamin supplements) at military bases, Hydroxycut, is sold in various forms as a thermogenic weight-loss product; it contains herbal extracts (e.g., Gymnema sylvestre extract), caffeine, and several tea extracts among other ingredients. Ripped Fuel, another popular product among military personnel, is sold for its weight-loss effects. Its ingredients include ma huang (Ephedra spp.), guarana (Paullinia cupana) extract, and green tea leaf. One form of Xenadrine—marketed as providing energypromoting herbs and amino acids that support the body’s natural fat-burning capacity—includes a “proprietary Thermoxanthin Blend” with l-tyrosine, yerba mate (Ilex paraguarensis) leaf, guarana seed, green tea leaf, green coffee bean extract, and caffeine. The survey of army health care providers about dietary supplements found that, as shown by sales data, Hydroxycut, Ripped Fuel, and Xenadrine are among the five products most frequently reported used to health care providers. Perceptions About Safety of Dietary Supplements Products Sold at Installations Dietary supplements are widely marketed and available from both civilian stores and websites and more recently are offered for sale in military installations in independent retail outlets and in fitness centers. While the military has not specifically endorsed the use of dietary supplements other than multivitamins (usually prenatal multivitamins), the fact that there are specific dietary supplement stores on many installations, dietary supplement sections in other stores (e.g., exchanges and commissaries), as well as products being offered for sale in health promotion and fitness centers on base, may induce belief that the military leadership has evaluated and approved of their use. This impression may not be entirely logical, since the military also has policies discouraging consumption of tobacco and alcohol, yet, in response to Overweight is defined as a body mass index (BMI) of 25.0 to 29.9 kg/m2 and obesity as a BMI • 30.0 kg/m2. 1

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consumer demand, still offers these products for sale on military installations. The only apparent difference between the sale of dietary supplements and the sale of tobacco and alcohol is that tobacco and alcohol have a long tradition of availability to service members, and the movement has been to reduce their negative health impact after these products had long been widely available, while selling dietary supplements other than traditional vitamins and minerals is a relatively new phenomenon, and they were introduced for sale by a stand-alone commercial vendor in the last decade. Specific Subpopulations Within the Military Within the general military population, there are subpopulations with heightened concerns for both the benefits and safety of dietary supplement use, based on special military mission requirements and possibly special nutrition needs. These subpopulations may be defined by the type of strenuous performance required as part of their mission or by the unusual environment in which routine activities must be performed. Some of the adverse effects that may not pose a serious health threat in the general civilian population may result in significant reduction in mission readiness or greater danger owing to the increased potential for impact of injury. Specifically, the committee attempted to respond to its statement of task with a focus on the needs of military subpopulations that engage in types of physical or mental performance that differ from those of the general public, and so would warrant additional considerations (Box 13). A deployed service member does not have the option to retreat from a mission and wait until symptoms subside. Because of their differences from the general civilian population, guidelines to manage the use of dietary supplements need to be tailored for them. The methods to evaluate these products in the general population might not be directly applicable to the military facing special conditions (e.g., high altitude, extreme heat and cold, intense or prolonged physical activity, caloric restriction) or risks (e.g., drug interactions, dehydration, infectious disease, injury or bleeding, impaired gastrointestinal or immune function, renal health, liver health/metabolism, cardiovascular health, and changes in mood/behavior or alertness).

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BOX 1-3 Military Subpopulations Whose Tasks and Risks Differ from Those of the General Population x

x x

x

x

x

Military units or specialties where there are requirements for high levels of physical activity and/or prolonged periods of mental alertness may have unique needs. In the case of high physical activity, these service members may be more similar to elite athletes than to the general population. Military units that are deployed and need to perform their mission in extreme hot or cold environments that are unlike those of the general population. Military members who may need to modify their diets or have periods of limited food consumption owing to specific types of missions. Special military rations are designed for their specific needs and logistical limitations (e.g., limited volume and weight). These missions and diets may also be conducive to the temporary use of dietary supplements in response to their availability during deployments or to the availability of other types of dietary supplements from local markets that might not be found in the U.S. marketplace. Military members deployed in combat or peacekeeping situations are at much higher risk of injury than the general population. Thus, any dietary supplement that has an impact on the response to or recovery from injury (e.g., bleeding) would be of greater concern. Military aviators share some of the same characteristics as commercial airline pilots but their performance demands differ from those of civilians. For example, unique requirements to limit substances that would affect inner ear balance, cardiovascular function, and hydration are important to ensure that military aviators are capable of flying missions that may subject their bodies to significant g-forces. Military members who are part of the Personnel Reliability Program (i.e., those having access to nuclear weapons) also have unique requirements to ensure that they are not taking any dietary supplements that would affect their ability to perform their mission (e.g., induce mood alterations).

Current Military Policies to Manage Dietary Supplement Use As a large organization and with a focus on health protection and readiness, many responsibilities of the DoD are dedicated to maintaining the health and well-being of the armed forces and their families; these responsibilities include policy development and education regarding dietary supplements. The Office of the Assistant Secretary of Defense (Health Affairs) (OASD[HA]) is the main policy office for dietary supplement issues. For example, there is the DoD Directive (representing the highest level of DoD policy) on Health Promotion stating that the DoD should meet Healthy People 2010 goals and objectives, including those listed in Chapter 19, “Nutrition and Overweight,” which mentions the use of dietary supplements. However, although it is “standard of care” to discuss dietary supplement use at patient encounters, there is little written policy on the use of dietary supplements. There are also campaigns to educate military populations on the use and safety of dietary supplements, but their effectiveness is not known. While the OASD(HA) has the responsibility and authority to direct DoD policy on dietary supplements, each military service has the capacity and authority to write specific dietary supplement policies for its own members. For example, there are service-specific policies or

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processes addressing the use of some nonprescription dietary supplements or prescription substances in particular controlled settings, for example, pilots on extended missions. Each military service has its own medical department led by a surgeon general (medical issues for the Marines are overseen by the navy surgeon general; there is also a senior navy officer titled Medical Officer of the Marine Corps). The surgeons general provide the medical care policies for their respective services. The DoD writes servicewide policy; the services may write policies that are even more specific or stringent. For example, when the DoD wrote a policy to ban ephedra-containing products, each of the surgeons general advised their service secretary and defined the methodology to enact that policy for their own service (i.e., to accomplish the actual removal of the products) and educate their service members on the potential risks from these products (Lynn Pahland, personal communication, Office of the Assistant Secretary of Defense [Health Affairs], October 2, 2007). Some of the military leadership are aware of risks derived from dietary supplements because of the evidence from associated adverse effects seen in military theaters, but still there is no consensus on a roadmap or guidance that provides a more uniform, consistent management approach. Concerns within the military over safety and efficacy led to the creation of a committee (DoD Dietary Supplements and Self-Care Products Committee), whose charter is pending approval by OASD(HA). This commmittee, which includes representatives from the OASD(HA), Uniformed Services University of the Health Sciences (USUHS), and the military medical departments, will have formal authority and means to gather and discuss preliminary data about dietary supplement usage and provide policy recommendations regarding the use of dietary supplements. The USARIEM has already explored current usage as well as the benefits and adverse effects of a few dietary supplements (e.g., caffeine, tyrosine, and creatine). The DoD has also added a large bank of questions about dietary supplement use and knowledge to the Survey of HealthRelated Behaviors Among Active Duty Personnel, conducted every 2 to 3 years, and to the recent Survey of Health-Related Behaviors Among Reserve Component Personnel. These two surveys provide important information on dietary supplement use and identify areas of improvement in education or monitoring. Several other DoD surveys have addressed dietary supplement use with varying levels of scientific rigor. In summary, the DoD has provided many policies and regulations on nutrition for military personnel in different settings; however, there is currently no systematic approach to evaluate the risks and benefits of the use of dietary supplements by the military or parallel servicewide policies to address their management. In the absence of such policies, the DoD relies on the monitoring of dietary supplement safety by the FDA and its Center for Food Safety and Applied Nutrition. This approach might be adequate for the general public and for those in the military service performing tasks similar to those of civilians; however, as discussed above, a different approach is needed for specific military subpopulations (Box 1-3) so that risks that might compromise the success of military operations are not overlooked, and potential benefits in performance or health from use of dietary supplements by military personnel are realized.

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REFERENCES Atwater, J., J. Montgomery-Salguero, and D. B. Roll. 2005. The USP Dietary Supplement Verification Program: Helping pharmacists and consumers select dietary supplements. U.S. Pharm 30(6):61-64. Bhattacharyya, L., T. Cecil, R. Dabbah, D. Roll, S. Schuber, E. B. Sheinin, and R. L.Williams. 2004. The value of USP public standards for therapeutic products. Pharm Res 21(10):1725-1731. CFSAN (Center for Food Safety and Applied Nutrition). 2002. Dietary supplement strategic plan cost out. http://www.cfsan.fda.gov/~dms/ds-stra2.html (accessed January 31, 2008). DoD (U. S. Department of Defense). 2006. Department of Defense survey of health related behaviors among active duty military personnel. http://www.ha.osd.mil/special_reports/ 2005_Health_Behaviors_Survey_1-07.pdf (accessed October 17, 2007). DoD. 2007a. Armed forces strength figures for December 31, 2007. http://siadapp.dmdc.osd.mil/ personnel/MILITARY/ms0.pdf (accessed January 31, 2008). DoD. 2007b. DoD 101: An introductory overview of the Department of Defense. http://www.defenselink.mil/pubs/dod101/dod101.html#whatwedo (accessed October 17, 2007). FDA (U.S. Food and Drug Administration). 2004. Food ingredients and colors. http://www.cfsan.fda.gov/ ~dms/foodic.html#foodadd (accessed October 29, 2007). Gardiner, P. 2007. Prevalence of dietary supplements in the U.S. young adult population. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC. IOM (Institute of Medicine). 1997. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press. IOM. 1998. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press. IOM. 1999. Military strategies for sustainment of nutrition and immune function in the field. Washington, DC: National Academy Press. IOM. 2000. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press. IOM. 2001. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press. IOM. 2002/2005. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. Washington, DC: The National Academies Press. IOM. 2004. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: The National Academies Press. IOM. 2005. Dietary supplements: A framework for evaluating safety. Washington, DC: The National Academies Press. IOM. 2007. Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press. Kelly, J. P., D. W. Kaufman, K. Kelley, L. Rosenberg, T. E. Anderson, and A. A. Mitchell. 2005. Recent trends in use of herbal and other natural products. Arch Intern Med 165(3):281-286. ODS (Office of Dietary Supplements). 2006. Computer access to research on dietary supplements (CARDS) database. http://dietary-supplements.info.nih.gov/Research/CARDS_Database.aspx (accessed October 31, 2007). ODS. 2007. About the Office of Dietary Supplements (ODS). http://dietarysupplements.info.nih.gov/about/about_ods.aspx (accessed February 4, 2008). Radimer, K. B. Bindewald, J. Hughes, B. Ervin, C. Swanson, and M. F. Picciano. 2004. Dietary supplement use by US adults: Data from the National Health and Nutrition Examination Survey, 1999–2000. Am J Epidem 160(4):339-349.

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Saldanha, L. G. 2007. The dietary supplement marketplace: Constantly evolving. Nutr Today 42(2): 5254. Schiff, P. L., Jr., V. S. Srinivasan, G. I. Giancaspro, D. B. Roll, J. Salguero, and M. H. Sharaf. 2006. The development of USP botanical dietary supplement monographs, 1995-2005. J Nat Prod 69(3):464472. U.S. Army. 2006. Army regulation 600-9. Personnel-General. The Army Weight Control Program. Washington, DC: Department of the Army. USP (United States Pharmacopeia). 2007. USP Council of Experts and expert committees. http://www.usp.org/aboutUSP/governance/expertList.html (accessed December 13, 2007). USP. 2008a. General chapters status. http://www.usp.org/USPNF/submitMonograph/ generalChapterWorkplans.html (accessed February 4, 2008). USP. 2008b. USP verified. http://www.usp.org/USPVerified/ (accessed February 4, 2008). U.S. Senate, Oversight of Government Management, Restructuring, and the District of Columbia Subcommittee of the Committee on Governmental Affairs. 2002. Ephedra: Who is protecting the American consumers? 107th Cong., 2nd Sess. October 8.

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2 Recent Survey Findings and Implications for Future Surveys of Dietary Supplement Use

INTRODUCTION Dietary supplements are widely available through a rapidly expanding market of products that are commonly advertised as being beneficial for health, performance enhancement, and disease prevention. These claims may influence the use of dietary supplements by military personnel, given the importance and frequent evaluation of physical performance and health as criteria to join and remain in the military. Given the large number and wide variety of supplements readily available, as well as a lack of scientific evidence addressing health benefits or safety, it is important to monitor the use of supplements by military personnel. One effective approach to this is the use of surveys with comprehensive data collection (e.g., well-designed questions on patterns of use). Previous reports from the Institute of Medicine (IOM) have recommended monitoring dietary intake and supplement use (IOM, 1999, 2006). Two national surveys have recently collected data on dietary supplement use, the National Health and Nutrition Examination Survey (NHANES) and the National Health Interview Survey (NHIS), both conducted by the Centers for Disease Control and Prevention’s National Center for Health Statistics (see Gardiner et al. in Appendix B). These data, collected through in-home interviews, are representative of the U.S. population. Although to conduct military surveys might be perceived as duplicative, there is ample justification for such surveys, given the differences in population, settings, and products used. The specific characteristics of some military subpopulations (e.g., Rangers, Special Forces) justify the continuation and improvement of data collection from distinct dietary supplement use surveys from military personnel for the following reasons: (1) the higher physical fitness demands of some military subpopulations (e.g., Special Forces, Rangers) compared to those of the general population; (2) the lower proportion of women in these subpopulations; (3) the differences in motivation for using dietary supplements (e.g., meeting military weight standards and improving performance); and (4) differences in military culture and behavior patterns. As an example, the military imposes serious consequences for weight gain and substandard performance, which likely leads to supplement use in the military that differs from that of the civilian population. Data from civilian populations may also not provide an accurate description of the prevalence, patterns of use, and key issues of certain military populations (e.g., Special Forces, Rangers). In general, survey research uses questionnaires or interviews in relatively large groups of people and, if appropriately planned and conducted, gathers reliable and valid data on various characteristics of the population of interest. The use of survey methodology can be effective to investigate and monitor supplement use in the military. Since it is not feasible to survey PREPUBLICATION COPY: UNCORRECTED PROOFS 2-1

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everyone, survey data can be collected from a well-defined sample of individuals and, from this, generalized to an entire group (e.g., all military personnel or all Rangers). Challenges in performing surveys include ensuring high response rates, comprehensive data collection, and the validity of the individual responses. The validity of the data from these surveys may be compromised by several factors: incorrect sample selection, unclear terminology (common usage terms versus scientifically defined terms), or survey respondents’ lack of knowledge of and inability to determine total dose or exposure of supplements or inability to remember their supplement use accurately. A low response rate can lead to a biased sample that does not represent the supplement use of the targeted military population. The benefits of survey use include having data on the extent of the use of dietary supplement products, changes in patterns of use, and insights on specific health behaviors (e.g., reasons for use, degree of consultation with physician, views on dietary supplements). As also recommended in Chapter 5, an important application of survey data on changes in patterns of use is its utilization as a trigger to initiate a safety review of a specific dietary supplement when there is an initial signal for concern (e.g., because it chemically resembles a hazardous product or there are adverse events associated with its consumption). The outcome of this safety review should be the basis for policy-making decisions by military leadership. A systematic evaluation of patterns of use can therefore be used to develop effective educational messages for military personnel and to formulate health policy. If survey data are representative of the targeted military subpopulation, then the frequency of use can also be used to calculate the reporting proportion (adverse events associated with a particular dietary supplement divided by level of use), an estimate of the occurrence of adverse events compared to the level of use. When using surveys to track supplement use, it is important to clearly define the term dietary supplement. Published literature often includes various products in the category of dietary supplement that might not conform with the legal definition.1 These include sport drinks or bars or gels, products not legally qualifying as dietary supplements but which include dietary supplement ingredients in their formulas. For practical purposes, however, it is justifiable to include them in the surveys as dietary supplements. In this report, the committee’s deliberations about dietary supplements also included products that meet the legal definition as well as food products that are commonly perceived as nutritionally enhanced with dietary ingredients, botanicals, or vitamins and minerals (e.g., sports drinks, sports bars). Fortified foods were not included in the report because they are not generally perceived as dietary supplements. Several surveys (published and unpublished) have been conducted on dietary supplement use by military personnel (Tables 2-1 and 2-2). Most of these surveys have been administered in the U.S. Army, with a focus on Rangers and members of Special Forces. This chapter briefly reviews the questionnaires and findings from the latest unpublished surveys on dietary supplement use conducted among various military groups and makes recommendations to improve various aspects of survey design and administration. A summary of the survey results is shown in Table C-1 (Appendix C). Table 2-1 describes the surveys’ populations and focus. This 1

As defined by Congress in the Dietary Supplement Health and Education Act (http://www.fda.gov/opacom/laws/dshea.html#sec3), which became law in 1994, a dietary supplement is a product (other than tobacco) that is intended to supplement the diet; contains one or more dietary ingredients (defined as vitamins; minerals; herbs or other botanicals; amino acids; or other dietary substances for use by man to supplement the diet by increasing the total dietary intake, or concentrates, constituents, metabolites, extracts, or combinations of any of the aforementioned dietary ingredients); is intended to be taken by mouth as a pill, capsule, tablet, or liquid; and is labeled on the front panel as being a dietary supplement.

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chapter examines limitations of the data that decrease the value of the survey findings; it also provides recommendations for overcoming these limitations and improving the design of the surveys, including suggestions for the phrasing of specific questions and for collecting additional information. Published data from the civilian and military populations are also reviewed for comparison. For the purposes of this chapter, supplement use will be characterized by the available research (published and unpublished) in three separate general supplement categories: multivitamins, single vitamins/minerals, and ergogenic/health enhancement food supplements, including botanicals. Ergogenic dietary supplements are those that may improve performance, remove psychological constraints that affect performance, and increase the speed of recovery from training and competition. The committee did not attempt to analyze the data collected but relied on analyses provided to them; in some instances, the committee requested that further analyses be conducted, and results were provided by military researchers. Likewise, this chapter does not provide an account of the statistical methods used; the reader is referred to excellent publications in this matter (Aday, 1996; Bernard, 1999; Converse and Presser, 1986).

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Copyright © National Academy of Sciences. All rights reserved.

Army physicians and ancillary care providers

General Army Ongoing

Jaghab

Lieberman

Electronic survey on Army Medical Department (AMEDD) Knowledge Management website. Participants were emailed a link to the survey. Response rate: 15%

A 43-question survey was used for this armywide assessment. At each study site, a health care professional administered the questionnaire. Response rate: 80%

Survey of Army health care providers on dietary supplement usage, supplement types, usage concerns, educational interventions for soldiers; goal was to develop educational tools for health care providers from these data sets Use of dietary supplements in U.S. Army populations (type and frequency of use, reasons for use, user demographics, supplement knowledge, amount spent on supplements)

Physicians, n=573 Ancillary, n=614

Males, n=444 Females, n=40 Average age= Males, 29.5 r10.1 y Females, 28.8 r8.2 y

Online survey. Response rate not known.

Military vs. nonmilitary supplement use Profile and motivations of military supplement users

Adults, 18+ y n=376

Sampling Method and Response Rate Center for Health Promotion and Preventive Medicine (CHPPM)-Europe health promotion teams administered the questionnaire to soldiers as part of their in-processing at the military base. Response rate not known.

Focus and Details of Survey Dietary supplement use by soldiers (frequency of use, reason for use, adverse effects, information sources, and purchasing locations), with a focus on education efforts

Gender, Age, and Number of Respondents Males, n=3,789 (77%) Females, n=1,146 (23%) Mean age=25.4 y

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Military (“currently serving in the military, National Guard, or Reserve”) 2005

Study Population and Year of Survey Army Fiscal years 2003 to 2005

French

Reference (see Appendix B) Corum

TABLE 2-1 Most Recent Surveys (Unpublished Data), Presented at February 2007 Workshop “Dietary Supplement Intake by Military Personnel”

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Air Force 2006

Thomasos

n=11,000

Dietary supplement use by Air Force personnel (frequency of use, amount spent on supplements, where supplements were purchased, reasons for use, adverse effects, information sources)

Dietary supplement use by active duty military personnel (type of use, frequency of use, reasons for use, information sources); data collected as part of the 2005 DoD Survey of Health Related Behaviors Among Active Duty Military Personnel

n=16,146 (Army: 3,636; Navy: 4,626; Marine Corps: 3,356; Air Force: 4,627)

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Active duty military (Army, Navy, Marine Corps, Air Force) 2005

Marriott

The surveys were administered in a classroom setting by U.S. Army Research Institute of Environmental Medicine (USARIEM) staff. Response rate not known. This 13-question survey was one of many administered as part of a Health and Fitness Assessment (HFA) at the Army War College. Response rate not known. Questions were included in the 2005 Department of Defense (DoD) Survey of HealthRelated Behaviors Among Active Duty Military Personnel. Military liaison officers at each installation coordinated the survey, a 50minute questionnaire either completed in group sessions or returned by mail. Response rate: 51.8% An electronic link to the survey was sent in an e-mail invitation signed by the U.S. Air Force Surgeon General. Response rate: 24 %

Same as above

Same as above

Response rate not known.

Same as above for General Army

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Males, n=284 Females, n=31 Average age= Males, 44.0 r3.7 y Females, 44.7 r5.1 y

Males, n=152 Average age=31.3 r6.1 y

Special Forces 2000

Army War College (senior-level officers) 1999–2001

Males, n=768 Average age=23.6 r4.3 y

Rangers 1999

TABLE 2-1 Continued

SURVEY FINDINGS

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Copyright © National Academy of Sciences. All rights reserved.

U.S. Army soldiers, retirees, spouses in military hospitals n=291

U.S. Army Rangers n=367

U.S. Army Special Forces n=152 males

U.S. Army Special Forces (SF) and support soldiers (non-SF) n=157 males (119 SF, 38 non-SF)

McPherson and Schwenka, 2004

McGraw et al., 2000

Bovill et al., 2000

Bovill et al., 2003

Use of supplements and associated factors Use of supplements and nutrition knowledge Use of supplements and nutrition knowledge

Average age=31 y

Average age=31 y

Use of complementary and alternative medicine (CAM)

Average age=39 y (18–83 y)

Average age=22 y

Use of supplements

Use of vitamins, minerals, performance or other supplements

Average age=25 y (18–47 y)

Average age= Civilian 33 y Military 30 y

Focus of Survey

Age of Respondents

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U.S. civilian and military health club users n=229 (133 military)

U.S. Army Special Forces and Ranger training schools n=2,215 males

Arsenault and Kennedy, 1999

Sheppard et al., 2000

Study Population

Reference

TABLE 2-2 Published Surveys Used to Collect Data on Supplement Use by Military Personnel

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A questionnaire containing 54 items was administered to volunteers. Response rate: 89%

Response rate not known.

Response rate not known.

A random, anonymous, selfadministered survey on the frequency of use of 18 different CAM therapies. Response rate: 73%

A two-page survey was placed in 12 health clubs in eastern Virginia for one month. Response rate: 40%

Sampling Method and Response Rate Voluntary respondents among trainees entering the Special Forces Assessment and Selection School at Fort Bragg and the Ranger Course at Fort Benning. Response rate: 99%

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Average age=23 y

U.S. Army Rangers n=294

Johnson et al., submitted

Use of supplements, factors potentially associated: age, participation in competitive or recreational athletics, weight training; sources of information.

Use of supplements and motivation for use; sources of information; adverse events.

Use of alcohol, tobacco, and supplements; diet and physical activity patterns

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Average age=24.9 y (17–49 y)

Average age=25 y (18–40 y)

U.S. Army enlisted active duty n=874 (750 males, 124 females)

U.S. Army Rangers n=38

Brasfield, 2004

Deuster et al., 2003

TABLE 2-2 Continued

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This survey was part of another study that examined the effects of creatine on military performance. It included measures of body weight and height, a food frequency questionnaire, a health assessment questionnaire, and a symptoms checklist questionnaire designed to assess side effects that might be associated with supplement use. Response rate: 100% The 15-question survey on dietary supplement use and demographic information was administered at 16 Army posts in the United States. Response rate: 64% Members of the 1st Ranger Battalion completed an anonymous, self-reported survey administered by the battalion surgeon. Response rate: 40%

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PREVALENCE OF USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Overall Use and Behavioral Patterns This section summarizes the results from surveys (published and unpublished) conducted on dietary supplement use by military personnel (Tables 2-1 and 2-2). Most of these surveys have been administered in the U.S. Army, with a focus on Rangers and members of the Special Forces. The reliability of the survey results depends strongly on the response rate. Therefore, the committee emphasizes the importance of obtaining response rates on the surveys. As Table 1-2 shows, the committee did not obtain the response rate for all surveys. The conclusions from those surveys for which response rate is not available should be drawn with this limitation in mind. Surveys performed in the general population might not be directly applicable to military surveys because of variation in respondent demographics or differences in the questionnaires themselves. Comparison of the results can nonetheless suggest some differences in the rate of use. Gardiner et al. (2007) (see Appendix B) provides a summary of the NHANES III (1999– 2002) and NHIS (2002) data on dietary supplement use for a cohort close in age to military personnel. The NHANES data from 1971–1974, 1976–1980, and 1999–2002 in response to the question, “Have you used or taken any vitamins or other dietary supplements in the last month?” indicate that the rate of dietary supplement use has increased from 23 percent to 37 percent of the U.S. population (see Gardiner et al. in Appendix B; Radimer et al., 2004). Results from NHANES I (1971–1974) showed that the prevalence rate for dietary supplement use in adults was 23 percent; NHANES II (1976–1980), 35 percent; and NHANES III (1999–2002), 37 percent (see Gardiner et al. in Appendix B; Radimer et al., 2004). In contrast, the 2005 DoD Survey of Health-Related Behaviors found that 60 percent of active duty personnel reported using a dietary supplement at least once a week over the previous 12 months (Marriott, 2007). In the 2006 survey of active duty Air Force personnel, only 31 percent of respondents had never used a dietary supplement (Thomasos, 2007), and data published by Arsenault and Kennedy (1999) show that 85 percent of those entering Special Forces and Ranger training reported current or previous use of dietary supplements, and 64 percent reported current usage. The patterns of dietary supplement use among athletes might be expected to be similar to those of military populations. A review of 51 studies found that among athletes participating in various sports, the overall mean prevalence of supplement use was 46 percent, and most studies reported over half the athletes used vitamins and minerals (ranging from 6 to 100 percent). Larger studies, however, found lower prevalence levels. They also found that patterns of supplement use varied by sport, with weight lifters and body builders consuming the most supplements. Elite athletes were also found to use supplements more than high school and college athletes, and women used them more often than men. Only 32 of the 51 studies provided information about the types of supplements used. The most frequently used supplements, in descending order, were: multivitamins/multiminerals, vitamin C, iron, B-complex vitamins, vitamin E, calcium, and vitamin A (Sobal and Marquart, 1994). Lieberman and colleagues (2007) reported the armywide usage in ranges of number of supplements used per week (one or two; three or four; and five or more). Those figures showed that 30–36 percent reported using one to two different supplements per week. Among males, 12–

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14 percent reported using five or more supplements per week compared to 18–23 percent of females; among elite units, 41–45 percent of Special Forces and Rangers reported using one to two different supplements per week and 7–15 percent reported using more than five supplements (Lieberman et al., 2007). Multivitamin/Multimineral Supplement Use Vitamin and mineral supplements are often used in combination by athletes as ergogenic aids. The composition of products with vitamin and mineral combinations varies; this chapter refers to this range of supplement products as multivitamins/multiminerals (MV/MMs). National surveys report that 18–26 percent of Americans routinely take MV/MMs (see Gardiner et al. in Appendix B; French, 2007; Kaufman, 2007). The usage of MV/MM supplements by military personnel varies from 23–45 percent (Lieberman et al., 2007; Marriott, 2007). In a 2005 survey conducted by French (2007), 18 percent of civilians reported using MV/MMs as the only supplement versus 23 percent of those serving on active duty, in the National Guard, or in the Reserves. This contrasts with the 45 percent of active duty service members reporting such use in the 2005 DoD Survey of Health Related Behaviors (Marriott, 2007), a difference perhaps reflecting a higher use of dietary supplements among active duty personnel compared to those in the National Guard or Reserves, although they might also be on active duty. Various smaller surveys suggest a similar level of usage among active duty military personnel. In the ongoing armywide survey, 30 percent of male respondents reported using MV/MM supplements (Lieberman et al., 2007). Among active duty Army personnel assigned to Europe from 2003 to 2005, 33.8 percent reported using them (Corum, 2007). Another survey found that 39 percent of active duty senior Army officers attending the U.S. Army War College in 1999–2001 used MV/MMs (Lieberman et al., 2007). Within the subpopulations of special interest—active duty Rangers and Special Forces—23 and 32 percent respectively were routinely taking MV/MMs (Lieberman et al., 2007). Although perhaps a less definitive source because it requires users to have reported to a physician, 13 percent of 573 Army physicians surveyed indicated that their patients reported using MV/MM supplements and 20 percent of 614 ancillary health-care personnel surveyed indicated that their patients reported using MV/MM supplements (Jaghab, 2007). The available survey data also report usage of individual vitamin and mineral supplements (see Table 2-3); however, only one set of survey data (Personal communication, Sonya Corum, U.S. Army Training and Doctrine Command, April 10, 2007) was analyzed for use of MV/MM supplements concurrent with the use of single-nutrient supplements. The single nutrients most prevalently taken in conjunction with MV/MMs were vitamin C (43 percent) and calcium (38 percent). Single Vitamin/Mineral Supplement Use A previous IOM report (IOM, 2006) suggested that in addition to strategies to increase nutrient intake from foods, dietary supplements may be warranted for some individuals, such as iron and folate for women of childbearing age and MV/MMs for individuals restricting calorie intake for weight loss. Intake levels higher than the tolerable upper intake level might incur hazardous consequences to health. As with MV/MMs, it is likely that most users take individual vitamins or minerals to supplement their diets or with expectations of improving general health. Table 2-3 shows the percentage of individuals (by gender, when known) of both military and civilian populations using single nutrient supplements. In the 2005 DoD Survey of Health PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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TABLE 2-3 Percentage Ranges of Respondents Using Individual Nutrient Supplements (from military and civilian surveys) Type of Supplement

Antioxidants (unspecified) Vitamin E Vitamin C Vitamin A/Beta-carotene Calcium Vitamin B Complex Vitamin D Vitamin B6 Iron Folate Magnesium Potassium

Military Population (%) Unspecified Male Gender 21 6–14 6–9 6–22 24 11–17 13 5 6–19 5–6 8 6 3–5 5 12 14

Female 23 8–32 13–29 16 15–32 13 8 10 10 13 13

Civilian Population (%) Unspecified Gender

2–20 7 3–26 1–14 3–8 2

12

SOURCE: Data extracted from Table C-1, Appendix C.

Related Behaviors (Marriott, 2007), 27 percent of respondents reported taking a single mineral or vitamin supplement. Based on the limited survey results reported, compared to civilians, usage by military personnel of three (i.e., vitamins E, B complex, and D) of the four single vitamin supplements, appears to be similar, and usage of vitamin C and iron is slightly higher. However, the military population reported usage of single nutrients (vitamin A/beta-carotene, vitamin B6, folate, magnesium, and potassium) not reported in the civilian surveys. Except for the 2005 DoD Survey of Health-Related Behaviors (Marriott, 2007), the surveys did not define the term antioxidant, so it is unclear if it was understood to refer to a specific individual ingredient, a specific combination of vitamins and minerals, or botanicals. No statistical comparisons can be made between the military and civilian survey results. Ergogenic/Health Enhancement Dietary Supplements The third category of supplements includes single bioactive substances or combinations, other than vitamins or minerals, that are intended to enhance performance or health (e.g., creatine, ginseng). Bathalon (2000) reported that 54 percent of senior officers attending the U.S. Army War College reported using “health-promoting” dietary supplements, and among Rangers, 30 percent used performance-enhancing supplements. Analysis of data from NHANES 1999–2002 shows that dietary supplements other than vitamins and minerals are used by seven percent of the U.S. population (see Gardiner et al. in Appendix B). Among the these products, echinacea, ginseng, Ginkgo biloba, and garlic are the most popular. The 2005 Slone Survey reported that among Americans older than 18 years, 23 percent had taken herbals or other “natural supplements” during the week preceding the interview (Kaufman, 2007). The most commonly used herbal/natural supplements were lutein (9.4 percent), lycopene (7.8 percent), glucosamine (4.0 percent), garlic (2.6 percent), chondroitin (2.5 percent), ginkgo biloba (1.6 percent), and coenzyme Q10 (1.5 percent). It should be noted that the most commonly used botanical supplements, lutein and lycopene, appear almost exclusively as ingredients in MV/MM supplements. The 2002 Health and Diet Survey, a national

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telephone survey sponsored by the U.S. Food and Drug Administration (FDA), found that 73 percent of participants (n=2,743) had consumed dietary supplements (including vitamins, minerals, MV/MMs, herbs, and/or other supplements) in the preceding 12 months. Of this number, 42 percent reported taking an herb, botanical, or other nonvitamin dietary supplement. The nonvitamin supplements most commonly reported used were echinacea (19.5 percent), garlic (16.6 percent), ginkgo biloba (14.6 percent), ginseng (11.7 percent), and glucosamine (10.9 percent) (Timbo et al., 2006). When categorized by perceived effect, the 2005 DoD Survey of Health-Related Behaviors indicated that among active duty military users of dietary supplements other than vitamins and minerals, 21 percent used “bodybuilding” supplements, 18 percent used “weight-loss products,” 9 percent used “joint health” products, 8 percent used “performance-enhancing” products, and 9 percent reported using other types of supplements (Marriott, 2007). Among active duty Air Force personnel, the nonvitamin, nonmineral supplements most commonly reported being used five or more times are creatine, glutamine, caffeine, protein powders, fish oils, Hydroxycut (a multiingredient product containing botanicals and minerals, sold to promote weight loss), chondroitin, and nitric oxide (Thomasos, 2007). The use of single bioactive substances seen in data from the surveys reviewed varies significantly, but the following examples show the percentage of respondents reporting use of: androstenedione (6–13 percent); glucosamine/chondroitin (glucosamine hydrochloride and sodium chondroitin sulfate) (7–11 percent); conjugated linoleic acid (3 percent); garlic (5–7 percent); ginseng (7–21 percent); ginko biloba (4–5 percent); caffeine (3–18 percent); Ephedra, ephedrine, or ma huang (15–21 percent); echinacea (4 percent); creatine (5–45 percent); coenzyme Q10 (2 percent); protein (5–16 percent); arginine (1 percent); and lycopene (2 percent) (Brasfield, 2004; Corum, 2007; French, 2007; Johnson et al., submitted; Lieberman et al., 2007; Sheppard et al., 2000). Of the 573 Army physicians surveyed, 32.5 percent listed creatine as one of the top 10 supplements used, 7.7 percent reported Ephedra, and 3.5 percent reported glucosamine/chondroitin. Results from other health care personnel supported these findings (Jaghab, 2007). Consumption of caffeine—a substance included as powdered instant coffee in rations and in the form of chewing gum as a supplement to enhance performance in some specialized military rations—was reported by 18 percent of respondents (Corum, 2007). However, this level is likely underreported, since respondents might not consider caffeine a dietary supplement or might not include other dietary intake of caffeine. Only one study specifically included both dietary supplement and dietary sources of caffeine (see Lieberman et al. in Appendix B), asking respondents to indicate the serving size for each caffeinated product consumed, including various coffee beverages, sodas, and other beverages, with clear instructions on how to measure consumption. The data from these questions have not been analyzed yet. Sports drinks and sports bars (or gels) are a broad and undefined category of dietary supplements that may contain a combination of vitamins, minerals, and other bioactive substances and essential nutrients and that are widely used. For example, 41 percent of Rangers and 36 percent of Special Forces reported using sport drinks (Lieberman et al., 2007). Within the overall Army population, 20 percent of males and 28 percent of females reported using sports drinks (Lieberman et al., 2007). Corum (2007) reported that 43 percent of active duty Army personnel assigned to Europe between 2003 and 2005 reported using sports drinks. The only military subpopulation reporting a relatively low usage of sports drinks was officers attending

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the Army War College, of whom only 10 percent reported routinely using sports drinks (Lieberman et al., 2007). The use of sports bars and gels is much higher among Special Forces (15–43 percent of Special Forces use sports bars) than among Rangers (6 percent and 3 percent of Rangers reported using sports bars and sports gels, respectively). This high use is also in contrast to the lower rate (5 percent) of use among general Army personnel surveyed (Bovill et al., 2000; Lieberman et al., 2007). Those assigned to Europe had also much higher rates of use (17 percent reported use of sports bars in 2003–2005) (Corum, 2007). Some of the questionnaires (e.g., DoD Survey of Health-Related Behaviors in 2005) did not have specific questions on these types of products, but reported on the use of unspecified “bodybuilding supplements” (20.5 percent) and performance-enhancing supplements (8.4 percent) (Marriott, 2007). Protein powders are also popular dietary supplements, their use being reported by 13 percent of males and 8 percent of females in the general Army population and by as many as 18 percent of Rangers and 16–22 percent of Special Forces (Bovill, 2000; Lieberman et al., 2007). Only one survey analyzed the concurrent use of other dietary supplements by MV/MM users (Personal communication, Sonya Corum, U.S. Army Training and Doctrine Command, April 10, 2007). It was found that among those taking MV/MMs , the performance enhancers most frequently reported used were creatine (13 percent), sports drinks (11 percent), and arginine (10 percent). In general, products perceived as bodybuilders, weight-loss promoters, and performance enhancers are the most popular nonvitamin, nonmineral products. Among Special Forces and Rangers, the use of sports drinks, protein bars, and protein powders was notable, supporting one of their major reported reasons for taking supplements, that is, for increased energy intake. Differences in Supplement Use by Demographic Factors In the military, age and rank are closely related. Some surveys presented data categorized by rank but not age; not all of the data sets presented were analysed by demographic factors such as age or gender. Among the surveys reviewed, the greatest quantity of demographic data is available for Special Forces and Rangers, who have a distinctly higher dietary supplement use, specifically for performance-enhancing supplements (Lieberman et al., 2007). The ongoing armywide survey of active duty personnel suggests that younger military members are more likely to use sports bars or gels, sports drinks, and dietary supplements believed to enhance physical performance than other products. Similarly, the 2005 DoD Survey of Health-Related Behaviors indicates that dietary supplement usage is highest among the oldest survey respondents; however, bodybuilding supplements are most likely to be used by service members less than 43 years old, and weight-loss products and performance-enhancing supplements are used most frequently by service members less than 34 years old. Military members over 44 years of age are more likely to be taking multivitamins and single-ingredient dietary supplements for health enhancement, such as individual vitamins and minerals, antioxidants, and products to improve joint health (see Marriott et al. in Appendix B). Some surveys also show differences in usage between men and women; for instance, preliminary results show that in the armywide survey, women appear to be more likely than men to take any dietary supplements (71 versus 58 percent) and more likely than men to take MV/MM supplements (37 versus 32 percent), but they are less likely than men to take protein supplements (10 versus 14 percent) (see Lieberman et al. in Appendix B).

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Behavioral Patterns Some questions in dietary supplement surveys are meant to elicit information on factors affecting use (e.g., consultation with health care providers, reasons for use, sources of information) to help develop effective educational programs and policies. Findings from survey questionnaires and published literature revealed that neither the general population nor military personnel typically discuss their dietary supplement usage with their health care providers. The 2002 NHIS survey showed that only about 24 percent of those who reported use of dietary supplements disclosed such use to their health care providers (see Gardiner et al. in Appendix B). Similarly, among those responding to the DoD Survey of Health Related Behaviors, 36.6 percent indicated they reported dietary supplement use to their physicians and 21.7 percent to a nurse practitioner or physician’s assistant. More women (62.5 percent) than men (45.2 percent) reported usage to a health care provider. A higher percentage (47.8 percent) of service members above 35 years of age report usage to medical professionals compared to service members less than 20 years old (23.5 percent). Among all military services, approximately 50 percent of Air Force personnel report usage to health care professionals compared to 32.6 percent of Navy personnel, 31.5 percent of Army personnel, and 25.3 percent of Marines (Marriott, 2007). Even the highest percentage of those reporting usage (50 percent for Air Force personnel) is quite low, and efforts to increase reporting (e.g., educational programs) are necessary. In response to behavioral questions about expectations of benefits and reasons for use, “health and well-being” was the top reason (given by 19 percent of respondents) to use dietary supplements in the general population (see Gardiner et al. in Appendix B). Members of the Army assigned to Europe reported different motivations for using different types of supplements. As might be expected, improvement of health and prevention of illness were more often linked with use of vitamin or mineral supplements, while performance enhancement and strength were more likely to be associated with ergogenic aids (Corum, 2007). Health improvement was consistently listed as the first or second most important reason for taking dietary supplements (Corum, 2007; Lieberman, 2007; Marriott, 2007; Thomasos, 2007). The ranking of other benefits was fairly consistent across surveys, as shown in Table 2-4. Other behavioral questions of interest include those related to users’ sources of information or their perception of beneficial effects, because these findings may help with the design of education programs.

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TABLE 2-4 Reported Reasons for Taking Supplements Among Military Personnel (and, for comparison, the general U.S. population) Study Population

Reasons Reported

Army personnel in Europe (Corum, 2007)

Health Prevent illness Performance enhancement Strength Prevent fatigue Promote health Weight loss Strength Increase lean muscle mass Stamina Fatigue reduction Cognition/alertness Memory Other Supplement diet Improve health Improve mental health Improve cognitive function Improve physical performance Increase muscle mass Lose weight Specific health problems Performance enhancement Gain weight Lose weight Increase muscle mass, conditioning, strength Cognitive enhancement, to stay awake Supplement diet, health maintenance Vitamin Supplement diet Health Physician recommended Energy Prevention, not otherwise specified Immune booster

Air Force personnel (Thomasos, 2007)

DoD Survey of Health-Related Behaviors Among Active Duty Military Personnel (Marriott, 2007)

Army health care personnel (Jaghab, 2007)

General U.S. population (adults aged 18 years and older) (Kelly et al., 2005)

Note: In order of percentage of respondents, from higher to lower.

Adverse Events In addition to asking questions about expectations of benefits, some surveys included questions about adverse events reported or experienced. This information is particularly valuable when obtained from the special military subpopulations facing higher risks because of demanding mental or physical tasks, and more likely to use dietary supplements. These types of survey questions are not meant to be used to draw causal inferences about dietary supplements

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and adverse events. Instead, they present a general view of the totality of adverse events in a representative sample and may signal a problem and corresponding need for action, for example, the need for focused attention during collection of data through the adverse event reporting system. Adverse events listed through the military surveys reviewed by the committee included abdominal pain, chest pain, dehydration, palpitations, numbness in extremities, and loss of consciousness. Corum (2007) reported that of 5,206 active duty Army survey respondents, 951 reported some adverse events they believed were associated with dietary supplement use (Table 2-5) and also indicated that they usually did not report these adverse events to health care personnel. The committee inquired about additional information on potential associations between specific dietary supplements and adverse events and received one such analysis. The frequency of adverse effects across each category of dietary supplement (vitamins, performance enhancers, and herbal) frequency of use (rarely/never, 1–2× weekly, 3–4× weekly and •5× weekly) was analyzed by Corum (Personal communication, Sonya Corum, U.S. Army Training and Doctrine Command, April 10, 2007). Of reported adverse events, the highest percentage, 19.4 percent, was associated with performance-enhancing supplements, compared to vitamins (5.9 percent) and herbal supplements (5.6 percent). Again, these individual incidents of association are not necessarily a cause for concern on their own, but they may signal a potential problem if the adverse event is severe or frequent and may prompt focused attention on a particular dietary supplement. With data from only one analysis, concrete conclusions about cause and effect could not be made. The committee’s best conclusion is that the rate of adverse effects was higher than normal, especially for performance enhancers. Of the approximately 11,000 service members who responded to the Air Force survey, about 8 percent reported adverse events. While these results may not be comparable to those from clinical drug trials, this rate exceeds the typical rate of adverse events resulting from placebo effects (3–5 percent). The most common adverse effects included heart palpitations, anxiety, dehydration, nausea/vomiting, chest pain, dizziness/confusion, abdominal pain, and tremors. Among those reporting adverse events, only about 15 percent reported discussing them with a health care provider. Serious adverse events were more likely to be reported to a health care provider; for example, 75 percent (3 of 4) of heart attacks were reported while only 7 percent (8 of 92) of cases of diarrhea were reported to the health care provider. Except for heart attacks, fewer than 50 percent of the perceived side effects from dietary supplements were reported to the health care provider (Thomasos, 2007). The percentage of Air Force personnel (50 percent) who indicated they discussed with their health care provider adverse effects they believed to be related to dietary supplement usage was higher than in other military services (31 and 33 percent in the Army and Navy, respectively) (Marriott, 2007).

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TABLE 2-5 Adverse Event Reports Dietary Supplement Survey Corum

Adverse Event

Dehydration Palpitations Muscle cramping Abdominal pain Diarrhea Dizziness Nausea/vomiting Numbness in extremities Tremors Chest pain Breathing difficulties Heart attack, heat stroke, or loss of consciousness Thomasos Palpitations Anxiety Nausea/vomiting Dehydration Dizziness/confusion Diarrhea Abdominal pain Tremors Muscle cramping/pain Chest pain Breathing difficulties Numbness/tingling in arms and legs Problems with heat tolerance Visual disturbances Heat exhaustion/heat injuries Blood in urine Loss of consciousness/fainting Heart attack SOURCES: Corum, 2007; Thomasos, 2007.

Rate of Adverse Event in % (number of events) 3 (n=148) 1.8 (n=91) 1.111 (n=54) .9 (n=44) 0.3 (n=22) 0.3 (n=17) 0.3 (n=16) 0.3 (n=17) 0.3 (n=13) 0.2 (n=8) 0.1 (n=7) 0. (n=1) 2.4 (n=182) 2.2 (n=170) 1.8 (n=137) 1.5 (n=116) 1.3 (n=98) 1.2 (n=92) 1.1 (n=86) 1.0 (n=76) 0.6 (n=47) 0.6 (n=43) 0.3 (n=25) 0.3 (n=25) 0.3 (n=20) 0.3 (n=20) 0.1 (n=9) < 0.1 (n=7) < 0.1 (n=6) < 0.1 (n=4)

RECOMMENDATIONS FOR CONDUCTING SURVEYS If the military elects to use surveys for surveillance, the committee urges attention to three broad areas of survey activities: (1) planning; (2) survey administration; and (3) data processing and analysis. This chapter provides general recommendations, followed by more specific recommendations in the planning and survey administration stages. The development of a sampling plan and the data processing and analysis are beyond the scope of this chapter, but a biostatistician can provide valuable assistance in these efforts. In the planning stage, the survey objectives must be formulated, the relevant scientific literature reviewed, variables and units of analysis selected (i.e., individuals, groups, communities), a population sampling plan developed, and the survey constructed. The design of the survey involves decisions about using a structured or unstructured approach and data collection mode. Use of highly structured surveys generally PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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results in higher-quality data by minimizing measurement error between respondents. However, efforts must be made to ensure validity as respondents may interpret the same questions differently. Unstructured interviews (open-ended questions) require administration by highly trained personnel as well as complex data analysis, and are more expensive to conduct than structured surveys. There are trade-offs that need to be considered when determining whether questions should be open-ended or structured. Because of limitations with open-ended questionnaires (e.g., need for highly skilled interviewer) the committee recommends the use of a structured questionnaire with some options for open-ended questions. Obtaining additional information from participants through the use of some open-ended questions could be valuable, but such information should be obtained using a highly skilled interviewer to conduct structured prompting of survey respondents. In addition, for open-ended questions statisticians, design experts as well as researchers should be engaged from the time of the planning stage, because the analysis of open-ended data requires more coding than structured questions. In the survey administration stage, respondents are recruited, survey data are collected by interviewers or self-reported, and nonrespondents are followed up. The basis for surveillance and research questions of interest should drive data collection and analysis efforts. In addition to survey instruments, other methods to routinely monitor use may be included in the larger surveillance program, for example, extracting data from electronic health records and monitoring sales data from intallation sources. Monitoring Surveys: Overall Recommendations Recommendation 1. Surveys to collect data on the use of dietary supplements need to continue. The committee recommends that DoD continue to exploit a large, generic survey by expanding the DoD Survey of Health Related Behaviors managed by the Office of the Assistant Secretary of Defense (Health Affairs) with questions related to adverse events and beneficial outcomes as well as the use of specific dietary supplements that might be of concern. Given the specific needs and challenges of military personnel, particularly of some military subpopulations, supplement use among military personnel is a special concern for DoD. This committee recommends that DoD continues to conduct the generic DoD Survey of Health Related Behaviors with the purpose of collecting data on use of dietary supplements. The survey should include multiple-choice questions, following the format of the current questionnaire. The value of this survey would be improved by the following: 1. Addition of a question prompting for adverse events (e.g., palpitations, seizures) experienced. 2. Addition of a question prompting for beneficial outcomes (e.g., improved performance, alertness, delayed fatigue) experienced. 3. Improvement of questions on frequency of use, health outcomes, and adverse events by specifying the time and circumstances surrounding the use of a product (e.g., respondent reports used creatine once a day from December through March while deployed). 4. Expansion of questions on types of dietary supplements used by adding a list of specific dietary supplements that might be of concern at the time of the survey (e.g., add entry about the use of a supplement recently suspected of causing seizures). This list must be kept up to date to reflect changes in marketing, habits of use, and occurrence of adverse events.

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Recommendation 2. More comprehensive data collection is needed from select populations. The committee recommends that in-depth, anonymous surveys about dietary supplement use be administered at select military installations. These select sites would be chosen because their military populations (e.g., Special Forces or Rangers) would be more likely to use dietary supplements and face higher or unknown risks due to greater mission demands and harsher environments (e.g., high altitude, extreme temperature) than most military personnel. For example, these in-depth surveys should capture data during intense military operations that are similar to combat (e.g., Special Forces training or situations of deployment, when data collection will not interfere with the completion of the mission). Military subpopulations currently deployed in Iraq and Afghanistan could be selected to participate in surveys because of the tasks (i.e. combat service) and extreme environments they encounter. For this study, however, the committee received no data from Iraq or Afghanistan. Periodically, these surveys might also be conducted at gymnasiums and fitness centers where military service members are more likely to be using performance-enhancing dietary supplements. These in-depth surveys or interviews should incorporate the improvements for questions recommended in the section below; it is also important that questions be included about dietary supplements of particular concern. This kind of more comprehensive survey would be expensive, especially if administered as an interview; if the less costly self-reported survey is administered, then a subset of the survey population should be recruited for in-depth probing about amount, frequency, and pattern of supplement use to verify the accuracy of the self-reported survey data. Data from surveys conducted in these select locations would complement the data collected from DoD’s Survey of Health Related Behaviors Among Active Duty Military Personnel. The study designers should coordinate with the designated oversight committee (see Chapter 6) to determine specific research questions and study design. The committee believes it would be appropriate for the military to manage such surveys as separate subcontract(s) funded by DoD Health Affairs. To develop the surveys, the military should consult with experts in the fields of nutrition, nutrition epidemiology (for survey design), pharmacognosy (for terminology used), and biostatistics (for analytical needs). Most importantly, it is vital that the military consults with individuals with deep expertise in survey design. To obtain a comprehensive description, these reports must be combined with other data, for example, data about dietary supplement use derived from electronic health records (see also Chapter 5) and sales data from military installations both on the base and temporary duty stations (e.g., BX/Px, GNC outlets, Fitness Centers, and commissaries). Surveillance efforts should also consider monitoring of new supplements that enter the market. The DoD can develop contractual limitations for products sold on installations to require manufacturers to at least meet USP requirements. Contract requirements could also specify that suppliers of dietary supplements notify an appropriate health care professional when new dietary supplements in categories of interest are being introduced for sale on base. Nevertheless, electronic health records are unlikely to contain accurate information on dietary supplement use because of low report rates, while sales data. do not reflect actual consumption. For example, sales data would be undersestimated since they will not include purchases made off base. Thus, the best source of information on supplement use remains the results from surveys. To improve the accuracy of data on dietary supplement use in electronic

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health records, this committee recommends that efforts be directed to educate health care personnel (see Chapter 6). Recommendation 3. Data quality needs to be improved. Surveys should be designed in consultation with the proposed designated oversight committee, which could oversee many aspects of dietary supplement management including adverse event reporting, as described below. Improvement of Survey Design The committee recommends modifications and additions to surveys to improve the design (i.e., terminology, wording, and order) and comprehensiveness of the questions. Regardless of the methodology used to administer it (i.e., self-reported questionnaires or one-on-one interviews), a comprehensive survey should include questions on dose, frequency of use, duration of use, user demographics, adverse events, motivation and expectations for use, health and performance outcomes for all dietary supplements of interest, and opportunities to review dietary supplement containers. For example, survey data that estimate total dietary exposure to a dietary supplement ingredient have been limited to sources of caffeine. As recommended above, questionnaires need to be more comprehensive, particularly when administered at installations with special subpopulations (e.g., Rangers or Special Forces). Such a comprehensive survey requires more respondent time as well as careful thought to steps from sample selection to survey design and administration. Approaches to Increase Sample Selection and Response Rate Sampling—the process of selecting a subset of cases that allow conclusions to be drawn about the entire population—should be designed in consultation with a survey statistician; the committee recommends that a probability sampling design be used to minimize researcher bias in selecting survey respondents. Power calculations should be conducted to ensure that the study is large enough to detect the associations for which the military is interested in testing. Increasing the rate of response for surveys is a common challenge with population surveys. A generally acceptable range of response rate is 60–80 percent. Researchers should attempt to increase response rates by following-up with people and communicating the importance of the survey, as well as providing appropriate incentives. Obtaining Data from Longitudinal Studies Needs to Be Considered All of the research data reviewed on dietary supplement surveys were collected from crosssectional study designs. Patterns of behavior are likely to be affected by changes in supplement policies, and this needs to be monitored. If resources permit, the committee recommends that the military conducts surveys over an extended period of time or repeat them at certain intervals in order to evaluate time trends in supplement use. Longitudinal data would provide the opportunity to discern trends in dietary supplement use and patterns of behavior that are affected by changes in supplement policies, as well as examine relationships between dietary supplement use and health outcomes. Health- or performance-related outcomes of interest to the military would include those that are suspected of being affected by dietary supplements, such as weight loss, cardiovascular disease, palpitations, headaches, diminished alertness, or gastrointestinal

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disturbances. As part of the analysis of trends in use, longitudinal assessment of use of new supplements introduced into the market could be conducted. Longitudinal studies can be conducted by following up the same individual over a period of time and collecting information at prescribed times or by using a different sample each time data is collected. By following the same individuals, the variances in estimated changes in use may be lessen but other factors need to be considered, such as a higher level of dropouts. If different samples are selected, investigators need to ensure the selection of appropriate samples throughout the length of the study to minimize within sample variance. Planning Stage: Recommendations for Better Survey Designs This committee believes that making a few adjustments to the surveys could remarkably improve the quality and value of the information collected. Important information gaps identified in surveys include the inability to accurately characterize respondents as users or nonusers of supplements, since frequency of use is not well characterized; and the incomplete assessment of total dose/exposure, especially of potentially important types of supplements (e.g., caffeine). Some surveys are also limited in their ability to assess prevalence of use (e.g., frequency) and difference in use by demographic factors. The surveys also, unfortunately, often used a convenience sample of respondents, making it difficult to ensure that data were adequately representative of the entire military population and decreasing the value of the data. A common challenge in conducting surveys is ensuring the data’s validity. Although complete verification of the information reported about dietary supplement use by respondents could not be attained, the validity of the questionnaires would be enhanced by greater attention to improvement of areas such as the use of defined terminology, assesing total dosage/exposure, and verifying self-reported data. This section describes overall pitfalls of the questionnaires reviewed and makes recommendations for enhancing them. Table 2-7 includes specific examples of how to improve the language and format of questions. These questions should be taken only as examples; prior to their use in questionnaires, they should be validated in the military context (i.e., in the field) so it is understood how they are interpreted and answered. Terminology A critical issue in using survey methods is ensuring that information is elicited in a manner that is reliable and unbiased. There is a lack of consistency in terminology used across questionnaires. If clear definitions are not provided to respondents, simple words can be misinterpreted, which may compromise the validity of a survey. The committee reviewed some questionnaires that used ambiguous terms such as energy and health, which consumers might define differently. If left undefined, interpretation of results by analysts might be difficult. Other examples include terms such as antioxidants, multivitamins/multiminerals, or anabolic supplements. Antioxidants might be understood as referring to vitamins and minerals, botanicals, or some combination of both. Sports drinks, sports bars, and protein powders are highly variable in their composition and may contain any combination of vitamins, minerals, caffeine, botanicals, or other ingredients. The committee recommends that decisions be made early in the planning stage about the appropriateness, wording, and order of questions. Ambiguous terms such as health and antioxidants should be clearly defined. To the extent possible, if ambiguous terms are necessary, they should be used in a consistent manner. To help ensure the use of accurate, clear dietary

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supplement terminology as well as with interpretation of data, a pharmacognosist or similar expert with in-depth knowledge of botanical and bioactive substance sources and nomenclature should be included as a member of the survey design team or as a consultant. Ingredient Identification and Total Dosage Questions pertaining to product dosage, composition, and frequency of use are difficult for respondents to answer. This information, however, is critical to identify signals of harm or benefit. Unfortunately, dietary supplement surveys rarely capture dosage or intake details, as questionnaires do not include entries for the number of capsules taken, weight of the product consumed, or the concentration of the active ingredients. Survey questions to establish use and determine frequency vary, as shown in Table 2-6. More attention is needed to improve accuracy in data on supplements used and quantities taken. To complicate the exposure question, many foods and medications can contribute significantly to the total consumption of a particular substance, a factor which has not been adressed in the military dietary supplement questionnaires reviewed. This might be the case for vitamins and minerals, for example, as well as other bioactive substances such as caffeine, for which the dietary intake from several sources must be included in order to determine potential impact on military personnel. Given the broad range in caffeine content in products in the market, this is a challenging task, as shown by a recent publication that analyzed products sold in various delivery forms and found that taking the amount of product recommended on the label resulted in intake of amounts of caffeine ranging from 1–820 mg/day (Andrews et al., 2007). One survey (see Lieberman et al. in Appendix B) reviewed included an assessment of caffeine intake from dietary sources as well as from supplements, but the results were not available at the time of this publication. In summary, acquiring data on prevalence of use is a first step in determining the extent of dietary supplement use by military personnel; however, total dose/exposure data (e.g., from dietary supplements, food, and medication sources) is necessary to determine whether military personnel are exposed to hazardous levels of a particular dietary supplement. The committee recommends that dietary supplement surveys be complemented with questions about intake from dietary sources (foods and beverages) as well as from pills or powders. This was also supported by the IOM Committee on Mineral Requirements for Military Personnel (IOM, 2006). Special attention needs to be paid to the changing ingredients and amounts in military rations, and future determinations of total dosage and exposure should also incorporate emerging vehicles of dietary supplement ingredient delivery, such as lotions, patches, swabs, and intradermal routes. If it is not feasible to collect data on total dose, it is important to collect descriptive data of the supplements being taken and the frequency and timing of their use. The validity of survey responses is also compromised when the respondents are not fully aware of the ingredients of the dietary supplement product they are consuming. This lack of knowledge was evident in one ongoing armywide survey in which only 16.7 percent of respondents reported knowing all the ingredients in their supplements, and 9.3 percent of those taking supplements were unable to identify any of their ingredients (see Lieberman et al. in Appendix B). The majority reported knowledge of some or most of the ingredients. Some questionnaires to the general population (see Gardiner et al. in Appendix B; Kaufman, 2007) expanded this question to request that the subjects bring in containers to have the product ingredients verified, but the majority of the surveys were based on self-reporting, when PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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verification of ingredients was unlikely. These figures demonstrate that the difficulty in acquiring dosage data on specific ingredients originates not only from the questionnaire design but also from poor consumer knowledge and lack of label accuracy. One feasible approach to address the challenge of obtaining accurate ingredient information from survey respondents would be to record detailed information about the product name and usage. The emphasis in product information collection should be on obtaining a comprenhensive list and quantities of the products used so that the ingredients can be identified later. As Kaufman (2007) observes (Appendix B), when questionnaires are self-administered, as was the case with the ones reviewed, there is no control over the quality of the information received. Data quality is also easily compromised when obtaining information about dosage. Because there are many approaches to obtaining dosage information, such as open-ended questions or collection of product containers from users, it is important to establish an unbiased, practical approach to gather this information. One approach is to provide instructions on how to record product names, ingredients, and quantities.

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Copyright © National Academy of Sciences. All rights reserved.

Use the table to estimate your use of each of the following vitamin and mineral supplements during the past year. Please fill in one circle for each item for estimated use and then record the reason(s) for using the supplement. Do not fill out multivitamin/mineral information under the single item section.

Do you fairly regularly (once a week or more often) take any nutritional supplements? x Yes x No

Lieberman (2007) (Army War College) Have you taken dietary supplements over the past year? x Yes x No

What was your reason for using creatine? x Increase muscle mass, strength, and/or power x As an energy source x Promote general health x Physician directed x Other

How much creatine do you consume during the loading phase?

How frequently did you use creatine? x Seldom (less that once per week) x Occasionally (1–3 times per week) x Frequently (3–6 times per week) x Daily

How much creatine do you consume during the maintenance phase?

Lieberman (2007) (Special Forces) Based on the past 6 months, use the table to estimate your use of each of the following supplements. Please fill in one circle for each item, then record the reason for the use and side affects.

Lieberman (2007) (Rangers) Have you used creatine during the past 3 months? x Yes x No

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During the past 12 months, did you let any of the following conventional medical professionals know about your use of dietary supplements?

In the past 12 months, what were your reasons for taking the following supplements?

Estimate how often you use(d) each of the following individual vitamin supplements (pills, tablets, gel caps, etc.). x Never x Rarely x 1–2 times a week x 3–4 times a week x 5 times a week or more x

In the past 12 months, how often did you take any of the following supplements? (Note: only a few examples of each category are listed.) x Two or more times a day x Once a day x Every other day x Once a week x Once a month x Never in the past 12 months

Do you use or have you used any type of dietary supplements? x I have never used dietary supplements. x I have in the past, but I'm not currently using dietary supplements. x I am currently using dietary supplements.

Estimate how often you use each of the following vitamin and mineral supplements. x Rarely/never x 1–2x per week x 3–4x per week x 5x per week or more

Marriott (2007)

Thomasos (2007)

Corum (2007)

TABLE 2-6 Examples of Questions Used in Military Surveys to Characterize Frequency of Use of Dietary Supplements

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Frequency of Use Although none of the surveys of military populations was designed to obtain dose information, some surveys ask questions regarding frequency of use (e.g., “Are you taking it five or more times per week?”). However, the number of pills or doses per day or the amount of active component per dose was not requested. With the amount of active substance in products varying substantially, it is critical that survey respondents note the amount from the product label (though it should be noted that product labels can also be inaccurate [Andrews et al., 2007]). In an effort to define a true “user” of supplements, the committee recommends that future surveys assess the time period of use more accurately. This would allow for consistency and clarification of prevalence of use of dietary supplements. For example, supplement use might be characterized as episodic (e.g., for short-term weight management), long-term (e.g., most of adult life), short-term (e.g., before a physical assessment), current use (recently began regular use), past use, or never use (Table 2-6). When respondents are properly characterized by usage categories, analyses can be conducted by subgroups of users of interest (e.g., those who use only sports bars or gels) who are subsequently classified by types of dietary supplements and doses. As mentioned above, questions on frequency should be expanded to specify the period of time and circumstances surrounding the use of a product (e.g., respondent reports used creatine once a day from December to March while deployed). Association Between Adverse Effects and Dietary Supplement Consumed The committee recommends enhancement of questions intended to assess associations between consumption of dietary supplements and adverse events. For example, given the common use of caffeinated products in the military and their potential synergistic effects with other stimulants, there is a need to better characterize total intake of caffeine. Several surveys included self-reported (with no adjudication) adverse effects perceived to be attributable to dietary supplements. In-depth probing about adverse events or outcomes (heart palpitations, headaches, etc.) thought to be associated with supplements should be added to the surveys. These questions are especially relevant when conducting surveys in special subpopulations, such as Rangers and Special Forces, with heightened risks and higher dietary supplement usage. As with the data on frequency of use, questions on adverse events should be linked to information about the environment and conditions in which respondents consume the specific dietary supplement (e.g., soldiers might be taking creatine only before deployment or in between sustained missions). Questions on adverse events and beneficial outcomes should be posed prior to questions on dietary supplement use to minimize the potential for biases in responses. Demographic Factors Differences between U.S. military personnel and the general population (e.g., service members have higher socioeconomic status and education, different age distribution, a higher minority representation, and different levels of stress) are substantial enough to require specific military surveillance. Available survey data on supplement use by military personnel give important clues about such use; however, they are limited in their ability to allow assessment of prevalence of use and differences in use by demographic factors across multiple studies. Surveys conducted to date do

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not collect this information consistently; even demographic data (e.g., age, rank, geographic area, organizational unit) collected varies among surveys. A consistent method of collecting and analyzing data by demographic characteristics would allow for a comprehensive, comparable description of dietary supplement use in various populations and across time.

TABLE 2-7 Suggestions for Improving Survey Questions Objective of Question/Response Determine whether the respondent is a supplement user

Original Question

Improved Question

Considerations

Have you ever used any type of dietary supplement?

Have you used or taken any dietary supplements (i.e., vitamins, minerals, or other dietary supplements) in the past year? On the figure below, please circle the months in which you used a dietary supplement.

Important to specify time period of interest (i.e., past week, month, year), duration, and proximity of consumption period to the present time period

Have you used or taken any dietary supplements in the past month? How many days in the past month did you use a dietary supplement? Assess type of supplement use

Do you use antioxidant supplements?

When you used supplements in the past month, did you use antioxidants? Definition of antioxidants should be included.

Important to define supplements to ensure consistency in participant responses Important to include specific questions about dietary supplements of concern

Assess dose/amount of dietary supplement consumed

How much creatine do you consume during the loading phase? gm/day

Please retrieve the container for your dietary supplement before answering these questions. When you took creatine, how much did you take in one day? <500 mg, 400–499 mg, etc.

Important to have respondent retrieve the supplement container and provide information directly from it

Provide response options to determine reasons for use of dietary supplements

Select the reasons that you use supplements: a. promote general health b. reduce fatigue c. lose weight d. prevent illness

Select the reasons that you use supplements: a. promote general health (health is defined as…) b. reduce fatigue c. lose weight d. prevent illness e. other _______ (please explain)

Include appropriate options that are consistent with respondents’ actual experiences. May be necessary to add a response such as “Other ____(please explain).” Response options may be obtained from open questions in preliminary interviews or pretests of the survey.

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TABLE 2-7 Continued Determine whether supplement users experience adverse events when using a specific dietary supplement

Current surveys do not ask for this information.

During the time that you were using (insert supplement name here), did you experience any of the following symptoms: a. shortness of breath b. sleeplessness c. heart palpitations d. seizures e. other: _________

Response options may be composed of symptoms that are reported in civilian populations, reported through surveillance methods such as MedWatch, or obtained from open questions in preliminary interviews or pretests of the survey.

Determine whether supplement users perceive benefits when using a specific dietary supplement

Current surveys do not ask for this information.

During the time that you were using (insert supplement name here), did you experience any of the following: a. better job performance b. increased alertness c. delayed fatigue d. diminished fatigue e. weight loss f. other: __________

Response options may be obtained from product labels (i.e., health claims made by manufacturer), open questions in preliminary interviews, or pretests of the survey.

Determine circumstances of supplement use

Current surveys do not ask for this information.

Under what circumstances do you take dietary supplements (circle all that apply)? a. all the time b. only during deployments c. only when not deployed d. when need to do my job better e. before performance evaluations f. other: __________ Why do you take dietary supplements? a) improve job performance b) increase alertness c) delay fatigue d) diminish fatigue e) weight loss f) other: ___________

Additional Questions Questions on health and performance The committee recommends the collection of data on the association of dietary supplement use with health and performance outcomes. Data should be linked to information about the environment and conditions in which respondents consume the specific dietary supplement.

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Such data would provide evidence of whether the expectations of benefit are being met under the real-life circumstances of the U.S. military. In addition, these questions help determine whether there are differences in outcomes for individuals with healthy lifestyle patterns versus those who use supplements to counter unhealthy behaviors such as smoking, drinking alchohol to excess, and eating a poor-quality diet. Such analyses may be possible if DoD linked dietary intake to dietary supplement intake. Although one survey collected self-reported Army Physical Fitness Test (APFT) results and would therefore allow correlation between dietary supplement use and APFT scores, the data to evaluate the impact of confounding factors (e.g., training regimen) are not available. Data on possible confounders are needed in the analyses of relationships between health outcomes and dietary supplement intake. Potential confounders (i.e. variables that are related to both supplement use and the health outcome of interest but are not in the causal pathway between these two variables) should be considered prior to creating surveys so they are included in the questionnaire; it may be helpful to consult with an epidemiologist for assistance with determining confounders a priori. Questions on effectiveness of communication The committee recommends that questions about sources of information on dietary supplements that military personnel consult be added to questionnaires as these would help determine the most effective methods to disseminate accurate information. Once strategies to disseminate information are implemented, survey questions to measure the level of outreach and effectiveness of the information strategy will also be needed. Administration Stage: Recommendations for Data Collection In the survey administration stage, respondents are recruited, survey data are collected by interviewers or self-report, and nonrespondents are followed up. Each survey should be pretested. Follow-up efforts may be necessary to ensure an adequate response rate. During this stage, data should also be inspected for systematic biases in response patterns and efforts made to adjust the participant demographics or account for bias in the data analysis stage. Presurvey a Few Individuals To validate the survey, the committee recommends that it be pretested on a small number of persons with characteristics similar to the target group of respondents. These data should also be inspected for systematic biases in response patterns. Statistical expertise should be sought prior to survey administration to prevent biases in the questions or the demographics of participants. Verify Self-Reported Data in a Subpopulation A choice must be made between a self-reported or personal interview survey, and the questionnaire should be designed accordingly. When validated, self-reported questionnaires provide higher quality data if designed as highly structured surveys because they minimize biases caused by misinterpretation of questions. Unstructured surveys (using open-ended questions) work better when interviews are conducted; however, they require administration by trained personnel and entail complex data analysis, resulting in higher expenses than structured surveys. Although a personal interview may be more informative than self-reported surveys, responses can be influenced by the manner, tone, and opinion of the interviewer. Thus, while personal interviews offer better survey compliance and in-depth information, interviewer training and quality control are key elements to minimize potential sources of data bias.

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Surveys will likely be administered more often with self-reported questionnaires than with personal interviews due to cost considerations. Self-reported surveys present the following limitations: (1) lower response rates; (2) a higher rate of incomplete or inaccurate responses; (3) a need for simpler, structured designs to elicit reliable responses. The committee recommends the application of strategies to overcome these limitations, which will assist with interpreting self-reported data and revising the questionnaires and, ultimately, help improve self-reported data. One strategy consists of conducting personal interviews with a smaller group of individuals, and correlating these results with self-reported data. These personal interviews allow for more controlled resposes and ensure higher accuracy and data quality. For example, to verify responses related to ingredient accuracy, this subgroup could be asked to bring in the bottles/containers of the products consumed. Lack of statistical power limits comparisons, so statistical power calculations should be conducted to ensure sufficient ability to relate findings from this group to those of the targeted military population. Another strategy to verify responses on use patterns is to compare survey results to sales data from military bases, considering both the types of products that are being purchased and the ingredients in those products.

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REFERENCES Aday, L. 1996. Designing and conducting health surveys. San Francisco: Jossey-Bass. Andrews, K. W., A. Schweitzer, C. Zhao, J. M. Holden, J. M. Roseland, M. Brandt, J. T. Dwyer, M. F. Picciano, L. G. Saldanha, K. D. Fisher, E. Yetley, J. M. Betz, and L. Douglass. 2007. The caffeine contents of dietary supplements commonly purchased in the US: Analysis of 53 products with caffeine-containing ingredients. Annal Bioanal Chem 389(1):231-239. Arsenault, J., and J. Kennedy. 1999. Dietary supplement use in U.S. Army Special Operations candidates. Mil Med 164(7):495-501. Bathalon, G. P., S. M. McGraw, L. D. Hennessy, W. F. Barko, J. F. Creedon, and H. R. Lieberman. 2000. Comparison of reported nutritional supplement intake in two army populations. Suppl J Am Diet Assoc 100(1):A102. Bernard, H. R. 1999. Social research methods: Qualitative and quantitative approaches. Thousand Oaks, CA: Sage Publications. Bovill, M. E., S. M. McGraw, W. J. Tharion, and H. R. Lieberman. 2000. Supplement use and nutrition knowledge in a special forces unit. FASEB Journal 15(5):A999. Bovill, M. E., W. J. Tharion, and H. R. Lieberman. 2003. Nutrition knowledge and supplement use among elite U.S. army soldiers. Mil Med 168(12):997-1000. Brasfield, K. 2004. Dietary supplement intake in the active duty enlisted population. U.S. Army Med Dept J 44-56. Converse, J. M., and S. Presser. 1986. Survey questions: Handcrafting the standardized questionnaire. Thousand Oaks, CA: Sage Publications. Corum, S. J. C. 2007. Dietary supplements questionnaire. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Deuster, P. A., A. Sridhar, W. J. Becker, R. Coll, K. K. O'Brien, and G. Bathalon. 2003. Health assessment of U.S. Army Rangers. Mil Med 168(1):57-62. French, S. 2007. Insights into dietary supplement usage by U.S. active military personnel. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. IOM (Institute of Medicine). 1999. Military strategies for sustainment of nutrition and immune function in the field. Washington, DC: National Academy Press. IOM. 2006. Mineral requirements for military personnel: Levels needed for cognitive and physical performance during garrison training. Washington, DC: The National Academies Press. Jaghab, D. 2007. Survey of Army health care providers concerning dietary supplements. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Johnson, A. E., C. A. Haley, and J. A. Ward. Submitted. Hazards of dietary supplement use. Kaufman, D. W. 2007. Design and conduct of surveys on dietary supplement use. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 12. Kelly, J. P., D. W. Kaufman, K. Kelley, L. Rosenberg, T. E. Anderson, and A. A. Mitchell. 2005. Recent trends in use of herbal and other natural products. Arch Intern Med 165(3):281-286. Lieberman, H. R., T. Stavinoha, S. McGraw, and L. Sigrist. 2007. Use of dietary supplements in U.S. Army populations. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Marriott, B. M. 2007. Dietary supplement use by active duty military personnel: A world wide sample. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. McGraw, S. M., W. J. Tharion, and H. R. Lieberman. 2000. Use of nutritional supplements by U.S. Army Rangers. FASEB Journal 14(4):A742.

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McPherson, F., and M. A. Schwenka. 2004. Use of complementary and alternative therapies among active duty soldiers, military retirees, and family members at a military hospital. Mil Med 169(5):354-357. Radimer, K., B. Bindewald, J. Hughes, B. Ervin, C. Swanson, and M. F. Picciano. 2004. Dietary supplement use by US adults: Data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol 160(4):339-349. Sheppard, H. L., S. M. Raichada, K. M. Kouri, L. Stenson Bar Maor, and J. D. Branch. 2000. Use of creatine and other supplements by members of civilian and military health clubs: A cross-sectional survey. Int J Sport Nutr Exerc Metab 10(3):245-259. Sobal, J., and L. F. Marquart. 1994. Vitamin/mineral supplement use among athletes: A review of the literature. Int J Sport Nutr 4(4):320-334. Thomasos, C. 2007. Assessment of Air Force dietary supplement usage by major commands. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Timbo, B. B., M. P. Ross, P. V. McCarthy, and C. T. Lin. 2006. Dietary supplements in a national survey: Prevalence of use and reports of adverse events. J Am Diet Assoc 106(12):1966-1974.

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3 Vitamins and Essential Minerals for Military Personnel

INTRODUCTION Vitamins and minerals, whether taken in combination or individually, are the most frequently consumed dietary supplements among military personnel in all surveys reviewed (Chapter 2). Although levels for specific military subpopulations have been recommended in other Institute of Medicine (IOM) reports (IOM, 2005; 2006a), potential concerns with high levels of use were not addressed. This chapter includes a summary of recommendations provided in those reports and discusses safety concerns associated with the use of vitamins and mineral supplements. Unlike other dietary supplement ingredients, vitamins and certain minerals are considered essential nutrients for which standards of adequacy are needed. These standards are developed to ensure that the nutrient needs of different populations are met. In the United States, the nutrient standards or Dietary Reference Intakes (DRIs) are compiled in various IOM reports (IOM, 1997, 1998a, 2000a, 2000b, 2002/2005, 2004) (Table 3-1). The DRIs comprise the following four nutrient-based reference values established by gender and age group: the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL). The IOM EARs and RDAs are the average intake levels that meet respectively the requirements of 50 and 97–98 percent of the healthy individuals in a population in a particular life stage and gender group. An RDA is the reference value— derived mathematically from the EAR population distribution—for planning individual intakes. An AI (estimated intake by a population, based on observed or experimentally determined approximations of nutrient intakes) can also be used for planning individual intakes. The IOM UL is the highest intake level likely to pose no reported risk of an adverse health effect to almost all individuals. Because vitamins and minerals are required to maintain health and therefore supplementation might be needed if deficiencies occur, deliberations about their safety and benefits are fundamentally different from those about nonessential dietary supplements, which are discussed in Chapter 4. For nonessential dietary supplements, any discussion on prevention of nutrient deficiencies with dietary supplements would not apply. The 2006 IOM report Mineral Requirements for Military Personnel indicates that compared to the general population, some groups in the military may require higher intakes of specific nutrients to maintain health because of sweat losses during high-intensity physical activities (IOM, 2006a). Higher nutrient intakes might also be needed to optimize military performance. Nutrient standards distinct from those for the general population have been developed for the military population: the Military Dietary Reference Intakes (MDRIs) and the nutritional standards for operational rations (NSORs), which are based on MDRIs (U.S. Departments of the Army, Navy, and Air Force, 2001). The MDRIs are based on the IOM DRIs; the 2006 IOM report recommends that the MDRIs continue to reflect the IOM DRIs and that they be updated periodically by considering scientific evidence from studies on the benefits of specific nutrients (e.g., for improved cognitive function) or from studies revealing altered nutrient metabolism due PREPUBLICATION COPY: UNCORRECTED PROOFS 3-1

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to military performance (e.g., increased sweat losses) (IOM, 2006a). The committee made specific recommendations for a systematic approach to develop MDRIs for all nutrients and how to apply them. In every case, it recommended that the intake level should be lower than the UL for the age range.

TABLE 3-1 Military Recommended Intakes for Men in Garrison Feeding, Operational and Restricted Rations Compared to Recommended Intakes for Men Aged 19–30 Years in the General Population. Nutrient or Energy

RDA, AI, or AMDR (per day) 3,600 56 g (10–35%) 20–35%

Military Daily Recommended Intake 3,250 91 (10–15%) d 35 %

Tolerable Upper Level

Energy intake (kcal) Protein (for an 80 kg male) (g) (% of kcal) Fat (% of kcal) PUFA (% kcal) 0.6–1.2% n-3 as D-linolenic 5–10% n-6 as linoleic acid Carbohydrate (g) (% of kcal) 130 (45–65%) ND Vitamin A (μg) 900 RAE 1,000 μg RE 3,000 Vitamin C (mg) 90 90 2,000 Vitamin D (μg) 5 5 50 Vitamin E (mg) 15 15 1,000 Vitamin K (μg) 120 80 ND Thiamin (mg) 1.2 1.2 ND Riboflavin (mg) 1.3 1.3 ND Niacin (mg NE) 16 16 35 Vitamin B6 (mg) 1.3 1.3 100 Folate (μg DFE) 400 400 1,000 Vitamin B12 (μg) 2.4 2.4 ND Biotin (μg) 30 ND ND Pantothenic acid (mg) 5 ND ND Choline (mg) 550 ND 3,500 Calcium (mg) 1,000 1,000 2,500 Chromium (μg) 35 ND ND Copper (μg) 900 ND 10,000 Fluoride (mg) 4 4 10 Iodine (μg) 150 150 1,100 Iron (mg) 8 15 45 Magnesium (mg) 400 420 350 Manganese (mg) 2.3 ND 11 Molybdenum (μg) 45 ND 2,000 Phosphorus (mg) 700 700 4,000 Potassium (mg) 4,700 3,200 ND Selenium (μg) 55 55 400 Sodium (mg) 5,000; (4,550–5,525) 2,300 1,500; d 2,300 Zinc (mg) 11 15 40 NOTE: AI=adequate intake; AMDR=acceptable macronutrient distribution ranges; DFE=dietary folate equivalents; ND=not determined; NE=niacin equivalents; RAE=retinol activity equivalents; RE=retinol equivalents; PUFA=polyunsaturated fatty acids; RDA= recommended dietary allowance. SOURCES: IOM, 2004; U.S. Departments of the Army, Navy, and Air Force, 2001.

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The safety of vitamins and minerals therefore needs to be determined with consideration of both risks from toxicity and risks from deficiency. This chapter comments on recent recommendations made by other IOM committees on the establishment of requirements for nutrients, including vitamins and minerals, for military personnel performing high-intensity physical tasks. This committee concurs with those recommendations and provides a list of research needs. SAFETY OF VITAMINS AND MINERALS Risks of Vitamin and Mineral Deficiencies Some military subpopulations engage in high-intensity physical activities while they consume low-calorie diets. Their diets might therefore be deficient in vitamins and minerals, and increasing intake might be necessary to meet nutritional requirements and maintain health. There are four basic strategies that can be applied to improve nutrient intake and nutritional status of military personnel: food-based approaches, fortification, supplementation, and complementary public health control measures (IOM, 1998b). The uses, advantages, and disadvantages of each strategy were described in the 2006 IOM report; and this section provides a summary on using supplementation as a strategy to increase intake of essential nutrients in the military. In the 1994 Dietary Supplement Health and Education Act (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress, October 25, 1994), Congress defines a dietary supplement as a product (other than tobacco) that is intended to supplement the diet; that contains one or more dietary ingredients (defined as vitamins; minerals; herbs or other botanicals; amino acids; other dietary substances for use by man to supplement the diet by increasing the total dietary intake; or concentrates, constituents, metabolites, extracts, or combinations of any of the aforementioned dietary ingredients); that is intended to be taken by mouth as a pill, capsule, tablet, or liquid; and that is labeled on the front panel as being a dietary supplement. In general, the scientific community agrees that selecting a balanced diet of foods providing sufficient amounts of vitamins and minerals should be encouraged, and supplements should be used only in cases where food does not provide sufficient vitamins and minerals. If levels higher than the RDAs are necessary to achieve optimal health benefits or because of greater needs in the military subpopulations, supplementation may be the only recourse. For example, the 2006 IOM report showed that the average mineral composition of three different Meals, Ready-to-Eat (MRE) rations and three different First Strike Ration menus provided by the U.S. Army Research Institute of Environmental Medicine (USARIEM) did not meet the iron requirements for women and the zinc requirements for both men and women. Since iron supplementation can be a highly effective approach to treating iron deficiency but can also be toxic, it is important to find the best means to protect women who participate in heavy training from a decrease in iron status, such as supplementation, iron fortification, dietary adjustments, or other means. When mineral sweat losses cannot be balanced with dietary intake or when there is evidence to suggest that a higher intake might benefit physical or mental function, supplementation should be considered. Supplementation might also be advisable when individuals are relying on a low-caloric diet that does not meet the RDAs or if research shows that a low-calorie diet increases micronutrient needs to higher than the RDA. For example, although confirmatory research is needed, the Committee on Mineral Requirements for Military Personnel recommended calcium intakes of at least 1,000 mg/day and as much as 1,500–1,700 mg/day to minimize bone loss during weight-loss regimes (IOM, 2006a).

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In all cases, providing such high levels of nutrients must be justified; even among the general population, the relationship between high intake levels and associated benefits or additional needs is, for many nutrients, still unclear (IOM, 2006a; Lichtenstein and Russell, 2005; Perelson and Ellenbogen, 2002), and intervention studies are needed to demonstrate conclusive nutrient– health benefit links before high levels of nutrients can be recommended. When there are deficiencies, supplementation can generate changes in micronutrient status relatively quickly, although compared with fortification or dietary diversification, it reaches relatively small numbers of consumers and requires action on the part of many individuals. Another advantage is that, unlike other strategies mentioned, dietary supplements do not require major changes in the food supply, food processing, or distribution. Still, in general, the IOM reports have endorsed supplementation with specific nutrients only for situations in which there is clear evidence of potential harm due to dietary inadequacy. For the military, the following factors need to be considered when selecting a strategy to increase nutrient intakes: x x x x x x x

the prevalence and severity of a population’s nutritional inadequacy; the consequences of failing to raise intakes to RDAs or other nutrient standard levels; the number of nutrients in which a population is deficient; the amount of time required to affect the health outcomes linked to the nutrient in question; the phase, appropriateness, and feasibility of the intervention; other characteristics unique to the particular setting; and other characteristics of the nutrient under consideration.

In contrast, the proposition that taking a multivitamin or multimineral (MV/MM) supplement each day should be recommended is debatable, because the efficacy of using dietary supplements to alter the risk of chronic disease is not well established (Caballero, 2003), and this practice presents public health concerns if intake regularly exceeds the UL. In addition, when supplementary doses of nutrients are high, nutrient interactions tend to be accelerated. There might be harmful consequences from shifting the emphasis away from intake of nutrients from food and toward use of nutrient supplements (Caballero, 2003; Lichtenstein and Russell, 2005), in that changes in nutrient profiles might lead to alteration in absorption or metabolism of other constituents. Upper Limits as Safety Levels for Vitamins and Minerals As mentioned above the unique demands of some military situations suggest that nutrient requirements for the military might differ from those for the general population; however, there is no scientific basis to establish different military ULs (for chronic intake). Establishment of the DRIs (and the UL in particular) is an area of nutrition undergoing considerable changes and attracting much attention both nationally and internationally. As with previous IOM committees that have addressed questions related to the nutrient needs of military personnel, this committee recommends that the military defers to the standards established by IOM when it evaluates the safety of vitamins and minerals (IOM, 1997, 1998a, 2000a, b, 2002/2005, 2004). The premises and thought process that precede the establishment of ULs are being reconsidered; as recently recognized in the IOM workshop summary Dietary Reference Intakes Research Synthesis, experts recognize the need for improved ULs. Much progress is needed not only in collection of data to determine ULs, but also in the establishment of clear objectives; for instance, for each

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particular nutrient it is critical to define the adverse effects or health end points to be used in establishing the UL. The IOM workshop summary identified data on dose–response; measures of exposure; exposure in subpopulations, especially for the upper percentiles; and long-term exposure as both critical and lacking. Finally, understanding the interactions of multiple nutrients and identifying approaches to deal with the challenges associated with human intervention studies (e.g., approaches for extrapolating conclusions from animal data) were highlighted as areas of research requiring attention (IOM, 2006b). Efforts are being made to enhance the approaches used to establish the DRIs, including models for ULs. The military leadership responsible for setting nutrition policy should closely follow current and future developments in this area. One question that might arise during performance of military tasks is the appropriate acute intake of a mineral or vitamin. The ULs are based on chronic intakes, not acute intakes. The safety of vitamins or minerals when a large amount is consumed over a short period of time is unknown. For example, in case of injury, a patient’s acute intake of doses of vitamin E lower than the UL might still be lethal because of its antithrombotic effect. On the other hand, shortterm consumption of other nutrients in amounts that exceed the UL might not present a significant risk. This is an issue of concern for military personnel in combat. Are There Safety Concerns for Vitamin and Mineral Use Among Military Populations? Survey Data Chapter 2 summarizes unpublished survey data on dietary supplement use that was collected during the past several years and presented during the 2007 workshop Dietary Supplement Use by Military Personnel and data from a small number of published surveys (Appendix C). The most recent unpublished surveys indicated that products with a combination of vitamins and minerals (MV/MM) are among the most frequently used dietary supplements in both the general active duty population (Corum, 2007; Marriott, 2007; Thomasos, 2007) and special military subpopulations (approximately 23 percent, 32 percent, and 39 percent of U.S. Army Rangers, Special Forces, and Army War College students, respectively) (Lieberman et al., 2007). The published literature also concurs with a high frequency of use of multivitamin or multimineral products or both compared to other dietary supplements among military personnel (Arsenault and Kennedy, 1999; Bovill et al., 2000; Brasfield, 2004; McGraw et al., 2000; Sheppard et al., 2000). In addition to MV/MM supplements, individual minerals or vitamins were also frequently used. A high percentage of the subjects reported “improvement of health” or “to supplement diet” as the reasons for their use of MV/MM supplements (76%) or individual vitamins or minerals (65%) (Marriott, 2007) (Chapter 2). Data Limitations The limitations of survey designs are presented in Chapter 2. One major limitation is that although surveys have collected partial information on frequency of use, none of the questions addressed the specific dosages or amounts of a supplement consumed, which is a critical piece of information when evaluating safety. Even with the assumption that consumers ingest one pill or tablet per day, the broad range of levels in commercially available brands would hamper any accurate estimation of consumption level. In fact, from the data available to the committee, it is

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not possible to determine whether the current uses of specific minerals or vitamins might be cause for concern. This state of affairs was eloquently and extensively described in the 30th National Nutrient Database Conference Report Progress in Developing Analytical and LabelBased Dietary Supplement Databases at NIH’s Office of Dietary Supplements (Dwyer et al., 2007). This report concluded that the widespread use of dietary supplements increases the need for better data on dietary supplement composition and possible health effects. These data are critical for an accurate estimate of total intake of vitamins and minerals, including dietary. Recognizing this, the government has led several initiatives such as the development of a validated MV/MM supplement ingredient database and the update of the National Health and Nutrition Examination Survey (NHANES) dietary supplement label database as well as a study to assess the feasibility of a label database for all dietary supplements marketed in the United States. The panel at the 30th National Nutrient Database Conference concluded that the evidence was insufficient to either recommend or discourage the use of MV/MM supplements (Dwyer et al., 2007). One factor that hinders the availability of total intake data is the lack of information on vitamin and mineral intake from food sources. For example, the 2006 IOM report Mineral Requirements by Military Personnel stated that the few studies available on mineral intake suggest that military servicemen’s dietary intake of some minerals (i.e., magnesium and zinc) might be marginal, but the latter does not provide a clear picture of the mineral and vitamin intake from food among service members (Baker-Fulco, 2005; Personal communication, Carol J. Baker-Fulco, USARIEM, April 23, 2007). This committee concurs with other IOM committees that there is an important need to collect intake data on essential minerals and vitamins from both dietary supplements and the diet. Interactions with Other Dietary Components or Medications Data from only two of the available surveys were analyzed to answer questions related to concomitant consumption of various dietary supplements; for example, what is the proportion of users of mineral or vitamin supplements who also consume other dietary supplements? Are some supplements taken frequently in combination? The analysis of the data from the armywide survey found that among multivitamin users, 21 percent take one other supplement, 22 percent take three or four other supplements, and 31 percent take five or more other supplements (Lieberman et al., 2007). The most popular "other" supplements were protein powder (taken by 29 percent of respondents), sports drinks (24 percent), vitamin C (21 percent), calcium (15 percent), other vitamins (vitamins E, D, or A) (30 percent), creatine (9 percent), or other antioxidants (9 percent). Likewise, the analysis of data from the army survey administered to active duty personnel deployed in Germany showed that among those taking multivitamins, multiminerals, or both, many also used other vitamins or minerals such as vitamin C (43 percent), calcium (38 percent), vitamin E (32 percent), or iron (30 percent); a smaller proportion were also taking performance enhancers such as creatine (13 percent), sports drinks (11 percent), and arginine; others were also taking herbal supplements such as ginseng (11 percent), garlic (8 percent), ginkgo biloba (7 percent), or echinacea (6 percent); and others were also taking caffeine (5 percent) (Personal communication, Sonya Corum, U.S. Army Training and Doctrine Command, April 10, 2007). In addition to consumption of a combination of dietary supplements, there are concerns related to the use of dietary supplements while using prescription medications. Yetley (2007) briefly reviewed potential undesirable effects that may result. For instance, intake of calcium, PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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frequently used among military personnel, may reduce absorption of some medications and reduce their efficacy. Other reported interactions include vitamin E and aspirin, with the potential for an antithrombotic effect (Yetley, 2007). Because vitamins and minerals are essential nutrients, this committee recommends that if a dietary supplement compromises the effectiveness of a medication, an alternative medication should be prescribed if possible. Similarly, if doses higher than the RDA of a specific vitamin or mineral are known to reduce the effect of medication, then advising a reduction in intake of the vitamins or minerals to the RDA level would be appropriate. As with other supplements, however, there is little research conducted on the effects of interactions between medications and vitamins or minerals. SUMMARY Two IOM committees have recently addressed the nutrient needs of military personnel and highlighted several areas where research is warranted, including mineral losses under highintensity military situations; iron status and total calcium intake throughout the time served at military service; and potential beneficial effects on performance of supplementation with specific vitamins and minerals, such as iron and zinc, alone or in combination. These two IOM committees demonstrate the lack of information regarding nutrient requirements for specific subpopulations in the military as well as the lack of information on mineral or vitamin deficiencies that might result in health or performance decrements. As suggested by the IOM Committee on Nutrient Composition of Rations for Short-Term, High-Intensity Combat Operations (IOM, 2005), nutrients should be provided in whole foods, and fortification and the use of supplementation should be limited to the extent possible owing to the potential for nutrient–nutrient interactions. To remedy deficiencies of essential vitamins or minerals, the military may find it useful to implement combined strategies that involve typical diets, fortified foods, and dietary supplements. Whether supplement use is institutionally implemented or not, an individual might still decide to use a MV/MM dietary supplement; unfortunately, as outlined above, there is very little information on the doses and frequency of current use. In the absence of information on total dietary intake of vitamins and minerals, and assuming that individual users of MV/MM dietary supplements take one unit (e.g., pill) per day and that the amounts of essential nutrients per unit are comparable to the military RDA, the committee concluded that the potential for adverse health effects from the use of these dietary supplements would be minimal. Acute intake beyond UL levels of some minerals and vitamins might, however, pose some risks in specific highintensity military situations that would not be predicted by considering the ULs, which are based on chronic intake levels. Likewise, the acute intake of other mineral and vitamins beyond the UL might not pose significant risks. Thus, the recommendation to use ULs as the upper limit should be based on chronic use, as intended when the ULs were established by the IOM. RESEARCH NEEDS The committee recommends that research efforts for vitamins and minerals be made in the following areas: 1. Gather data on nutrient composition of rations and on total dietary intake of vitamins and minerals by military personnel. To gather these data, the military should:

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a. Design and conduct surveys on dietary supplement use by military personnel following the guidance provided in Chapter 2. In particular, more accurate information about dosage and frequency needs to be gathered. b. Continue conducting ration composition analysis, and conduct studies to estimate the dietary intake of minerals and vitamins. 2. Participate in current government-led initiatives to construct a label database and a composition database for vitamins and minerals products. 3. Follow closely the current and future UL developments and include them in their MDRI tables. Consider establishing ULs for the military in special conditions (i.e., during combat when the risk of injury is high, when clotting medications are being used, or during wound healing when vitamin E intake might need to be restricted). 4. If surveys of use reveal that the intake of specific vitamins or minerals are approaching ULs within short periods of time, then research should be conducted to determine the safety of acute intakes of those minerals or vitamins under military conditions of concern. Consider establishing upper limits for acute intakes.

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REFERENCES Arsenault, J., and J. Kennedy. 1999. Dietary supplement use in U.S. Army Special Operations candidates. Mil Med 164(7):495-501. Baker-Fulco, C. J. 2005. Derivation of the military dietary reference intakes and the mineral content of military rations. Institute of Medicine Workshop on the Mineral Requirements for Cognitive and Physical Performance of Military Personnel, Washington, DC. Bovill, M. E., S. M. McGraw, W. J. Tharion, and H. R. Lieberman. 2000. Supplement use and nutrition knowledge in a special forces unit. FASEB J 15(5):A999. Brasfield, K. 2004. Dietary supplement intake in the active duty enlisted population. US Army Med Dept J 44-56. Caballero, B. 2003. Fortification, supplementation, and nutrient balance. Eur J Clin Nutr 57(Suppl 1):S76-S78. Corum, S. J. C. 2007. Dietary supplements questionnaire. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC. Dwyer, J. T., M. F. Picciano, J. M. Betz, K. D. Fisher, L. G. Saldanha, E. A. Yetley, P. M. Coates, J. A. Milner, J. Whitted, V. Burt, K. Radimer, J. Wilger, K. E. Sharpless, J. Holden, K. Andrews, J. Roseland, C. Zhao, A. Schweitzer, J. Harnly, W. R. Wolf, and C. R. Perry. 2007. 30th National Nutrient Database Conference: Report: Progress in developing analytical and label-based dietary supplement databases at NIH’s Office of Dietary Supplements. Honolulu, HI IOM (Institute of Medicine). 1997. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press. IOM. 1998a. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press. IOM. 1998b. Prevention of micronutrient deficiencies: Tools for policymakers and public health workers. Washington, DC: National Academy Press. IOM. 2000a. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press. IOM. 2000b. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press. IOM. 2002/2005. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. Washington, DC: The National Academies Press. IOM. 2004. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: The National Academies Press. IOM. 2005. Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press. IOM. 2006a. Mineral requirements for military personnel: Levels needed for cognitive and physical performance during garrison training. Washington, DC: The National Academies Press. IOM. 2006b. Dietary reference intakes research synthesis: Workshop summary. Washington, DC: The National Academies Press. Lichtenstein, A. H., and R. M. Russell. 2005. Essential nutrients: Food or supplements? Where should the emphasis be? JAMA 294(3):351-358. Lieberman, H. R., T. Stavinoha, S. McGraw, and L. Sigrist. 2007. Use of dietary supplements in U.S. Army populations. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC. Marriott, B. M. 2007. Dietary supplement use by active duty military personnel: A worldwide sample. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC.

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McGraw, S. M., W. J. Tharion, and H. R. Lieberman. 2000. Use of nutritional supplements by U.S. Army Rangers. FASEB J 14(4):A742. Perelson, A. M., and L. Ellenbogen. 2002. Rationale for use of vitamin and mineral supplements. In Handbook of nutrition and food, edited by C. M. Berdanier, E. B. Feldman, W. P. Flatt, and S. T. St. Jeor. Boca Raton, FL: CRC Press. Pp. 1333-1361. Sheppard, H. L., S. M. Raichada, K. M. Kouri, L. Stenson Bar Maor, and J. D. Branch. 2000. Use of creatine and other supplements by members of civilian and military health clubs: A cross-sectional survey. Int J Sport Nutr Exerc Metab 10(3):245-259. Thomasos, C. 2007. Assessment of Air Force dietary supplement usage by major commands. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC. U.S. Departments of the Army, Navy, and Air Force. 2001. Nutrition standards and education. AR 4025/BUMEDINST 10110.6/AFI 44-141. Washington, DC: U.S. Department of Defense Headquarters. Yetley, E. A. 2007. Multivitamin and multimineral dietary supplements: Definitions, characterization, bioavailability, and drug interactions. Amer J Clin Nutr 85(Suppl):269S-276S.

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4 Other Dietary Supplements for Military Personnel

INTRODUCTION The committee was asked to select a limited number of dietary supplements from those identified as commonly used and, on the basis of published reports, to identify those that may be of benefit or might pose serious hazards. The committee used the information provided at the February 12–13, 2007, workshop to select dietary supplements to review based on their frequency of use, potential for adverse events, and interest for the military. This chapter includes a review of the following dietary supplements: caffeine, chromium, creatine, dehydroepiandrosterone (DHEA), Ephedra, garlic, Ginkgo biloba, ginseng, ȕ-hydroxy-ȕmethylbutyrate (HMB), melatonin, quercetin, sports bars, sports drinks, tyrosine, and valerian. HMB, creatine, sports drinks and bars, garlic, Ginkgo biloba, and ginseng were reviewed owing to their high frequency of use (see Appendix C). A review of DHEA was conducted because the use of anabolic supplements was shown as high, it is legally considered a dietary supplement, and because DHEA is popular among athletes. The committee also considered other factors in their selection, such as severity and number of adverse events reported for a supplement or interest of the military in a particular dietary supplement. Ephedra was selected for review by the committee owing to its high frequency of use by military personnel in the past, mainly to achieve weight loss and enhancement of performance, and its adverse event profile. Ginkgo biloba extracts were selected based on their potential to enhance mental performance. Although quercetin is not frequently used by military personnel, research evaluating its effects on performance and immune response was partially supported by the Department of Defense (DoD), indicating the level of military interest in this dietary supplement. Likewise, although the frequency of use of tyrosine was not apparent, this amino acid has been of interest to the military and the object of research investigations to counteract the decrements in cognition that are associated with stress. Because of the reported use of weight-loss products, chromium was chosen as an example of a dietary supplement ingredient that is often found in such products. The known chronobiotic effects of melatonin may justify its use to ease the effects of jet lag as well as of long or night shifts, and therefore it was included for review. Similarly, valerian could be used for its alleged sedative properties and potential to alleviate sleep disorders, common in military life especially during demanding military operations that require long periods of wakefulness or unusual working shifts. Details about the strategies used in conducting literature searches are described in Chapter 5. In general, the committee evaluated reviews that concentrated on safety and efficacy. For some dietary supplements (e.g., Gingko biloba), research on use is so broad and encompasses so many areas that the committee decided to focus the review on effects that would be of interest to the military (e.g., effects on cognition). This is especially recommended for those supplements that have already been extensively studied. Reviews of safety emphasized two areas: bioactivity and PREPUBLICATION COPY: UNCORRECTED PROOFS 4-1

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interactions with other dietary supplements or medications. For the latter, a list of the medications most frequently dispensed to active duty U.S. Army personnel was obtained from the DoD Pharmacy Operations Center, as a representation of typical medications used by military personnel. Although the committee was also asked to provide information on potential withdrawal effects, and the committee recognizes their importance, caffeine is the only supplement for which such information was found. The committee did not perform an evidencebased classification of original research on each supplement. As requested in the statement of task for this study and in accordance compliance with the primary intent to identify supplements that pose serious concerns, the committee relied, as much as possible, on existing reviews by other authors to produce the summaries for each dietary supplement. If a review was not available for the last 10 years, original research was included. In those cases, limitations were noted where appropriate (see tables in Chapter 4). Although the committee emphasized review of safety, the management of dietary supplements for the military needs to follow an evaluation of both risks and benefits, as the recommended framework notes. The reviews therefore also include information about benefits. When reviewing safety, effects judged to be especially pertinent to specific military subpopulations because of performance demands (e.g., cognitive or physical fitness), mission environments (e.g., high altitude, extreme temperatures), or the impact of adverse events associated with the supplement (e.g., bleeding, gastrointestinal disturbances, infectious diseases) received particular attention. The committee recognizes that when trying to identify safety concerns, the fact that dietary supplements are taken in combination and also with medications is a challenge. The committee emphasizes that it is very important that interactions between dietary supplements, medications, nutrients, and other dietary supplements be considered in all elements of this framework: when conducting surveys, when applying the framework and conducting reviews, and when examining and associating adverse events with dietary supplement use. However, when conducting the reviews, it would not be feasible for this committee to address all the potential combination scenarios for dietary supplements, and only a few known and potential interactions with medications have been noted. Because new dietary supplements are being rapidly introduced into the market, information about their quantity and purity would quickly become obsolete and, therefore, it was not included in this chapter. Although many other dietary supplements could have been reviewed, this chapter provides a selected subset as examples of monographs developed for each dietary supplement. For example, although there are risks from the misuse of growth hormones and anabolic steroids, a review of those substances is beyond the scope of this report because they are illegal, and/or there is also no evidence of use among the military. The monographs in this chapter were developed in order to evaluate the review process outlined in Chapter 5. They present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. Monographs are intended to serve as one key tool for making decisions about how to manage each dietary supplement. Other factors affecting the decision-making process on managing use of a specific dietary supplement relate to the characteristics of the targeted population (see Box 1-3 in Chapter 1); that is, decisions about weighing benefits and risks as well as the level of concern will have to consider the tasks (i.e., mission risks and environments) of the subpopulation. The committee recognizes that the military leadership (e.g., local commanders, or leadership at the service or DoD level) is best informed to make such assessments. Examples of how conclusions from the panel of experts could be synthesized are shown in Chapter 5, Table 53. This table includes summary conclusions about the level of concern and the putative benefits

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that will be useful in making management decisions and for developing outreach materials. Also, Appendix D shows examples of how these monographs could serve as a scientific basis for decision making and includes suggestions for management actions for DHEA, melatonin, and Ephedra. A barrier to the application of the committee’s framework was the lack of data from studies designed with subpopulations or circumstances similar to those of the military. Also, data from interactions with medications were infrequently found. It should be noted that the monographs are not exhaustive and present mainly data from reviews. The committee did not provide a list of research recommendations for each dietary supplement because research priorities need to be outlined within the scope of an overall research agenda for dietary supplements; such priorities are delineated in Chapter 7.

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CAFFEINE Background *

Caffeine (1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione) is arguably the most widely consumed psychoactive substance in the world. It is an alkaloid that occurs naturally in the leaves, seeds, and fruit of tea, coffee, cacao, kola trees, and more than 60 other plants (Reid and Sacha, 2005). It is rapidly absorbed from the gastrointestinal tract into the bloodstream. Within 1–1.5 hours following ingestion, maximum caffeine concentrations are reached in blood, and it is readily distributed throughout the body (Nawrot et al., 2003). Natural sources of caffeine generally also contain varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such as polyphenols that can form insoluble complexes with caffeine. Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (1A2 isozyme) into three metabolic dimethylxanthines: (1) paraxanthine, which increases lipolysis leading to elevated levels of glycerol and free fatty acids; (2) theobromine, the principal alkaloid in cocoa and chocolate, which dilates blood vessels and increases urine volume; and (3) theophylline, which relaxes smooth muscles of the bronchi, and is therefore used to treat asthma (but at therapeutic doses much higher than those achieved from caffeine metabolism). Caffeine is a central nervous system (CNS) stimulant that can also have physiological effects on the autonomic nervous system (ANS) as well as the cardiovascular, respiratory, and renal systems. The actions of caffeine and its metabolites on these systems are mediated by way of several mechanisms, including antagonism of adenosine receptors (caffeine and paraxanthine are nonselective antagonists for A1 and A2a receptors, but the effect of caffeine on A3 receptors is unknown). A1 receptors have been identified in many brain regions, including the hippocampus, cerebral cortex, cerebellar cortex, and thalamus (Porkka-Heiskanen, 1999). Other mechanistic pathways for the effects of caffeine and its metabolites include inhibition of phosphodiesterase activity, increased calcium mobilization, and antagonism of benzodiazepine receptors. Caffeine’s inhibition of phosphodiesterase activity may account for its effects on both the cardiovascular and respiratory systems in that nonxanthine phosphodiesterases are cardiac stimulants as well as effective bronchiolar and tracheal relaxants (IOM, 2001). Caffeine in Dietary Supplements A recent review of caffeine content in common U.S. dietary supplements evaluated 53 products with caffeine-containing ingredients as part of a study initiating the development of an analytically validated Dietary Supplement Ingredient Database (DSID) (Andrews et al., 2007). Selection of products for analysis was based on market share information and included those sold as tablets, caplets, or capsules and listing at least one caffeine-containing ingredient, including botanicals such as guarana, yerba mate, kola nut, and green tea extract on the label. Products were analyzed using high-pressure liquid chromatography. Caffeine intake per serving and per day was calculated using the maximum recommendations on each product label. Laboratory *

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. PREPUBLICATION COPY: UNCORRECTED PROOFS 4-4

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analyses revealed product means ranging from 1 to 829 mg caffeine per day. “For products with a label amount for comparison (n=28), 89 percent (n=25) of the products had analytically based caffeine levels per day of between í16 percent and +16 percent of the claimed levels. Lot-to-lot variability (n=2 or 3) for caffeine in most products (72 percent) was less than 10 percent” (Andrews et al., 2007). This review article also noted that caffeine can be present in supplements as a proprietary blend, but not be listed as an ingredient on the label. Less than one-third (11 of 36) of the products whose caffeine content was more than that of one cup of brewed coffee/day listed caffeine as an ingredient, although a majority of these products (27 of 36) did voluntarily list a caffeine level on the label (Andrews et al., 2007). Changes in Caffeine Consumption over the Past Several Decades It appears that coffee remains the primary source of caffeine in the diets of persons in the United States. However, the Continuing Survey of Food Intakes by Individuals (CSFII) found the consumption of caffeine from soft drinks now exceeds the consumption of caffeine from tea (Frary et al., 2005). Frary et al. compared mean values of caffeine consumption as reported by the 1989 Market Research Corporation of America (MRCA) study and the CSFII study. MRCA reported a daily mean consumption value for tea of 0.54 mg/kg, and for soft drinks, 0.27 mg/kg. In contrast, the more recent CSFII study showed that soft drink consumption exceeded tea consumption, reporting mean values of 30.6 mg (16 percent of sample size) and 23.4 mg (12 percent of sample size) respectively (Frary et al., 2005). Table 4-1 summarizes what is known about changes in caffeine consumption over the past several decades. Most studies do not find an increase in caffeine consumption, although in 2005, Frary et al. concluded that “During the past 20 years it appears the percentage of persons consuming caffeine has increased while mean caffeine intakes may have decreased” (Frary et al., 2005). With regard to overall changes in beverage consumption, Nielsen and Popkin (2004) concluded that “Within every age group for all other beverages—including coffee and tea, alcohol, fruit drinks, and fruit juices—the changes have been minor between 1977 and 2001.” Caffeine in Energy Drinks Energy drinks have acquired a considerable market in recent years, substantially contributing to caffeine consumption. Consumers Union recently tested 12 carbonated energy drinks and found caffeine levels ranging from 50 mg to 145 mg per 8 ounce serving (Energy drinks, 2007). Most of the drinks tested were sold in packages containing more than 8 ounces, so consumption of the entire contents could amount to intake of over 200 mg of caffeine. Furthermore, most of the energy drinks tested contained multiple stimulants, and because caffeine content is not required by law to be listed, the amount of caffeine in an energy drink (or any food for that matter) is often unknown (Energy drinks, 2007). Although caffeine is not classified as addictive in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (APA, 1994), it has been asserted in a comprehensive review of caffeine that habitual daily use of over 500 mg of caffeine (i.e., four to seven cups of coffee or seven to nine cups of tea) represents a significant health risk and may therefore be regarded as abuse (Nawrot et al., 2003). Other mental disorders such as dependence, withdrawal syndrome, and intoxication can be caused by caffeine (Pardo et al., 2007). Therefore, “Depending on its use, caffeine can be considered a nutrient, a drug, or a drug of abuse” (Pardo et al., 2007).

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Update on Institute of Medicine (IOM) Caffeine Report (2001)—Putative Benefits The IOM Committee on Military Nutrition Research (2001) concluded in its report on the use of caffeine for the sustainment of mental task performance for military operations that “Research shows that caffeine in the range of 100–600 mg is effective in increasing the speed of reaction time without affecting accuracy and in improving performance on visual and audio vigilance tasks” (IOM, 2001, p. 7). The report indicated that caffeine in doses of 100–600 mg can be used to maintain cognitive performance—particularly in situations of sleep deprivation—and doses of 200–600 mg can be effective in enhancing physical endurance. Moreover, caffeine ingestion has been often associated with a increase in endurance time in physical activities of moderate intensity and long duration (IOM, 2001). Caffeine improves aerobic endurance by increasing fat oxidation and sparing muscle glycogen (IOM, 2001). Four separate reviews (Dodd et al., 1993; Graham et al., 1994; Spriet, 1995; Tarnopolsky, 1994) concluded that caffeine consistently “enhances endurance performance in a variety of activities (i.e., running, cross-country skiing, cycling), with doses from 2 to 9 mg/kg, in naïve and habituated, trained and untrained test subjects” (IOM, 2001). Similar conclusions and recommendations regarding the effects of caffeine on cognitive performance during sleep deprivation were reached in a 2005 review of stimulants by the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Their review concluded that Caffeine is a readily available, short-acting stimulant that has been shown to reduce some of the deficits associated with sleep loss. Studies suggest that caffeine can provide improved alertness and performance at doses of 75 to 150 mg after acute restriction of sleep and at doses of 200 to 600 mg after a night or more of total sleep loss. Caffeine is unlikely to have major disruptive effects on the sleep that follows 8 hours or longer after administration. However, frequent use of caffeine can lead to tolerance and negative withdrawal effects (Bonnet et al., 2005). While caffeine consumed too close to sleep time can interfere with sleep, caffeine appears to help reverse the effects of sleep inertia (i.e., grogginess and psychomotor lethargy immediately upon awakening from deep sleep) (Van Dongen et al., 2001). Update on IOM Caffeine Report (2001)—Safety Concerns The safety of caffeine as a food and beverage additive has been evaluated several times (IOM, 2001). In 1987, the U.S. Food and Drug Administration (FDA) concluded that caffeine added to beverages at a level of 0.02 percent (200mg/L) or less did not present a health risk. Another FDA review in 1992 concluded that there was no evidence that the consumption of 100 mg per day or less of caffeine in cola beverages posed a hazard to human health (but this does not imply safety at higher doses) (Bonnet et al., 2005). It was also noted in the 2001 IOM report that caffeine might be associated with a small increase of spontaneous abortion in the first trimester of pregnancy and that it can significantly increase 24-hour urine output. These effects were not seen as limitations on the military use of caffeine, although increased urine output could provide practical problems under some operational conditions. It was recommended that daily

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doses should not exceed 600 mg due to possible negative effects on mood and performance at higher doses. Nawrot et al. (2003) concluded that there is ample evidence indicating that for healthy adults, there is no association between caffeine intakes of 400 mg per day and general toxicity, increase in incidence of cancer, adverse effects in the cardiovascular system, behavior, or male fertility. However, recent data from studies at the Walter Reed Army Institute of Research (WRAIR) show that caffeine may not benefit all aspects of neurobehavioral function in sleep-deprived subjects. During military operations, the ability to make advantageous and safe decisions is vital. A 2007 WRAIR study demonstrated that after 51 continuous hours of sleep deprivation, the decision-making process was impaired under conditions of uncertainty on the Iowa Gambling Task (Killgore et al., 2007). Caffeine was reported to have no significant beneficial effects that compensated for the detriments of sleep deprivation on the performance of this risk-taking task. Even when administered caffeine, sleep-deprived study participants frequented disadvantageous high-risk scenarios as opposed to the advantageous low-risk scenarios that were learned prior to sleep deprivation (Killgore et al., 2007). Additional effects of caffeine may be undesirable in certain environmental conditions. Among the other physiological effects of caffeine that are relevant to the military are its effects on thermoregulation. While these effects are advantageous to tolerance of cold temperatures, in a heat stress situation, the effects would be undesirable. A review of the literature found no conclusive evidence of caffeine’s effect on body temperature (Armstrong et al., 2007). However, a carefully controlled study of sustained low-dose (0.3 mg/kg/hour) caffeine intake (in tablet form) by healthy adults undergoing sleep deprivation found a reliable increase in core body temperature (measured with a continuous rectal probe) (Rogers et al., 2001). It was also found that caffeine markedly increased circulating levels of noradrenaline relative to a placebo (Price et al., 2000). Research on effects of an ephedrine–caffeine mixture showed that this mixture might also have beneficial thermoregulatory effects for cold tolerance. This effect might be in part due to an 18.6 percent increase in energy expenditure compared to placebo (Vallerand et al., 1989). In a different experiment the additive effects of caffeine and cold water exposure on energy production during submaximal exercise were observed (Doubt et al., 1991). In another placebocontrolled experiment where individuals were subjected to heat stress through physical activity, Bell et al. (1999) reported that although caffeine and ephedrine treatment increased metabolic rate during moderate exercise in a hot, dry environment, there was no increase in internal body temperature; this was possibly due to heat-loss mechanisms that offset the increase in metabolic rate. At higher dosages and/or sustained intake, caffeine can have unwanted physiological and neurobehavioral effects. In addition to the elevated core body temperature and increased plasma noradrenaline levels described by Rogers and Dinges (2005), the adverse effects of caffeine can include locomotor agitation, tachycardia, diuresis, and increased anxiety. Numerous studies of the effect of caffeine on fluid homeostasis (diuresis) have generally found a positive correlation between caffeine consumption and increased urine output (IOM, 2001). For example, Neuhäuser-Berthold et al. (1997) administered coffee containing 642 mg of caffeine to healthy volunteers over a single day and monitored fluid homeostasis in comparison with a control group given an equal amount of mineral water. The caffeine group had a highly significant increase in 24-hour urine output, corresponding to negative fluid balance and a decrease in body weight (IOM, 2001). Decreased electrolyte (sodium and potassium) levels have also been documented as a result of diuresis; however, a normal diet will restore the homeostatic balance (Armstrong et

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al., 2007; IOM, 2001). Moreover, fluid and food intake should be monitored under conditions of sustained military operations in hot and cold environments or at high altitudes, as these may present potential for augmented risk of dehydration (IOM, 2001). Interactions with Other Dietary Supplements or Medications Research has shown that caffeine interacts with other drugs in many different ways, although the magnitude of interaction is dependent on dosage. For example, diazepam (i.e., Valium) is an anxiolytic that is prescribed as a muscle relaxant, sedative-hypnotic, and anticonvulsant (Roache and Griffiths, 1987). Caffeine and diazepam produce disparate effects on the CNS through functionally opposing mechanisms. Caffeine has been demonstrated to antagonize subjects’ ratings of sedation and impairment of psychomotor vigilance caused by diazepam, while diazepam countered the restlessness and subject ratings of tension, alertness, and arousal caused by caffeine (Roache and Griffiths, 1987). Less is known about the extent to which caffeine has synergistic effects with other stimulants. Caffeine Withdrawal The most commonly reported symptoms following withdrawal of caffeine, even at doses as low as 100 mg, are headache, irritability, increased fatigue and drowsiness, decreased alertness, difficulty concentrating, nervousness, confusion, depressed mood, and decreased energy and activity levels (Nehlig, 1999). These symptoms are typically short lived and mild to moderate in severity. Despite the long history of use of caffeine, there have been few studies that systematically examined the nature of caffeine withdrawal (Rogers and Dinges, 2005). Depending on dosage and proximity to sleep time, caffeine can disturb sleep by lengthening sleep latency and reducing total sleep time and sleep efficiency (Rogers and Dinges, 2005). Care should therefore be taken to ensure that caffeine use by military personnel does not interfere with sleep when the latter is desirable. Considerations Specific to the Military Military engagements often involve extended periods of sleep restriction that are accompanied by well-documented physical and cognitive impairment (Killgore et al., 2007). Consistent with the 2001 IOM report on the military use of caffeine, studies continue to find that caffeine is an effective countermeasure to the detriments of sleep deprivation. These studies support “the recommendation for the use of caffeine to extend the period of operational effectiveness during the conduct of military operations that involve unavoidable periods of sleep loss over a three to four day period” (McLellan et al., 2007). In this 2007 study, the use of 800 mg of caffeine throughout three overnight periods maintained alertness and vigilance in comparison to a placebo group (without caffeine) (McLellan et al., 2007). However, it must also be noted that chronic frequent use of caffeine can lead to tolerance and reduce the benefits of caffeine as a countermeasure for sleep deprivation during military operations. To the extent that caffeine is being consumed in ever-larger doses via coffee, soft drinks, energy drinks, and dietary supplements or medications, the military benefits of caffeine as a cognitive and physical performance enhancer may be reduced by tolerance from such widespread consumption of caffeine. In addition, caffeine may not benefit all aspects of cognitive and neurobehavioral functions (e.g., risk-taking decisions), and it may produce physiological effects (e.g., heat

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retention, diuresis) that may compromise physical performance in certain environments (e.g., hot climates). A summary of average daily consumption (ADC) of caffeine in the United States is shown in Table 4-1.

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

MRCA: National Household Menu Census Survey, 1989 NFO WorldGroup: Share of Intake Panel Survey, 1999

USDA: CSFII, 1994, 1996, and 1998

Pao et al., 1982

Barone and Roberts, 1996

Knight et al., 2004

Frary et al., 2005

The ADC calculations in this paper are unreliable.

Adults: 1.5–2.3 mg/kg

Adults: 2.4 mg/kg Children: <1 mg/kg

Coffee drinkers: 3.3 mg/kg Tea drinkers: 1.1 mg/kg Cola drinkers: 0.4 mg/kg

Adults: 227 mg/day Children: 101 mg/day

Mean ADC

Adults: 3.2–5.2 mg/kg

Adults: 5.2 mg/kg Children: <2 mg/kg

90th Percentile ADC

The authors conclude that the percentage of American adults who consume caffeine is increasing when comparing the 1977 GRAS surveys and 1998 CSFII (82% and 87%).

Men and nonpregnant women in the same age groups consumed similar amounts of caffeine.

The authors report slight declines in ADC when comparing the MRCA surveys of 1975 and 1989, but slight increases when comparing the USDA NFCS surveys of 1977 and 1987.

Conclusions

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b

a

National Academy of Sciences U.S. Department of Agriculture

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NOTE: Average consumption numbers are based on responses from “caffeine consumers,” not the entire population. The most recent paper attempting to determine average caffeine intake was published in 2004, using data from a survey taken in 1999. Thus, none of the data takes into consideration the recent surge in sales of energy drinks. In addition, the results of different papers cannot be validly and reliably compared when trying to quantify a change in average caffeine consumption in recent years because the methodology is poorly defined. Finally, no paper includes caffeine obtained through dietary supplements.

USDAb: Nationwide Food Consumption Survey (NFCS), 1977–1978

Graham, 1978

Source Data NASa: Generally Recognized as Safe (GRAS) survey, 1977

Reference

TABLE 4-1 Summary of Average Daily Consumption (ADC) of Caffeine in the U.S.

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REFERENCES APA (American Psychiatric Association). 1994. Diagnostic and statistical manual of mental disorders (DSM-IV). Arlington, VA: APA. Andrews, K. W., A. Schweitzer, C. Zhao, J. M. Holden, J. M. Roseland, M. Brandt, J. T. Dwyer, M. F. Picciano, L. G. Saldanha, K. D. Fisher, E. Yetley, J. M. Betz, and L. Douglass. 2007. The caffeine contents of dietary supplements commonly purchased in the US: Analysis of 53 products with caffeine-containing ingredients. Annal Bioanal Chem 389(1):231-239. Armstrong, L. E., D. J. Casa, C. M. Maresh, and M. S. Ganio. 2007. Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance. Exerc Sport Sci Rev 35(3):135-140. Barone, J. J., and H. R. Roberts. 1996. Caffeine consumption. Food Chem Toxicol 34(1):119-129. Bell, D. G., I. Jacobs, T. M. McLellan, M. Miyazaki, and C. M. Sabiston. 1999. Therman regulation in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med 70(6):583-588. Bonnet, M. H., T. J. Balkin, D. F. Dinges, T. Roehrs, N. L. Rogers, N. J. Wesensten, and Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. 2005. The use of stimulants to modify performance during sleep loss: A review by the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep 28(9):1163-1187. Dodd, S. L., R. A. Herb, and S. K. Powers. 1993. Caffeine and exercise performance: An update. Sports Med 15(1):14-23. Doubt, T. J., and S. S. Hsieh. 1991. Additive effects of caffeine and cold water during submaximal leg exercise. Med Sci Sports Exerc 23(4):435-442. Energy drinks: Behind the buzz. 2007. Cons Rep 72(9):6. Frary, C. D., R. K. Johnson, and M. Q. Wang. 2005. Food sources and intakes of caffeine in the diets of persons in the United States. J Am Diet Assoc 105(1):110-113. Graham, D. M. 1978. Caffeine—It’s identity, dietary sources, intake and biological effects. Nutr Rev 36(4):97-102. Graham, T. E., J. W. Rush, and M. H. van Soeren. 1994. Caffeine and exercise: Metabolism and performance. Can J Appl Physiol 19(2):111-138. IOM (Institute of Medicine). 2001. Caffeine for the sustainment of mental task performance. Formulations for military operations. Washington, DC: National Academy Press. Killgore, D. S., E. L. Lipizzi, G. H. Kamimori, and T. J. Balkin. 2007. Caffeine effects on risky decision making after 75 hours of sleep deprivation. Aviat Space Environ Med 78(10):957-962. Knight, C. A., I. Knight, D. C. Mitchell, and J. E. Zepp. 2004. Beverage caffeine intake in US consumers and subpopulations of interest: Estimates from the Share of Intake Panel Survey. Food Chem Toxicol 42(12):1923-1930. McLellan, T. M., G. H. Kamimori, D. M. Voss, T. Charmaine, and S. J. R. Smith. 2007. Caffeine effects on physical and cognitive performance during sustained operations. Aviat Space Environ Med 78(9):871-877. Nawrot P., S. Jordan, J. Eastwood, J. Rotstein, A. Hugenholtz, and M. Feeley. 2003. Effects of caffeine on human health. Food Addit Contam 20(1):1-30. Nehlig, A. 1999. Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev 23(4):563-576. Neuhäuser-Berthold, M., S. Beine, S. C. Verwied, and P. M. Lührmann. 1997. Coffee consumption and total body water homeostasis as measured by fluid balance and bioelectrical impedance analysis. Ann Nutr Metab 41(1):29-36. Nielsen, S. J., and B. M. Popkin. 2004. Changes in beverage intake between 1977 and 2001. Am J Prev Med 27(3):205-210. Pao, E. M., K. Fleming, P. M. Guenther, and S. J. Mickel. 1982. Foods commonly eaten by individuals: Amount per day and per eating occasion. USDA Home Economics Research Report No. 44.

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Pardo, L. R., G. Y. Alvarez, T. D. Barral, and A. M. Farré. 2007. Caffeine: A nutrient, a drug, or a drug of abuse. Adicciones 19(2):225-238. Porkka-Heiskanen, T. 1999. Adenosine in sleep and wakefulness. Ann Med 31(2):125-129. Price, N. J., J. M. Mullington, S. Kapoor, S. Samuel, M. P. Szuba, and D. F. Dinges. 2000. Plasma norepinephrine during 66 hr of sustained low-dose caffeine intake and 88 hr of sleep deprivation. Sleep 23(Suppl 1):A119. Reid, T. R., and B. Sacha. 2005. Caffeine. National Geographic 207(1):2-33. Roache, J. D., and R. R. Griffiths. 1987. Interactions of diazepam and caffeine: Behavioral and subjective dose effects in humans. Pharmacol Biochem Behav 26(4):801-812. Rogers, N. L., and D. F. Dinges. 2005. Caffeine: Implications for alertness in athletes. Clin Sports Med 24(2):e1-e13. Rogers, N.L., N. J. Price, M. P. Szuba, H. P. Van Dongen, and D. F. Dinges. 2001. Effect of sustained caffeine on core body temperature during 88 hours of sustained wakefulness. Sleep 24(Abstract Suppl):A172-A173. Spriet, L. L. 1995. Caffeine and performace. Int J Sport Nutr 5(Suppl):S84-S99. Tarnopolsky, M. A. 1994. Caffeine and endurance performance. Sports Med 18(2):109-125. Vallerand, A. L., I. Jacobs, M. F. Kavanagh. 1989. Mechanism of enhanced cold tolerance by an ephedrine-caffeine mixture in humans. J Appl Physiol 67(1):438-444. Van Dongen, H. P., N. J. Price, J. M. Mullington, M. P. Szuba, S. C. Kapoor, and D. F. Dinges. 2001. Caffeine eliminates psychomotor vigilance deficits from sleep inertia. Sleep 24(7):813-819.

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CHROMIUM Background *

Chromium , an essential trace mineral, is important for the metabolism of carbohydrate, fat, and protein. Chromium enhances the action of insulin and is associated with improved glucose tolerance and lipid-lipoprotein profiles. In 2001, the Food and Nutrition Board of the Institute of Medicine (IOM) determined the Recommended Dietary Allowance for chromium to be 35 Pg for adult males and 25 Pg for adult females. Relatively high concentrations of chromium are found in processed meats, ready-to-eat bran cereals, whole-grain products, green beans, and broccoli, and relatively low concentrations in foods high in simple sugars (Lukaski, 1999). Estimates of nutrient intakes indicate that the diets of most Americans provide sufficient amounts of chromium (ODS, 2005; Vincent, 2003a). Absorption of dietary chromium in the intestines ranges from 0.5 percent to 2.0 percent. This variation is related to intake of the mineral: as dietary intake of chromium increases, absorption of the mineral decreases. Moreover, both dietary and nondietary factors can moderate chromium absorption. For example, foods containing ascorbic acid promote chromium absorption, while foods containing phytates, which bind to chromium, inhibit transport of the mineral across the intestinal tract (Lukaski, 1999). Chromium absorption is also reduced by medicines that alter stomach acidity, such as antacids, corticosteroids, and proton pump inhibitors, and by other medicines including beta-blockers, insulin, nonsteroidal anti-inflammatory drugs, and prostaglandin inhibitors (ODS, 2005). Although chromium deficiency is rare, patients maintained on intravenous solutions that do not contain the mineral can suffer from impaired control of blood glucose levels, elevated triglyceride and cholesterol levels, and peripheral neuropathy. Treatment with chromium rapidly reverse these symptoms (Lukaski, 1999; ODS, 2005; Stoecker, 2001; Vincent, 2003a). Marginal intake of chromium coupled with physiological stressors such as physical trauma and acute exercise that might occur in a military setting increases the possibility of chromium deficiency (Lukaski, 1999). Chromium in the form of chromium picolinate, which is the salt of chromium with three molecules of the intermediary metabolite picolinic acid, has been widely promoted as a dietary supplement for stimulating weight loss, increasing lean body mass, promoting longevity, and enhancing fitness (Evans, 1989; IOM, 2000; Pittler et al., 2003). Chromium picolinate is found both as a single-ingredient dietary supplement and as a component of multivitamin and multimineral products including pills, energy drinks, energy bars, and chewing gums (Andersson et al., 2007). Although chromium picolinate is the most widely used form of the mineral, chromium nicotinate, chromium chloride, and chromium histidine are also found in dietary supplements. The various forms of the mineral differ in absorbability; data indicating that the picolinate form was absorbed more readily than the nicotinate or chloride form contributed to the popularity of the picolinate form of the mineral in dietary supplements (DiSilvestro and Dy, 2007). However, more recent research demonstrating that chromium histidine is absorbed almost

*

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twice as well as chromium picolinate could lead to an increase in the use of supplements containing this form of the mineral (Anderson et al., 2004). Putative Benefits Initial support for a beneficial role of chromium picolinate supplements in the management of body composition came from a 1989 study. College-age athletes participating in a strengthtraining program who were given 200 mg of chromium picolinate for 6 weeks lost more weight and gained more lean body mass than athletes not taking the supplement (Evans, 1989). This report was followed by a spectacular rise in the sales of chromium picolinate, making it one of the most widely used nutrient supplements for weight loss and/or muscle development (Sharpe et al., 2006; Vincent, 2003b). The study by Evans, however, presents methodological problems; for instance, there was no control over prior training and differences found in anthropomorphic measurements appeared to be functionally not significant (Lefavi et al., 1992). Although chromium picolinate continues to be vigorously marketed and used, the supplement’s ability to alter body composition is questionable (Hallmark et al., 1996; Lukaski et al., 2007; Nissen and Sharp, 2003; Pittler et al., 2003; Stallings and Vincent, 2006; Vincent, 2003a,b). A 2003 meta-analysis of 10 double-blind, randomized control trials concluded that individuals taking 200 to 400 Pg of chromium picolinate on a daily basis for 6 to 14 weeks lost approximately 1.1 kg more (i.e., 0.08–0.2 kg/week) during the intervention and increased lean body mass to a slightly greater degree than those taking a placebo (Pittler et al., 2003). More detailed examination revealed that data from only two of the trials accounted for most of the observed differences in body composition between individuals taking chromium picolinate and those taking a placebo. These findings suggest that the effects of chromium picolinate on weight loss and body composition are small and of marginal clinical significance (Pittler et al., 2003). More recent studies have confirmed this suggestion (Lukaski et al., 2007). Taken together, the results of studies evaluating the effects of chromium picolinate on body weight and composition indicate that the supplement is not a useful adjunct to either weight reduction or body building programs. Safety Concerns No frequent, consistent adverse events have been reported in studies assessing the use of chromium picolinate for periods of up to 3 months. However, a few isolated reports of detrimental effects of taking chromium picolinate, including weight loss, changes in cognitive behavior, allergic skin disorders, renal failure, and liver dysfunction have appeared in the literature (Jeejeebhoy, 1999; Lamson and Plaza, 2002; Lukaski, 1999; Vincent, 2003b; Wani et al., 2006). Additional studies addressing the genotoxic and cytotoxic effects of trivalent chromium complexes have led to the conclusion that these toxic effects of chromium are not a concern for individuals taking supplements containing the mineral (Andersson et al., 2007; Hininger et al., 2007; Lamson and Plaza, 2002). Taking the preceding findings together, there is insufficient evidence to indicate concern about the safety of chromium-containing supplements as presently used, and therefore, a tolerable upper intake level has not been established by the IOM (IOM, 2005; Lukaski, 1999; ODS, 2005).

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Considerations Specific to the Military Studies on the effects of chromium picolinate on body weight and composition have not been conducted in military settings. However, research involving individuals engaged in strengthtraining programs similar to those that might be used in a military setting (e.g., weight lifters, varsity wrestlers) indicates that the benefits of chromium picolinate for decreasing body weight while increasing lean body mass are limited at best. Relevant data and conclusions on efficacy and safety reviews and publications identified for chromium are shown in Table 4-2.

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TABLE 4-2 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Chromium Review/Clinical Trial reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Campbell et al., 1999

Double-blind, randomized n=18 males, 56–69 y

Increasing lean body mass and strength

Placebo

500 μg, 2 times/d for 12 wk

Nutrition 21, San Diego, CA

Body composition, metabolic rate, muscle strength

Livolsi et al., 2001

Randomized n=15 female softball players

Increasing lean body mass and strength

Placebo

500 μg/d chromium picolinate for 6 wk

Nutrition 21, San Diego, CA

Body weight, percent body fat, lean body mass, strength

Nissen and Sharp, 2003

Meta-analysis of 12 studies involving chromium supplementation with weight training in healthy men and women

Increasing lean body mass and strength

Placebo

200 to 1,000 μg

Not specified

Body composition measured by skin folds, hydrostatic weighing, and DEXA†

Pittler et al., 2003

Meta-analysis of 10 trials that met all inclusion criteria and 7 studies that were not suitable for statistical pooling

Reducing body weight

Placebo

200 to 400 μg/d for 6 to 26 wk

Various

Body weight, body fat, lean body weight

Improving insulin sensitivity and glucose tolerance

Placebo

400 to 1,000 μg/d for 12 to 32 wk

Various

Insulin resistance and oral glucose tolerance test (OGTT)

Normal weight and obese males and females engaged or not engaged in weight training Trumbo and Ellwood, 2006

Review of 5 studies assessing effect of chromium picolinate on the risk of type 2 diabetes in obese and normal weight men and women. Studies included from 13 to 44 participants.

†

Dual-energy X-ray absorptiometry (DEXA) is an enhanced form of X-ray technology that is used to measure bone loss. DEXA is the established standard for measuring bone mineral density (BMD).

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Conclusions/Results

Adverse Events Profile

High-dose chromium picolinate supplements did not influence body composition, strength, or power development.

None reported

Interactions with Pharmaceuticals, Foods, or other Dietary Supplements None reported

No differences in muscle strength or body composition

None reported

None reported

Chromium supplementation associated with small, nonsignificant increases in lean body mass and strength

None reported

None reported

Small effect of chromium picolinate compared with placebo for reducing body weight; however, difference due primarily to results of two trials.

None reported

None reported

One intervention study showed a beneficial effect of chromium picolinate (CrPic) on insulin sensitivity. No studies showed a beneficial effect of CrPic on OGTT.

None reported

None reported

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TABLE 4-2 Continued Newer studies not included in reviews Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Martin et al., 2006

Double-blind, randomized n=37, age 25–75 y, with type 2 diabetes

Reducing body weight and adipose tissue, glycemic control, insulin sensitivity

Placebo

1,000 μg/d chromium picolinate for 6 mo

Not specified

DEXA measurement of body composition; glucose tolerance following a 75 g challenge; urinary chromium excretion; blood levels of triglycerides; free fatty acids, insulin, adiponectin, and Cpeptide

Lukaski et al., 2007

Double-blind, randomized n=83 females, age 19–50 y

Reducing body weight and altering body composition

Placebo

187 μg chromium for 12 wk

Nutrition 21

Body weight; skin fold thickness; bone mineral content; fat mass; lean body mass; hematocrit

Diaz et al., 2008

Randomized n=35 overweight females

Reducing body weight, increasing lean body mass, and improving aerobic fitness

Placebo

133 μg CrPic and 0.59 g conjugated linoleic acid 3 times/d for 3 mo in conjunction with dietary energy restriction and exercise program

None

Body composition measured by DEXA; aerobic fitness measured by heart rate and VO23 maximum during exercise

3

Oxygen uptake.

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Conclusions/Results

Adverse Events Profile

Improved glycemic control, increased insulin sensitivity, attenuated body weight gain, changes in body fat distribution with CrPic.

None reported.

Interactions with Pharmaceuticals, Foods, or other Dietary Supplements None reported

Participants given chromium and placebo lost similar amounts of weight and body fat. No differences in bone mineral content, fat-free or hematocrit as a function of supplementation or time.

None reported

None reported

No differences in heart rate, VO2 maximum, or body composition between participants receiving chromium or placebo

None reported

None reported

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REFERENCES Anderson, R. A., M. M. Polansky, and N. A. Bryden. 2004. Stability and absorption of chromium and absorption of chromium and absorption of chromium histidinate complexes by humans. Biol Trace Elem Res 101(3):211-218. Andersson, M. A., K. V. P. Grawe, O. M. Karlsson, L. A. Abramsson-Zetterberg, and B. E. Hellman. 2007. Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro. Food Chem Toxicol 45(7):1097-1106. Campbell, W. W., L. J. Joseph, S. L. Davey, D. Cyr-Campbell, R. A. Anderson, and W. J. Evans. 1999. Effects of resistance training and chromium picolinate on body composition and skeletal muscle in older men. J Appl Physiol 86(1):29-39. Diaz, M. L., B. A. Watkins, Y. Li, R. A. Anderson, and W. W. Campbell. 2008. Chromium picolinate and conjugated linoleic acid do not synergistically influence diet- and exerciseinduced changes in body composition and health indexes in overweight women. J Nutr Biochem 19(1):61-68. DiSilvestro, R. A., and E. Dy. 2007. Comparison of acute absorption of commercially available chromium supplements. J Trace Elem Med Biol 21(2):120-124. Evans, G. W. 1989. The effect of chromium picolinate on insulin controlled parameters in humans. Int J Biosoc Med Res 11(2):163-180. Hallmark, M. A., T. H. Reynolds, C. A. DeSouza, C. O. Dotson, R. A. Anderson, and M. A. Rogers. 1996. Effects of chromium and resistive training on muscle strength and body composition. Med Sci Sports Exerc 28(1):139-144. Hininger, I., R. Benaraba, M. Osman, H. Faure, A. M. Roussel, and R. A. Anderson. 2007. Safety of trivalent chromium complexes: No evidence for DNA damage in human HACaT keratinocytes. Free Radic Biol Med 42(12):1759-1765. IOM (Institute of Medicine). 2000. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press. IOM. 2005. Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press. Jeejeebhoy, K. N. 1999. The role of chromium in nutrition and therapeutics and as a potential toxin. Nutr Rev 57(11):329-335. Lamson, D. W., and S. M. Plaza. 2002. The safety and efficacy of high-dose chromium. Altern Med Rev 7(3):218-235. Lefavi, R., R. A. Anderson, R. E. Keith, G. D. Wilson, J. L. McMillan, and M. H. Stone. 1992. Efficacy of chromium supplementation in athletes: Emphasis on anabolism. Int J Sport Nutr 2(2):111-122. Livolsi, J. M., G. M. Adams, and P. L. Laguna. 2001. The effect of chromium picolinate on muscular strength and body composition in women athletes. J Strength Cond Res 15(2):161166. Lukaski, H. C. 1999. Chromium as a supplement. Annu Rev Nutr 19:279-302. Lukaski, H. C., W. A. Siders, and J. G. Penland. 2007. Chromium picolinate supplementation in women: Effects on body weight, composition, and iron status. Nutrition 23(3):187-195. Martin, J., Z. Q. Wang, X. H. Zhang, D. Watchel, J. Volaufova, D. E. Matthews, and W. T. Cefalu. 2006. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care 29(8):1826-1832.

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Nissen, S. L., and R. L. Sharp. 2003. Effect of dietary supplements on lean mass and strength gains with resistance exercise: A meta-analysis. J Appl Physiol 94(2):651-659. ODS (Office of Dietary Supplements). 2005. Dietary supplement fact sheet: Chromium. http://ods.od.nih.gov/factsheets/chromium.asp (accessed September 5, 2007). Pittler, M. H., C. Stevinson, and E. Ernst. 2003. Chromium picolinate for reducing body weight: Meta-analysis of randomized trials. Int J Obes Relat Metab Disord 27(4):522-529. Sharpe, P. A., M. L. Granner, J. M. Conway, B. E. Ainsworth, and M. Dobre. 2006. Availability of weight-loss supplements: Results of an audit of retail outlets in a southeastern city. J Am Diet Assoc 106(12):2045-2051. Stallings, D., and J. B. Vincent. 2006. Chromium: A case study in how not to perform nutritional research. Curr Topics Nutraceut Res 4(2):89-112. Stoecker, B. J. 2001. Chromium. In Present knowledge in nutrition, 8th ed., edited by B. A. Bowman and R. M. Russell. Washington, DC: ILSI Press. Pp. 366-372. Trumbo, P. R., and K. C. Ellwood. 2006. Chromium picolinate intake and risk of type 2 diabetes: An evidence-based review by the United States Food and Drug Administration. Nutr Rev 64(8):357-363. Vincent, J. B. 2003a. Recent advances in the biochemistry of chromium (III). J Trace Elem Exp Med 16(4):227-236. Vincent, J. B. 2003b. The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent. Sports Med 33(3):213-230. Wani, S., C. Weskamp, J. Marple, and L. Spry. 2006. Acute tubular necrosis associated with chromium picolinate-containing dietary supplement. Ann Pharmacother 40(3):563-566.

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CREATINE Background *

Creatine is a natural component of the body that is synthesized principally in the liver and composed of the essential amino acids methionine, arginine, and glycine. The daily turnover of creatine is about 2 g/day (Shao and Hathcock, 2006), with about half coming from the diet and half from endogenous synthesis with catabolism through nonenzymatic production of creatinine. The principal dietary sources are protein foods such as meat, fish, and poultry, since most creatine (approximately 95 percent) is found in skeletal muscle. Creatine’s primary role in human metabolism is as an intracellular storage form of high-energy phosphate bonds that can serve as a source of energy without the requirement for oxidative metabolism when the minute storage amount of adenosine 5'-triphosphate (ATP) is consumed during brief periods of high energy consumption, as during high-intensity muscular activity. Thus, as might be expected, short-term creatine administration primarily benefits anaerobic performance, while longer-term use increases the development of strength and fosters lean tissue accretion with resistance exercise (Volek et al., 2006); there is evidence suggesting that this increase is primarily caused by an anticatabolic effect in skeletal muscle (Parise et al., 2001). Creatine supplementation is thought to increase the size of the creatine phosphate pool in muscle, and a pattern of nonresponsiveness in a significant minority of subjects may be attributable to an already optimal pool of creatine phosphate (Calfee and Fadale, 2006). Although creatine was initially provided with up to a week of loading with 20–30 g/day followed by 5 g/day, the current mode of use is to provide the smaller dose daily in relation to the beginning or end of exercise (Bemben and Lamont, 2005; Shao and Hathcock, 2006). Putative Benefits Nearly 100 randomized trials of creatine supplementation have been conducted in the past decade, generally with beneficial results on short, repeated bouts of high-intensity exercise (Bemben and Lamont, 2005). Despite considerable variability in results, there is an average greater gain of 2–5 pounds of muscle mass and 5–15 percent of muscle power and strength with creatine compared to placebo (Bemben and Lamont, 2005; Shao and Hathcock, 2006). Although studies have been conducted mostly in men, similar results for improvement of performance in high-intensity activity or exercise or increased strength and improved body composition (lean body mass gains) with resistance training have been found in women (Volek et al., 2006). As might be anticipated from the mode of action, there is little or no evidence for improvement in endurance or aerobic performance (Bemben and Lamont, 2005). A recent review of the literature confirms the lack of effect for submaximal aerobic training in young men and women (Reardon et al., 2006), for tennis-specific training (Pluim et al., 2006), multiple sprint running performance (Glaister et al., 2006), and sprint skating in hockey players (Cornish et al., 2006). Thus, creatine can be a relatively safe and effective ergogenic aid, but its value for any specific activity does need to be examined. For the military, an additional cogent application is suggested by the recent preliminary report that creatine supplementation showed a *

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positive effect on cognitive and psychomotor performance and mood state following 24 hours of sleep deprivation (McMorris et al., 2006). This is in agreement with the fact that creatine is found in the brain, and creatine monohydrate supplementation increases brain creatine content (Dechent et al., 1999). A study by Warber et al. (2002) confirmed the ability of creatine to increase muscle strength and lean tissue but showed no benefit for the military obstacle course. There is also substantial evidence from animal studies that creatine intake may be useful in protecting against traumatic brain injury, perhaps through improvement of mitochondrial bioenergetics (Scheff and Dhillon, 2004; Sullivan et al., 2000). Safety Concerns The Tolerable Upper Intake Level (UL) for creatine was not derived from a recent risk assessment based on cumulative studies in animals and humans. Rather, a newer assessment method, the Observed Safe Level, was utilized. It suggests that the evidence for safety is strong for chronic intakes of 5 g/day (Shao and Hathcock, 2006). Although there was some concern about gastrointestinal side effects (Calfee and Fadale, 2006), these were either mild or not found in randomized trials (Shao and Hathcock, 2006). There is also concern about two noted cases of renal function compromise (Calfee and Fadale, 2006; Shao and Hathcock, 2006), one of whom had underlying renal disease, and a third case of reversible renal failure in a healthy 24-year-old taking creatine as well as multiple other supplements used for bodybuilding (Thorsteinsdottir et al., 2006). Interactions with Other Dietary Supplements or Medications Research on the pharmacokinetics of creatine is limited, but effects of caffeine and carbohydrate intake on creatine transporters have been noted (Persky et al., 2003). The limited data and studies available do suggest important interactions with caffeine that are relevant particularly because caffeine, widely used in the military, is so often employed as an ergogenic aid. One study reported an ergogenic effect of the combination (Doherty et al., 2002); another reported opposing effects on muscle-relaxation time that were nullified when creatine and caffeine were combined (Hespel et al., 2002). Several studies in human subjects have demonstrated improvements in glucose tolerance with creatine taken alone (Derave et al., 2003; Gualano et al., 2007) or combined with protein supplementation (Op't Eijnde et al., 2006), a popular combination for users of creatine. Although statin drugs interact with numerous other drugs, low levels of toxicity were found with use in combination with other drugs (Law and Rudnicka, 2006). The absence of reported interactions of creatine with the common statin drugs presumably implies a very low level of concern; most likely the absence of reported interactions is because populations that take statins are different from those who consume creatine. There is also a paucity of data on the interaction of creatine with analgesics and nonsteroidal antiinflammatory drugs, an instance in which the two patient populations should overlap in a significant manner. However, there is one interesting report of a significant positive interaction—the combination of creatine with cyclooxygenase-2 inhibitors produced additive neuroprotective effects and extended survival by 30 percent—in an animal model of amyotrophic lateral sclerosis (Klivenyi et al., 2004). Finally, although vitamin supplementation is probably common among those who take creatine supplements, data about significant interactions are sparse. There is one report that creatine lowers homocysteine concentration (Korzun, 2004),

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

which might be of some interest, given the effect of vitamins B12, pyridoxine, and folic acid on homocysteine. Considerations Specific to the Military Although studies are not definitive, some trials with creatine in subjects involved in highintensity activities and sports with a high likelihood of injury have shown very little evidence for concern (Greenwood et al., 2003; Hoffman et al., 2006; Santos et al., 2004). Performance is often enhanced or injury lessened. This suggests that there is, if anything, improvement in conditions where injury is common (e.g., sports), and no evidence for bleeding complications. There are no data on creatine intake and tolerance of cold. The available studies suggest either no impact or improvement in tolerance of thermal stress (Kilduff et al., 2004; Mendel et al., 2005; Volek et al., 2001; Weiss and Powers, 2006). There is no data available on the effect of creatine use at high altitudes. Given the large amount of creatine usually provided and its intracellular location, there have been concerns about dehydration or local fluid retention and even risk of heatstroke (Bailes et al., 2002). However, in clinical trials and experience in sports usage, there is little evidence for cramping, diarrhea, or dehydration (Graham and Hatton, 1999; Greenwood et al., 2003; Santos et al., 2004; Smith and Dahm, 2000). There was an increase noted in all fluid volumes in one study of creatine use (Weiss and Powers, 2006). A trial of 175 subjects showed few adverse effects, although edematous limbs presumed secondary to fluid retention were seen more commonly in those taking creatine than those in the placebo group (Groeneveld et al., 2005). However, a single randomized study of musculotendinous injury, which might be considered a consequence of overhydrated tissues, did not demonstrate this effect (Watsford et al., 2003). Although fluid retention may be related to the intracellular location of creatine, this does not seem to present a major concern in terms of effects on body weight. Diarrhea was generally not a problem associated with creatine use (Graham and Hatton, 1999; Greenwood et al., 2003; Santos et al., 2004; Smith and Dahm, 2000). In the trial of 175 subjects, severe diarrhea, responsive to discontinuation of creatine, was seen in two subjects (Groeneveld et al., 2005). No data are available on infectious disease and creatine intake. There has been concern about renal dysfunction as well as two reported cases of renal failure and three deaths in American wrestlers, but minimal impact of creatine intake on renal function was seen in short- and intermediate-term trials (Pline and Smith, 2005; Pritchard and Kalra, 1998; Watsford et al., 2003). Thus, renal function compromise may represent an idiosyncratic reaction, perhaps related to dose or related by association only. It does, however, remain a concern. Relevant data and conclusions on efficacy and safety reviews and publications identified for creatine are shown in Table 4-3.

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See Next Page for Table 4-3

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

TABLE 4-3 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Creatine Review/Clinical Trial Reference Bemben and Lamont, 2005

Type of Study and Subjects Review

Indication

Control

Dose

Product Specification

Outcomes Measured

Sport and exercise performance

Various

Various

None reported

Ergogenic effects related to sports and exercise performance (isotonic/dynamic peak force, isokinetic peak torque, isometric force production, muscle soreness and damage, jumping/sprinting, sprint power cycling, continuous and intermittent endurance)

Calfee and Fadale, 2006

Review

Effects of creatine use

None reported

None reported

None reported

Athletic performance

Cornish et al., 2006

Doubleblind, randomized, repeated measures

Athletic performance (sprint skating)

Placebo

0.3g/kg body mass/d creatine monohydrate for 5 d

Muscle Tech Research and Development Inc., Bramptom, ON, Canada

Sprint skating performance (skating treadmill test, lactate analysis, isokinetic testing, and dietary analysis)

Glucose tolerance

Placebo (maltodextrine)

2 week immobilization phase: 3 daily doses of 5 g creatine

None reported

Muscle GLUT-4† muscle glycogen, muscle creatine content, muscle fiber type composition, muscle force, and body weight

n=17 males, competitive college ice hockey players Derave et al., 2003

Doubleblind, randomized n= 33 healthy adults (26 male, 7 female, age 18–30 y)

†

6 week retraining phase: 2.5 g/d creatine or 2.5 g/d creatine, 40 g/d protein, and 6.7 g/d amino acids

GLUT-4 is a factor in the regulation of blood glucose and the primary glucose transporter in skeletal muscle.

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Conclusions/Results

Adverse Events Profile

Beneficial effects of creatine supplementation for repeated, short bouts of high-intensity exercises, particularly isotonic/dynamic peak force parameters.

No strong scientific evidence to support any reported adverse effects; however, no well-controlled long-term studies available

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Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Benefits seen for males and females of all ages.

Some beneficial effects on athletic performance: increasing strength in outcomes of short-duration anaerobic activities.

Weight gain (1.6-2.4 kg)

None reported

Minor gastrointestinal (GI) discomfort and muscle cramps

No improvement in endurance performance. No differences between placebo and treatment group for skating treadmill test, blood lactate, isokinetic testing, dietary intake, or changes in body mass.

Possible adverse renal effects None reported

None reported

None reported

None reported

Creatine monohydrate supplementation had no effects on sprint skating performance.

Changes in muscle GLUT-4 were not significantly different between groups during immobilization phase. Significant increases in GLUT-4 and muscle glycogen after retraining for creatine and creatine plus protein groups. No treatment effects observed for body weight. Creatine supplementation stimulates GLUT-4 and glycogen content in human muscle only when combined with changes in habitual activity level.

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TABLE 4-3 Review/Clinical Trial Reference Doherty et al., 2002

Continued

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Double-blind, randomized, crossover

Exercise performance (treadmill running)

Placebo (200 mL artificially sweetened water drink)

0.3 g/kg creatine monohydrate for 6 d (given as 4 doses/d); caffeine abstinence

Isotar Creatine Direct, Westcott and Westcott Ltd., Clevedon, UK

Plasma caffeine concentration, body mass, MAOD,‡ treadmill run time to exhaustion, total VO2, rating of exhaustion, and metabolic data

n=14 males, mean age (+/- SD) 22.7 +/- 3.5 y

5 mg/kg caffeine in 200 mL artificially sweetened water drink taken 1 hr prior to testing Glaister et al., 2006

Double-blind, randomized n=42 physically active male students

Exercise performance (sprint running)

Placebo (6 g maltodextrin for 4 d)

5 g creatine monohydrate and 1 g maltodextrin for 4 d

Starmax Nutrition, Hereford, UK

Body mass, mean sprint time, blood lactate

Graham and Hatton, 1999

Review of literature on creatine published from 1966 to 1999

Safety and efficacy

Various

Various

None reported

Various

Greenwood et al., 2003

Observational

Muscle cramping and injury

Non-creatine containing supplement

15.75 g/d creatine monohydrate for 5 d and an average of 5 g/d thereafter 1 5–10 g doses over a 3 y period

Experimental and Applied Sciences, Degussa Bioactives/Traco Labs (Champaign, IL), and MetaResponse Modifiers (San Clemente, CA)

Injury rates, number of missed practices

Neuroprotective and adverse effects

Placebo (Polycose) for 310 d

5 g creatine monohydrate 2x/d for 310 d

DSM Fine Chemicals Inc., Heerlen, the Netherlands

Reported adverse effects, renal function, urinary creatine

n=approximately 100 college football players, age 18–23 y

Groeneveld et al., 2005

Double-blind, randomized n=175 patients with ALS,§ age 18–75 y Patients taking 50 mg riluzole twice daily

‡ §

Maximal accumulated oxygen deficit Amyotrophic lateral sclerosis

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Conclusions/Results

Adverse Events Profile

Body mass increased during creatine supplementation and was maintained during placebo and caffeine trials. No increase in MAOD between trials.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

None reported

None reported

As of 1999, no high-quality research on the effects of creatine exists. Little data on short-term and long-term safety of creatine. Limited evidence of benefits. May enhance the performance of high-intensity, short-duration exercise.

May be related to renal dysfunction

Studies on drug interactions are needed.

Incidence of cramping, heat/dehydration, muscle tightness, noncontact joint injuries, contact injuries, illness, number of missed practices due to injury, players lost for the season, and total injuries/ missed practices were generally proportional or lower than the creatine use rate among players.

No evidence of significant adverse effects

None reported

Creatine supplementation was stopped in 3 patients due to complaints of diarrhea and nausea.

Severe diarrhea (n=2) and nausea (n=1)

None reported

No significant differences in occurrence of adverse effects between groups.

Water retention

Acute caffeine intake was ergogenic after creatine supplementation period and caffeine abstinence.

Increase in body mass relative to placebo (0.7 kg increase) and reduction in body fat (0.4% reduction). No significant between-group differences in fast sprint time, mean sprint time, fatigue, or posttest blood lactate concentration. Creatine supplementation has no benefit on multiple sprint running performance.

Creatine supplementation does not appear to increase the incidence of injury or cramping in college football players. Supplement intake was not blinded or randomized and compliance was self-reported.

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TABLE 4-3 Review/Clinical Trial Reference Gualano et al., 2007

Continued

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Double-blind, randomized

Glucose tolerance and insulin sensitivity; noninsulin dependent diabetes mellitus

Placebo (dextrose)

0.3 g/kg body weight per d creatine for 1st wk

None reported

VO2max test, aerobic exercise training, plasma glucose, and plasma insulin

Muscle relaxation; exercise performace

Placebo (maltodextrine)

Creatine Fuel, Twin Laboratories, New York, NY

Maximal knee extension torque, contraction time, relaxation time

None reported

Body composition, strength measures, biochemical and hormonal analyses, anaerobic power

None reported

ICW,** TBW,†† thermoregulato ry responses (heart rate, temperature), cardiovascular responses, time to exhaustion

n=22 sedentary healthy males, mean age 24 y

Hespel et al., 2002

Double-blind, randomized, crossover

0.15 g/kg body weight per d creatine for next 11 wks

n=10 students (9 male, 1 female), age 21–24 y

4 x 5 g/d creatine monohydrate for 4d 4 x 5 g/d creatine monohydrate and 5 mg/kg body weight per d caffeine 2 other protocols with just caffeine

Hoffman et al., 2006

Randomized n=33 male college football players

Endocrine changes, strength training performance

Placebo (10.5 g/d dextrose)

10.5 g/d creatine monohydrate or 10.5 g/d creatine monohydrate and 3.2 g/d ȕ-alanine 10 wk program

Kilduff et al., 2004

Double-blind, randomized n=21 endurance trained males, mean age 27 y

** ††

Cardiovascular, metabolic, and thermoregulatory responses and exercise performance in hot conditions

Placebo (160 g/d glucose polymer in warm/hot water for 7 d)

22.8 g/d creatine monohydrate and 35 g glucose polymer in warm/hot water for 7d

Intracellular water Total body water

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Conclusions/Results

Adverse Events Profile

Significant decrease in oral glucose tolerance test compared to placebo. No differences in fasting insulin.

No adverse effects were reported in either treatment group.

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Creatine supplementation in combination with moderate aerobic training over 3 months improved glucose tolerance in healthy sedentary males but did not alter insulin sensitivity.

No significant differences in muscle contraction time.

None reported

Caffeine and creatine have opposing effect on muscle relaxation time.

None reported

Additive benefit of ȕ-alanine in strength and power training

No reports of gastrointestinal distress or muscle cramping

None reported

Caffeine intake increased relaxation time; creatine intake shortened relaxation time, compared to placebo. Combined intake of caffeine and creatine have opposing effects. Short-term caffeine intake inhibits muscle relaxation and conteracts the benefits of creatine supplementation in muscle relaxation.

No significant differences in change in body mass. Greater changes in lean body mass and percent body fat with combination ȕ-alanine and creatine, than creatine alone. Increased strength improvement with creatine alone or with ȕ-alanine. Resting testosterone was elevated with creatine intake, but no other significant endocrine changes. No significant changes seen in power performance for any group. Addition of ȕ-alanine to creatine supplements enhanced strength performance more than creatine supplementation alone. Creatine supplementation increased ICW and TBW and reduced heart rate, temperature, sweat rate. No significant decrease in time to exhaustion. Creatine is beneficial for prolonged exercise in hot conditions.

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TABLE 4-3 Review/Clinical Trial Reference Klivenyi et al., 2004

Continued

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Animal study

ALS

Unsupplemen ted diet

Diet supplemented with 2% creatine, or 0.05 % rofecoxib, or 0.012% celecoxib or combinations of all these

Avicena, Inc., Cambridge, MA

Survival, PGE2‡‡ tissue content, motor performance, body weight

Hyperhomocys teinemia

Daily multivitamin for 8 wks

Daily multivitamin, for 4 wks

Experimental and Applied Sciences, Golden, CO

Serum folate, erythrocyte folate, serum vitamin B12, (tHcy)§§

Then, creatine monohydrate (equal to twice their daily creatinine excretion on a molar basis) and a daily multivitamin for 4 wks

Centrum One-aDay multivitamin

n=11–13 transgenic mice in each treatment group

Korzun, 2004

Randomized n=16 healthy adults, age • 19 y

McMorris et al., 2006

Double-blind n=20 students (17 male, 3 female), mean age 21.1 y

Mendel et al., 2005

Double-blind n=16 (15 male, 1 female), age 22–33 y

Op’t Eijnde et al., 2006

Animal study

Cognitive and psychomotor performance and mood state due to sleep deprivation

Placebo

5 g creatine monohydrate, 4x/d for 7 d

Creapure, Deguss AG, Dusseldorf, Germany

Cognitive tests [RMG***], verbal and spatial shortterm memory tests), psychomotor tests, mood state, plasma catecholamines and cortisol

Thermoregulatory response to exercising in the heat (cycling)

Placebo (10 g Solka-flok in 60 g Gatorade) for 5d

20 g creatine in 60 g Gatorade for 5 d

None reported

Body weight, temperature response to exercise in the heat

Type 2 diabetes

Unsupplemen ted diet

Diet supplemented with 2% creatine monohydrate

Creapure, Degussa, Freising, Germany

Body weight, food intake, blood Dglucose, blood insulin, insulinogenic index, muscle biochemistry

n=24 male Goto-Kakizaki rats with inherited type 2 diabetes

‡‡

Prostaglandin E2 Total plasma homocysteine *** A random movement generation test §§

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4-33

Conclusions/Results

Adverse Events Profile

Significant improvement of survival rates in all mice except those with unsupplemented diet. An additive neuroprotective effect was seen in mice fed combination diets, compared to single supplements. Improved motor performance in supplemented mice, with additive effect for combination diets.

None reported

Creatine used in combination with rofecoxib and/or celecoxib can be a useful strategy in the treatment of ALS. Significantly greater reduction in tHcy seen in creatine plus multivitamin group than multivitamin group.

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements Creatine used in combination with celecoxib and/or rofecoxib (COX-2 inhibitors) had an additive effect on motor performance and survival rate.

None reported

None reported

None reported

None reported

None reported

None reported

None reported

None reported

Modest doses of creatine supplements may lower tHcy in humans.

At 24 h of sleep deprivation, the creatine group had significantly less change in performance from 0 h in RMG, choice reaction time, balance, and mood state. No significant differences between groups in plasma concentrations of catecholamines and cortisol. Creatine supplementation has a positive effect on cognitive and psychomotor performance and mood state after 24 h sleep deprivation.

Significant increase in body weight for creatine group. Core temperature was lower after supplementation in both groups. No differences in mean body and mean skin temperatures. No significant effect of short-term creatine supplementation did not have a negative effect on thermoregulation during exercise in heat. Creatine supplementation significantly increased muscle creatine content and lowered the insulinogenic index; this was mainly attributable to a lowering of plasma insulin concentration. Creatine supplementation may improve the sensitivity to insulin in extrapancreatic sites of young male rats.

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TABLE 4-3

Continued

Review/Clinical Trial Reference Pline and Smith, 2005

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Review

Renal function

Various

Various

None reported

Measures of renal function

Pluim et al., 2006

Double-blind, randomized

Tennis performance

Placebo (maltodextros e and dextrose)

Loading phase: 0.3 g/kg body weight/d for 6 d

Podium, Synergen, Switzerland, and creatine monohydrate, MSD, the Netherlands

Speed of serve, ground stroke speed and precision, sprint test, strength measurements

15 g/d for 1 wk, then 2 g/d for 7 wks

None reported

Serum creatinine, creatinine clearance

Load: 20 g/d creatine monohydrate and 4 g/d maltodextrin for 7d

Musashi Pty Ltd

Muscle total creatine and glycogen content, body weight, body fat, oxidative capacity, endurance performance

None reported

Cell death, inflammation markers, muscle soreness markers (CK,††† lactate dehydrogenase, PGE2,‡‡‡ and TNFĮ§§§)

n=36 males, competitive tennis players, mean age 22 y

Pritchard and Kalra, 1998

Maintenance phase: 0.03 g/kg body weight/d for 28 d

Case report

Renal dysfunction

n=1 male, age 25 y with nephrotic syndrome taking cyclosporin Reardon et al., 2006

Controlled n=17 healthy, active adults (11 males, 6 females), age 18–27 y

Endurance training and performance (cycling)

Placebo (24 g/d maltodextrin for 7 d, then 6 g/d for 3 wk)

Maintenance: 5 g/d creatine monohydrate and 1 g/d maltodextrine for 3 wk Santos et al., 2004

Double-blind n=34 male athletes, age 21– 30 y, training for a marathon

Inflammation and muscle soreness associated with long distance running

Placebo (60 g maltodextrine for 5 d)

20 g/d creatine monohydrate and 60 g carbohydrate (maltodextrine) for 5 d

†††

Creatinase kinase Prostaglandin E2 §§§ Tumor necrosis factor-alpha ‡‡‡

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Conclusions/Results

Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

In healthy, young adults, creatine supplementation does not have a negative effect on renal function.

Two cases of renal dysfunction

No differences in performance or change in body weight during the loading phase

No gastrointestinal complaints or muscle cramps

None reported

Renal dysfunction

None reported

None reported

None reported

None reported

None reported

During maintenance phase, significant increase in body weight in creatine group. No differences in performance between groups. Creatine supplementation does not improve tennis performance and should not be recommended for tennis players. Serum creatinine levels increased (103 ȝmol/L to 180 ȝmol/L). One month after stopping supplementation, levels dropped to 128 ȝmol/L. In this case, there is strong circumstantial evidence that creatine is responsible for deterioration in renal function.

Muscle total creatine and glycogen contents were elevated in both groups. No significant anthropometric changes in either group, or changes in oxidative capacity. Both groups had significant reductions in carbohydrate oxidation; significant increases in lipid oxidation, total work, and average power output. No treatment effect of creatine supplementation on any parameter of endurance performance.

After running a 30 km race, increase of cell death and inflammation markers in placebo group. Increase of CK, PGE2, TNFĮ in creatine group. No significant difference between groups in time to finish the race. Supplementation with creatine reduced cell damage and inflammation after an exhaustive 30 km running race.

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TABLE 4-3 Review/Clinical Trial Reference Scheff and Dhillon, 2004

Continued

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Animal study, randomized

Neuroprotection following traumatic brain injury

Unsupplemen ted diet

Diet supplemented with 0.5% or 1.0% creatine monohydrate for 2 wk

Sigma Chemical Co., St. Louis, MO

Lactate and free fatty acids levels in cortex and hippocampus

Various

Various

None reported

n=85 adult male Sprague-Dawley rats subjected to moderate controlled cortical contusions Shao and Hathcock, 2006

Review of randomized, controlled human studies that address safety of creatine or risk assessment

Smith and Dahm, 2000

Survey of creatine use

Adverse effects

n=328 student athletes (182 males, 146 females), age 14–18 y Sullivan et al., 2000

Animal study, randomized n=40 adult ICR mice and 24 adult SpragueDawley rats subjected to moderate, controlled cortical contusions

Thorsteinsdottir et al., 2006

Neuroprotection following traumatic brain injury

Daily injections of 3 mg/g body weight olive oil for 1, 3, or 5 d before injury

Case report

Double-blind, randomized n=20 healthy males, mean age 23 y

Sigma Chemical Co., St. Louis, MO

15 g/wk creatine monophosphate, multiple herbs, nonherbal supplements, and vitamins for 6 mo

n=1 healthy male, age 24 y with acute renal failure and proteinuria

Volek et al., 2001

Daily injections of 0.1 ml/10 g body weight of creatine monohydrate suspended in olive oil for 1, 3, or 5 d before injury

Exercise performance in the heat (sprint cycling)

Placebo (powdered cellulose— equivalent amount to creatine intake)

0.3 g/kg body weight creatine monohydrate daily for 7 d

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Tissue damage, synaptic homeostasis

Adverse effects

Creatine Fuel, Twin Laboratories, Inc., Hauppauge, NY

Body mass, body water, cardiovascular responses, temperature responses, kidney function, and peak and mean power

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Conclusions/Results

Adverse Events Profile

Both lactate and free fatty acid levels were significantly increased in all tissues ipsilateral to the injury. Animals supplemented with creatine had significantly lower levels. Greater neuroprotection was seen in animals fed a 1% creatine diet than those fed a 0.5% creatine diet.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

In adult male rats, a diet supplemented with creatine can provide substantial neuroprotection in part by suppressing secondary brain injury.

The Observed Safe Level risk assessment method indicates that the evidence of safety of creatine intake is strong at intakes up to 5 g/d for chronic supplementation. Although much higher levels have been tested under acute conditions without adverse effects and may be safe, the data for intakes above 5 g/d are not sufficient for a confident conclusion of long-term safety.

None reported

8.2% of students surveyed reported creatine use.

Diarrhea, cramps, and loss of appetite, were reported.

None reported

Less cortical damage found in mice (up to 36%) and rats (up to 50%) that were given creatine. Significant increases in mitochondrial membrane potential; significant decreases in intramitochondrial oxygen levels of reactive oxygen species and calcium.

None reported

None reported

Renal dysfunction

Patient was also taking a large number of other herbs, supplements, and vitamins.

No adverse effects were found.

None reported

Based on this animal model, creatine may have effective use as a neuroprotective agent against acute and delayed neurodegenerative processes.

Previously healthy male presented with acute abdominal pain, polydipsia, and polyuria. He was diagnosed with acute renal failure. Biopsy showed acute interstitial nephritis. Kidney function returned to normal after cessation of supplement intake.

Significant increase in body mass in creatine group. No differences between groups for heart rate, blood pressure, and sweat rate responses. Greater increase in peak power found in the creatine group after sprints. Creatine supplementation had a positive effect on repeated sprint cycle performance in the heat without changes in thermoregulatory responses.

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TABLE 4-3

Continued

Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Volek et al., 2006

Review of the nutritional needs of female strength athletes

Efficacy of creatine supplementation for female athletes

Warber et al., 2002

Double-blind, randomized

Performance of military training tasks (obstacle course, mood state, and marksmanship)

Placebo (sports bar without creatine)

4 sports bars/d containing 6 g creatine monohydrate per bar for 5 d

M&M Mars, Inc.

Anthropometric data, body composition, maximal oxygen uptake, obstacle test performance, bench press performance, rifle marksmanship performance, and mood

Musculotendinou s stiffness and exercise performance

Placebo

20 g/d creatine for 7 d, then 10 g/d for 21 d

None reported

Body mass, isometric force, rate of force development, and musculotendinous stiffness

Exercise performance in the heat (cycling)

Placebo

25 g/d creatine monohydrate for 5 d

Creatine Fuel, Twin Laboratories, Inc., Ronkonkoma, NY

Heart rate, blood pressure, core temperature, body water volumes and sweat loss, relative humidity, side effects

n=26 male soldiers, mean age 32 y

Watsford et al., 2003

Double-blind, randomized n=22 healthy males, mean age 23.4 y

Weiss and Powers, 2006

Double-blind, randomized, counterbalanced

Control

Dose

Product Specification

Various

n=24 athletic, healthy males, mean age 22.9 y

High intensity exercise performance; leucine rate of appearance

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Outcomes Measured

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Conclusions/Results

Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Like men, women may also benefit from creatine supplementation for improving exercise performance.

Non reported

No difference between groups on obstacle test performance, rifle marksmanship, or mood. Creatine group had significant increase in bench press repetitions. Creatine usage resulted in 1.4 kg increase in body mass and a 0.5% decrease in body fat, both significantly different than placebo.

No reports of gastrointestinal distress or any other medical problems or symptoms

None reported

None reported

None reported

None reported

None reported

Short-term supplementation with creatine improved performance on strength tests, but did not significantly improve performance on a military obstacle course in male soldiers.

Significant gain in body mass, countermovement jump height, and drop jump height. No increase in musculotendinous stiffness. Creatine supplementation did not cause muscle strain injuries. Performance enhancement was found.

No differences in changes in heart rate, blood pressure, temperature, sweat loss, or relative humidity between groups. Creatine group had significant increase in body water volumes. Short-term creatine supplementation does not impair the thermoregulatory response during exercise in the heat.

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REFERENCES Bailes, J. E., R. C. Cantu, and A. L. Day. 2002. The neurosurgeon in sport: Awareness of the risks of heatstroke and dietary supplements. Neurosurgery 51(2):283-286. Bemben, M., and H. Lamont. 2005. Creatine supplementation and exercise performance: Recent findings. Sports Med 35(2):107-125. Calfee, R., and P. Fadale. 2006. Popular ergogenic drugs and supplements in young athletes. Pediatrics 117(3):e577-e589. Cornish, S., P. Chilibeck, and D. Burke. 2006. The effect of creatine monohydrate supplementation on sprint skating in ice-hockey players. J Sports Med Phys Fitness 46:90-98. Dechent, P., P. Pouwels, B. Wilken, F. Hanefeld, and J. Frahm. 1999. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol Regul Integr Comp Physiol 277(3):R698-R704. Derave, W., B. O. Eijnde, P. Verbessem, M. Ramaekers, M. Van Leemputte, E. A. Richter, and P. Hespel. 2003. Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans. J Appl Physiol 94(5):1910-1916. Doherty, M., P. M. Smith, R. C. Davison, and M. G. Hughes. 2002. Caffeine is ergogenic after supplementation of oral creatine monohydrate. Med Sci Sports Exerc 34(11):1785-1792. Glaister, M., R. Lockey, C. Abraham, A. Staerck, J. Goodwin, and G. McInnnes. 2006. Creatine supplementation and multiple sprint running performance. J Strength Cond Res 20(2):273-277. Graham, A. S., and R. C. Hatton. 1999. Creatine: A review of efficacy and safety. J Am Pharm Assoc (Wash) 39(6):803-810. Greenwood, M., R. B. Kreider, C. Melton, C. Rasmussen, S. Lancaster, E. Cantler, and P. Milnor. 2003. Creatine supplementation during college football training does not increase the incidence of cramping or injury. Mol Cell Biochem 244(1-2):83-88. Groeneveld, G. J., C. Beijer, J. H. Veldink, S. Kalmijn, J. H. Wokke, and L. H. van den Berg. 2005. Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med 26(4):307-313. Gualano, B., R. B. Novaes, G. G. Artioli, T. O. Freire, D. F. Coelho, F. B. Scagliusi, P. S. Rogeri, H. Roschel, C. Ugrinowitsch, and A. H. Lancha, Jr. 2007. Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids [Epub ahead of print]. Hespel, P., B. Op't Eijnde, and M. Van Leemputte. 2002. Opposite actions of caffeine and creatine on muscle relaxation time in humans. J Appl Physiol 92(2):513-518. Hoffman, J., N. Ratamess, J. Kang, G. Mangine, A. Faigenbaum, and J. Stout. 2006. Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int J Sport Nutr Exerc Metab 16(4):430-446. Kilduff, L. P., E. Georgiades, N. James, R. H. Minnion, M. Mitchell, D. Kingsmore, M. Hadjicharlambous, and Y. P. Pitsiladis. 2004. The effects of creatine supplementation on cardiovascular, metabolic, and thermoregulatory responses during exercise in the heat in endurancetrained humans. Int J Sport Nutr Exerc Metab 14(4):443-460. Klivenyi, P., M. Kiaei, G. Gardian, N. Y. Calingasan, and M. F. Beal. 2004. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 88(3):576-582. Korzun, W. J. 2004. Oral creatine supplements lower plasma homocysteine concentrations in humans. Clin Lab Sci 17(2):102-106. Law, M., and A. R. Rudnicka. 2006. Statin safety: A systematic review. Am J Cardiol 97(8):S52-S60. McMorris, T., R. Harris, J. Swain, J. Corbett, K. Collard, R. Dyson, L. Dye, C. Hodgson, and N. Draper. 2006. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and

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psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl) 185(1):93-103. Mendel, R. W., M. Blegen, C. Cheatham, J. Antonio, and T. Ziegenfuss. 2005. Effects of creatine on thermoregulatory responses while exercising in the heat. Nutrition 21(3):301-307. Op't Eijnde, B., H. Jijakli, P. Hespel, and W. J. Malaisse. 2006. Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes. Int J Mol Med 17(6):1077-1084. Parise G., S. Mihic, D. MacLennan, K. E. Yarasheski, and M. A. Tarnopolsky. 2001. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol 91(3):1041-1047. Persky, A. M., G. A. Brazeau, and G. Hochhaus. 2003. Pharmacokinetics of the dietary supplement creatine. Clin Pharmacokinet 42(6):557-574. Pline, K. A., and C. L. Smith. 2005. The effect of creatine intake on renal function. Ann Pharmacother 39(6):1093-1096. Pluim, B., A. Ferrauti, F. Broekhof, M. Deutekom, A. Gotzmann, H. Kuipers, and K. Weber. 2006. The effects of creatine supplementation on selected factors of tennis specific training. Br J Sports Med 40(6):507-511. Pritchard, N. R., and P. A.. Kalra. 1998. Renal dysfunction accompanying oral creatine supplements. Lancet 351(9111):1252-1253. Reardon, T., P. Ruell, S. Fiatarone, C. Thompson, and K. Rooney. 2006. Creatine supplementation does not enhance submaximal aerobic training adaptations in healthy young men and women. Eur J Appl Physiol 98(3):234-241. Santos, R. V., R. A. Bassit, E. C. Caperuto, and L. F. Costa Rosa. 2004. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30 km race. Life Sci 75(16):1917-1924. Scheff, S. W., and H. S. Dhillon. 2004. Creatine-enhanced diet alters levels of lactate and free fatty acids after experimental brain injury. Neurochem Res 29(2):469-479. Shao, A., and J. Hathcock. 2006. Risk assessment for creatine monohydrate. Regul Toxicol Pharmacol 45(3):242-251. Smith, J., and D. L. Dahm. 2000. Creatine use among a select population of high school athletes. Mayo Clin Proc 75(12):1257-1263. Sullivan, P. G., J. D. Geiger, M. P. Mattson, and S. W. Scheff. 2000. Dietary supplement creatine protects against traumatic brain injury. Ann Neurol 48(5):723-729. Thorsteinsdottir, B., J. Grande, and V. Garovic. 2006. Acute renal failure in a young weight lifter taking multiple food supplements, including creatine monohydrate. J Ren Nutr 16(4):341-345. Volek, J. S., S. A. Mazzetti, W. B. Farquhar, B. R. Barnes, A. L. Gomez, and W. J. Kraemer. 2001. Physiological responses to short-term exercise in the heat after creatine loading. Med Sci Sports Exerc 33(7):1101-1108. Volek, J., C. Forsythe, and W. Kraemer. 2006. Nutritional aspects of women strength athletes. Br J Sports Med 40(9):742-748. Warber, J., W. Thorian, J. Patton, C. Champagne, P. Mitotti, and H. Lieberman. 2002. The effect of creatine monohydrate supplementation on obstacle course and multiple bench press performance. J Strength Cond Res 16:500-509. Watsford, M. L., A. J. Murphy, W. L. Spinks, and A. D. Walshe. 2003. Creatine supplementation and its effect on musculotendinous stiffness and performance. J Strength Cond Res 17(1):26-33. Weiss, B. A., and M. E. Powers. 2006. Creatine supplementation does not impair the thermoregulatory response during a bout of exercise in the heat. J Sports Med Phys Fitness 46(4):555-563.

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DEHYDROEPIANDROSTERONE (DHEA) Background *

Dehydroepiandrosterone (DHEA), a steroid compound considered a prohormone, is secreted by the adrenal glands and produced in the brain. It can be converted to a variety of steroid hormones, including estrogen and testosterone. Most of the circulating DHEA in the body is in the sulfated form, DHEA-S. Blood concentrations peak in early adulthood and decline with age; at 70+ years old, they are approximately at 10–20 percent of peak levels (Allolio and Arlt, 2002). Some epidemiological studies demonstrate a correlation between lower blood DHEA and increased mortality in men (Allolio and Arlt, 2002). This fact, as well as the loss of lean body mass and muscle function with age, has prompted some to explore the use of DHEA as a supplement for aging individuals. There is some evidence linking DHEA to cognitive function including mood and sexuality (Allolio and Arlt, 2002). DHEA may exert its actions via conversion to estrogens or androgens or via direct action as a neurosteroid on receptors in the brain (Allolio and Arlt, 2002). Blood DHEA is reduced in some clinical conditions, including anorexia nervosa, cancer, lupus, HIV, kidney disease, and diabetes. Some drugs are known to reduce blood DHEA (e.g., dexamethasone, insulin, carbamazepine, phenytoin) while others (e.g., benfluorex, diltiazem) increase concentration of this prohormone (Kroboth et al., 1999; Salek et al., 2002). Although many other prohormones came under tighter FDA regulation (the Anabolic Steroid Control Act) in 2004, DHEA was exempt from this act and thus can still be sold as a dietary supplement (Handelsman, 2005). Putative Benefits Because the primary indication for use has been to restore reduced blood DHEA concentration to values typical of young adults, most studies have been performed on older individuals (60+ years of age). Most of these studies show that ingestion of DHEA can increase the blood DHEA concentration of elderly individuals to that of young adults (Morales et al., 1998; Percheron et al., 2003). There is a gender difference in DHEA’s effect on other steroid hormones in that women usually also have an increase in testosterone while men have an increase in estrogen (Allolio and Arlt, 2002). Although one of the earlier clinical trials reported a reduction in body fat, increase in lean body mass, and increase in muscle strength in men taking 100 mg/d DHEA for 6 months, this study had a small subject number (9 men and 10 women, aged 50–65 years) and no placebo group (Morales et al., 1998). Most subsequent studies using larger groups of subjects for up to 2 years report similar effects on blood hormone concentration but no effects on body composition or muscle function (e.g., Baulieu et al., 2000; Nair et al., 2006). One exception is a study reporting improved insulin sensitivity and reduced visceral and subcutaneous fat in subjects over 65 years of age subsequent to ingestion of 50 mg/d DHEA for 6 months (Villareal and Holloszy, 2004). Another study reported a modest but significant increase in bone mineral density in 87 elderly men (>60 years old), *

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. PREPUBLICATION COPY: UNCORRECTED PROOFS 4-42

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but as this change was much less than that reported for other therapeutic interventions, the authors concluded that this was of limited value (Nair et al., 2006). The few studies performed on younger individuals involved in resistance training did not report a benefit on lean tissue or strength gain (Bahrke and Yesalis, 2004; Brown et al., 2006). A Cochrane review of several randomized, placebo-controlled trials that investigated the effects of DHEA on individuals over 50 years of age concluded that DHEA did not improve cognitive function in older individuals (Evans et al., 2007). Although there is limited data, a few studies suggest potential benefit on mood and sexuality, especially in older women (Allolio and Arlt, 2002; Baulieu et al., 2000). In conclusion, while DHEA may be of medical value for people with certain clinical problems, including adrenal insufficiency, or for those under chronic glucocorticoid treatment, the largest, longest, and best-designed studies do not identify benefits of DHEA on body composition, muscle function, or cognitive function. Safety Concerns Negative effects of DHEA ingestion were primarily observed in women (and were likely secondary to an increase in endogenously synthesized testosterone) and included acne, hirsutism, and reduction in serum HDL cholesterol (Allolio and Arlt, 2002). Because of the effects of DHEA on steroid hormones, there has been concern about its potential effects on development of hormone-sensitive cancers such as breast and prostate. One study observed no effect on prostate size or serum prostate-specific antigen (PSA) in men who consumed 75 mg/d of DHEA for 2 years (Nair et al., 2006). However, this may not be long enough to detect an effect on neoplasia. Epidemiological and casecontrol studies of pre- and postmenopausal women who later developed breast cancer have identified an increase in breast cancer risk for those with the highest blood DHEA levels (Kaaks et al., 2005a,b; Missmer et al., 2004; Raven and Hinson, 2007). This suggests, but does not prove, an association between DHEA supplementation and risk of breast cancer. Caution is appropriate, at least in women already at higher risk of breast cancer, and for long-term users. Studies measuring typical health-related blood panels, including liver function, do not report a change attributable to DHEA taken in typical doses (50–100 mg/d) (Morales et al., 1998; Nair et al., 2006). However, because rodent studies have identified hepatic carcinogenic properties of DHEA (Mayer and Forstner, 2004) in rats fed 0.45–1 percent of their diet as DHEA for 52–100 weeks, safety cannot be assured. Although there is modest evidence for enhancement of neoplasia—mostly from large epidemiological studies in women, with some evidence for hepatic cancer in animal models—performance of additional research (i.e., clinical trials) is not warranted because of DHEA’s potential health risk combined with little evidence of benefit. Considerations Specific to the Military There are no reports of studies evaluating DHEA in conditions that would be specific to the military. However, there is no reason to suspect that effects would be different in different environmental or working conditions. In addition, study subjects were generally older than active duty military personnel. Most studies with participants who were demographically similar to the military population did not reveal benefits, so the research

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

conducted does not support the value of DHEA as a performance enhancer for military personnel. Relevant data and conclusions on efficacy and safety reviews and publications identified for DHEA are shown in Table 4-4.

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See Next Page for Table 4-4

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TABLE 4-4 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for DHEA Review/Clinical Trial Reference

Type of Study and Subjects

Kroboth et al., 1999

Review of changes in DHEA in aging, disease, and with drug or vitamin use. Individual studies had 5–36 subjects.

Salek et al., 2002

Review of effects of disease and drugs on DHEA

Allolio and Arlt, 2002

Review of epidemiological and clinical trial research in those with adrenal insufficiency as well as normal older adults

Indication

Reduce consequences of aging

Control

Various

Dose

Product Specification

Clinical Details and Outcomes Measured

Oral doses from 50 to 1600 mg/d

Various

Effects of various drugs and disease states on DHEA; effects of DHEA supplementation on blood DHEA, behavior (mood, depression, cognition), body composition

25, 50, 100 mg/d used in various studies

Various

Hormone concentration, blood lipids, well-being and mood, body composition and performance

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Conclusions/Results

Adverse events profile

Blood DHEA is lower in variety of clinical conditions including anorexia nervosa, renal disease, diabetes, and lupus.

The majority of studies showed an inverse relationship between DHEA/DHEA-S concentrations and cardiovascular disease.

Acute, strenuous exercise increased DHEA in two studies. One study on US Army Rangers during training observed an increase in morning DHEA that was interpreted as response to exercise, sleep, and energy balance stress. Blood DHEA increased from 1.7 to 14 fold depending on oral dose and gender.

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements Some drugs reduced (e.g., dexamethasone, insulin) while others increased (e.g., benfluorex, diltiazem) blood DHEA.

Minimal serious side effects; some include changes in hormone concentrations, increased facial hair, nasal congestion, headache, fatigue, and mild insomnia.

Inconsistent effects were reported on body composition. Some drugs decrease DHEA by inhibiting ACTH (dexamethasone), including P450 (central nervous system agents). Some drugs increase DHEA by inhibiting sulfatase (danazol) or measure clearance rate (insulin). One epidemiological study showed that blood DHEA-S was inversely associated with multivitamin use and positively with retinol supplementation. Increase in testosterone and decrease HDL in women, increase in estrogen in men. Neuronal growth and development affected. Low DHEA in men (no association in women) associated with reduced longevity and higher incidence of cardiovascular disease (unclear whether marker of illness or predictor/ contributor).

Mild and transient side effects: facial acne, increased sebum production; effect on promoting sex hormone-dependent cancer is still “unsettled” and requires more research.

Improved overall well-being, sexual satisfaction, and mood following months of treatment but no effect on cognitive performance Some studies report increase lean body mass and muscle strength but none of the double-blind trials observed these effects. Use in clinical populations with adrenal insufficiency and chronic glucocorticoid treatment may be warranted as well as in individuals with impaired well-being, mood, or sexuality. Not enough evidence to recommend use for reducing normal effects of aging.

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None reported

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TABLE 4-4 Continued Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Bahrke and Yesalis, 2004

Review of anabolic androgenic steroids and related substances

Performance, body composition, and health

Mayer and Forstner, 2004

Review of rodent studies

Liver cancer

0.45–1% of the diet for 52–100 wk depending on study

Brown et al., 2006

Review of several prohormone supplements for athletes

Performance and body composition

Doses up to 1,600 mg/d

Various

Evans et al., 2007

Cochrane Collaboration review of randomized, placebo-controlled trials in people age > 50 y without dementia who received DHEA of any dose for more than 1 d

Effect on cognitive function in elderly

50 mg/d

Various

Raven and Hinson, 2007

Update on review previously performed in 2001. Postmenopausal women

Chronic disease

Placebo

Dose

Product Specification

Liver metabolism, hepatocarcinogenesis, modulation of chemically induced hepatocarcinogenesis

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Clinical Details and Outcomes Measured

Serum hormone concentration, health and performance effects

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Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or other Dietary Supplements

DHEA may have some similar effects on androstenedione reduction in HDL. Speculation on possible effects on premature closure of epiphyseal plates during growth, hypertrophy of areas of the brain related to aggression, and prostate hypertrophy. No evidence of change in liver function markers.

None reported

One trial reported reduced performance in the visual memory recall test with DHEA. No consistent adverse effects, none longer than 3 mo.

None reported

Increase in testosterone or enhance adaptations to resistance training in young men; increases in testosterone and virilizing effects are noted in women. Not of benefit for male athletes and has masculinizing effects in women. Hepatic tumor promotion and inhibition effects depending on dose, rat strain, and duration of ingestion. Liver metabolism increases and becomes catabolic (e.g., reduction of glycogen).

Acute ingestion: Men—Increases serum DHEA, androstenedione, estrogen, but not testosterone. Women—Increases DHEA, androstenedione, testosterone. Chronic ingestion: Men—Dose-dependent increases in DHEA, androstenedione with no change in testosterone. Studies in young novice or older experienced weight lifters report no benefit on fat loss, muscle gain, or muscle function. Women—Increases serum testosterone, acne, facial hair, insulin resistance. Few studies evaluated effects on muscle size and strength concurrent with resistance training. Conclusion: No benefit of DHEA supplements for athletes No evidence of improvement in memory or other aspects of cognitive function in nondemented older people.

Supplementation is not recommended for majority of postmenopausal women. Only exceptions could be those with the lowest endogenous DHEA or those with low bone mineral density.

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TABLE 4-4 Continued Review/Clinical Trial Reference

Type of Study and Subjects

indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Morales et al., 1998

Double-blind, randomized, crossover n=9 males, 10 females

Aging-related reduction in muscle strength and hormones

Placebo for 6 mo

100 mg/d for 6 mo

Diosynth Corporation, Chicago IL. Purity confirmed with HPLC

Body composition (DEXA), serum hormones, muscle strength

Baulieu et al., 2000

Double-blind, randomized n=280 healthy males and females, age 60– 79 y

Reduce consequences of aging

Placebo for 12 mo

50 mg/d for 12 mo

Prasterone

Blood hormones, bone mineral density and turnover markers, libido parameters, skin integrity

Percheron et al., 2003

Double-blind, randomized n=280 healthy males and females, age 60– 80 y

Muscle function change during aging

Placebo for 12 mo

50 mg/d for 12 mo

Akzo Laboratories (Diosynth, France)

Muscle strength and cross-sectional area and serum DHEA

Missmer et al., 2004

Case-control nested within Nurses’ Health Study n=322 females who developed breast cancer

None reported

None reported

None reported

Blood samples collected 8–9 years prior to development of breast cancer. Measured for concentration of endogenous sex hormones and stratified into quartiles.

Villareal and Holloszy, 2004

Double-blind, randomized n=52 elderly males and females, age 65–78 y

Abdominal fat and insulin action

Placebo

50 mg/d for 6 mo

ScheringPlough (Munich, Germany)

MRI for visceral and subcutaneous abdominal fat, glucose and insulin response to oral glucose tolerance test

Kaaks et al., 2005a

Case-control nested within the European Prospective Investigation into Cancer and Nutrition cohort n=370 premenopausal females who developed breast cancer

Endogenous hormones and breast cancer risk in premenopausal women

726 cancerfree matched controls

None reported

None reported

Blood concentrations of endogenous sex hormones

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Conclusions/Results

Adverse events Profile

Both genders: Increased serum DHEA to young adult range Women: Increase in body weight by 1.4 kg, increased testosterone to concentrations greater than normal range Men: Elevation of serum IGF-1,b reduction in body fat mass of 1.0 kg, increase in muscle strength DHEA improved body composition.

None reported

Interactions with Pharmaceuticals, Foods, or other Dietary Supplements None reported

Small increase in estrogen and testosterone (particularly in women), reduced bone turnover and increased libido, improved skin integrity in women over 70 y, reduced some effects of aging on bone, skin, and libido.

None reported

None reported

Serum DHEA restored to ranges for young adults (increase of >200%) but no effect on muscle strength or cross sectional area No benefits found.

None reported

None reported

High DHEA was associated with higher risk of developing hormonesensitive breast cancer

Risk of breast cancer

Relative risk for those in highest DHEA quartile was 2.3 compared to those in lowest quartile.

More reduction in visceral and subcutaneous fat area, and insulin area under the curve compared with placebo. Glucose area under the curve was unchanged. Could play a role in reducing abdominal fat and improving insulin sensitivity in aged individuals.

None reported

Highest quartile of blood DHEA had relative risk of 1.48 for breast cancer compared to those at lowest quartile.

Risk of breast cancer

b

Insulin-like growth factor

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None reported

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TABLE 4-4

Continued

Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Kaaks et al., 2005b

Case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort n=677 postmenopausal females who developed breast cancer

Endogenous hormones and breast cancer risk in postmenopausal women

1,309 cancerfree matched controls

None reported

None reported

Blood concentrations of endogenous sex hormones

Nair et al., 2006

Double-blind, randomized n=87 males, 57 females, age > 60 y

Prevention of age-related disabilities

Placebo

Men: 75 mg/d Women: 50 mg/d, placebo, or testosterone patch 2 y treatment

Confirmed to be 95.5% pure upon analysis

Physical performance, body composition, bone mineral density, glucose tolerance, quality of life (Health Status Questionnaire), prostate imaging for size and PSA test

Muller et al., 2006

Double-blind, randomized n=100 males, age > 70 y

Prevention of frailty in elderly men

Placebo

50 mg/d DHEA (other arms included atamestane, atamestane and DHEA, or placebo)

Schering AG provided the tablets

Grip strength, leg extensor power

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Conclusions/Results

Adverse Events Profile

Highest quintile of blood DHEA had relative risk of 1.69 for breast cancer compared to those at lowest quintile.

Risk of breast cancer

DHEA: Men—Increase in plasma DHEA and slight but significant increase in bone mineral density (femoral neck), but no effect on body composition, peak oxygen consumption (aerobic fitness), muscle strength, insulin sensitivity, or adverse events. Women—Modest increase in plasma testosterone and increase in DHEA, slight increase in bone mineral density at ultradistal radius. No improvement in muscle strength, aerobic fitness, quality-of-life indicators, or major adverse events. Testosterone and DHEA: Reduction in HDL, slight (< 0.5kg) but significant increase in fat-free mass No evidence of benefit for physical performance. The modest effect on bone mineral density in one location for each gender is less than that for other pharmacological interventions, so is of limited value.

No effect on prostate size or blood PSA, liver function markers, electrolytes, or hemoglobin.

No effects of any treatment on any variable No support for use of DHEA to reduce frailty in elderly men.

None reported

Interactions with Pharmaceuticals, Foods, or other Dietary Supplements None reported

None reported

It was noted that 2 years of testing may not be sufficient to detect effects on prostate.

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REFERENCES Allolio, B., and W. Arlt. 2002. DHEA treatment: Myth or reality? Trends Endo Metab 13(7):288294. Bahrke, M. S., and C. E. Yesalis. 2004. Abuse of anabolic androgenic steroids and related substances in sport and exercise. Curr Opin Pharmacol 4:614-620. Baulieu, E. E., G. Thomas, S. Legrain, N. Lahlou, M. Roger, B. Debuire, V. Faucounau, L. Girard, M. P. Hervy, F. Latour, M. C. Leaud, A. Mokrane, H. Pitti-Ferrandi, C. Trivalle, O. de Acharriere, S. Nouveau, B. Rakoto-Arison, J. C. Souberbielle, J. Raison, Y. Le Bouc, A. Raynaud, X. Girerd, and F. Forette. 2000. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge study to a sociobiomedical issue. Proc Natl Acad Sci 97(8):4279-4284. Brown, G. A., M. Vukovich, and D. S. King. 2006. Testosterone prohormone supplements. Med Sci Sports Exerc 38(8):1451-1461. Evans, G. J., R. Malouf, F. Huppert, and J. K. van Niekerk. 2007. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people (review). Cochrane Database Syst Rev 4:CD006221. Handelsman, D. J. 2005. Editorial: Andro and the prosteroids: Bolting the stable door. J Clin Endocrinol Metab 90(2):1249-1251. Kaaks, R., F. Berrino, T. Key, S. Rinaldi, L. Dossus, C. Biessy, G. Secreto, P. Amiano, S. Bingham, H. Boeing, H. B. Bueno de Mesquita, J. Chang-Claude, F. Clavel-Chapelon, A. Fournier, C. H. van Gils, C. A. Gonzalez, A. B. Gurrea, E. Critselis, K. T. Khaw, V. Krogh, P. H. Lahmann, G. Nagel, A. Olsen, N. C. Onland-Moret, K. Overvad, D. Palli, S. Panico, P. Peeters, J. R. Quiros, A. Roddam, A. Thiebaut, A. Tjonneland, M. D. Chirlaque, A. Trichopoulou, D. Trichopoulos, R. Tumino, P. Vineis, T. Norat, P. Ferrari, N. Slimani, and E. Riboli. 2005a. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 97(10):755-765. Kaaks, R., S. Rinaldi, T. J. Key, F. Berrino, P. H. M. Peeters, C. Biessy, L. Dossus, A. Lukanova, S. Bingham, K.-T. Khaw, N. E. Allen, H. B. Bueno-de-Mesquita, C. H. van Gils, D. Grobbee, H. Boeing, P. H. Lahmann, G. Nagel, J. Chang-Claude, F. Clavel-Chapelon, A. Fournier, A. Thiébaut, C. A. González, J. R. Quirós, M.-J. Tormo, E. Ardanaz, P. Amiano, V. Krogh, V. Palli, S. Panico, R. Tumino, P. Vineis, A. Trichopoulou, V. Kalapothaki, D. Trichopoulos, P. Ferrari, T. Norat, R. Saracci, and E. Riboli. 2005b. Postmenopausal serum androgens, oestrogens and breast cancer risk: The European Prospective Investigation into Cancer and Nutrition. Endocr Relat Cancer 12(4):1071-1082. Kroboth, P. D., F. S. Salek, A. L. Pittenger, T. J. Fabian, and R. F. Frye. 1999. DHEA and DHEA-S: A review. J Clin Pharmacol 39(4):327-348. Mayer, D., and K. Forstner. 2004. Impact of dehydroepiandrosterone on hapatocarcinogenesis in the rat (review). Int J Oncol 25:1021-1030. Missmer, S. A., A. H. Eliassen, R. L. Barbieri, and S. E. Hankinson. 2004. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 96(24):1856-1865. Morales, A. J., R. H. Haubricht, J. Y. Hwang, H. Asakura, and S. S. Yen. 1998. The effect of six months with a 100 mg daily dose of dehydroenpiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and woman. Clin Endo 49(4):421-432.

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Muller, M., A. W. van den Beld, Y. T. van der Schouw, D. E. Grobbee, and S. W. J. Lamberts. 2006. Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men. J Clin Endocrinol Metab 91(10):3988-3991. Nair, K. S., R. A. Rizza, P. O'Brien, K. Dhatariya, K. R. Short, A. Nehra, J. L. Vittone, G. G. Klee, A. Basu, R. Basu, C. Cobelli, G. Toffolo, C. Dalla Man, D. J. Tindall, L. J. III, G. E. Smith, S. Khosla, and M. D. Jensen. 2006. DHEA in elderly women and DHEA or testosterone in elderly men. New Eng J Med 355(16):1647-1659. Percheron, G., J. Hogrel, S. Denot-Ledunois, G. Fayet, F. Forette, E. Baulieu, M. Fardeau, and J. Marini. 2003. Effect of 1-year oral administration of dehydroepiandrosterone to 60- to 80year-old individuals on muscle function and cross-sectional area. Arch Intern Med 163(6):720-727. Raven, P. W., and J. P. Hinson. 2007. Dehydroepiandrosterone (DHEA) and the menopause: An update. Menopause Int 13(2):75-78. Salek, F. S., K. L. Bigos, and P. D. Broboth. 2002. The influence of hormones and pharmaceutical agents on DHEA and DHEA-S concentrations: A review of clinical studies. J Clin Pharmacol 42(3):247-266. Villareal, D. T., and J. O. Holloszy. 2004. Effect of DHEA on abdominal fat and insulin action in elderly women and men: A randomized controlled trial. JAMA 292(18):2243-2248.

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EPHEDRA Background *

The genus Ephedra is composed of 40 different species all belonging to the family Ephedraceae (Andraws et al., 2005; Mahady et al., 1999). The correct scientific name for the most commonly used form of Ephedra is Ephedra sinica Stapf; however, other ephedrinecontaining species of the same genus are also used. While there are no botanical synonyms used for this plant, there are numerous vernacular (common) names used worldwide for Ephedra (for a listing, see Mahady et al., 1999). Ephedra sinica is a small, green, almost leafless shrub native to many parts of the world. Ephedra species are found in China, India, Mongolia, and Afghanistan, as well as regions of the Mediterranean and North and Central America (Mahady et al., 1999). Ephedra herb has a pinelike odor and an astringent taste, often having a numbing action on the tongue (Blumenthal and King, 1995). The traditional Chinese name by which it is commonly known, ma huang, is thought to refer to the astringent action (ma) and the yellow color (huang) of the twigs (Tyler et al., 1988). In traditional Chinese medicine, Ephedra-containing preparations have been used for 5,000 years for the treatment of colds, influenzas, fever, headache, bronchial asthma, nasal congestion, coughs, and wheezing (Blumenthal et al., 1995; Mahady et al., 2001). In Western medicine, some of the alkaloids in Ephedra, such as ephedrine and pseudoephedrine, are employed as drug therapy for the treatment of bronchial asthma, nasal congestion, acute bronchospasm, and idiopathic orthostatic hypertension (Mahady et al., 2001). In the United States, the Food and Drug Administration (FDA) has approved several alkaloids in Ephedra as ingredients in overthe-counter nasal decongestants and bronchodilator drugs. Pseudoephedrine is approved as an oral decongestant for the symptomatic treatment of the common cold, hay fever, allergic rhinitis, upper respiratory allergies, and sinusitis. Ephedrine has been approved as topical therapy only for the treatment of nasal congestion and asthma (Blumenthal et al., 1995). The plant and its alkaloids are also used for modern purposes that include weight loss and enhancement of athletic performance; however, the usefulness of Ephedra for these indications remains to be proven. Standardized extracts and other commercial products of Ephedra are prepared from the dried stem or aerial part of Ephedra sinica Stapf and other ephedrine-containing species of the same genus. The chemical constituents of Ephedra include (-)-ephedrine in concentrations of 40–90 percent of the total alkaloid fraction, accompanied by (+)-pseudoephedrine. Other compounds in the alkaloid complex include trace amounts of (-)-norephedrine, (+)-norpseudoephedrine, (-)methylephedrine and (+)-methylpseudoephedrine. Although the total alkaloid content can exceed 2 percent depending on the species, not all Ephedra species contain ephedrine or alkaloids (Mahady et al., 1999). The daily dose of Ephedra-containing products varies depending on the concentration of ephedrine in the preparation: for crude plant material, 1–6 g daily, generally given as a decoction; for liquid extract (1:1 in 45 percent alcohol), 1–3 ml daily; for tincture (1:4 in 45 percent alcohol), 6–8 ml daily (Mahady et al., 1999). *

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. PREPUBLICATION COPY: UNCORRECTED PROOFS 4-56

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Putative Benefits Ephedrine acts as a stimulant in the central nervous system (ODS, 2007). Of the Ephedra alkaloids, ephedrine is the most potent thermogenic agent. It may function as an anorectic by acting on the satiety center in the hypothalamus. A review of all of the clinical trials for Ephedra is beyond the scope of this work, and only clinical trials or case reports involving weight loss and athletic performance were assessed. Limited data from a meta-analysis of the clinical trials for Ephedra-containing supplements showed an increase in weight loss of 0.6 to 0.8 kg per month as compared with placebo. Ephedra taken in combination with caffeine resulted in a weight loss of 1.0 kg/month when compared with placebo, observed for only a 6-month period (Keisler and Hosey, 2005). No long-term data exist. The majority of the studies published in the literature show no effect on athletic performance (Keisler and Hosey, 2005). Clinical trials have assessed the effects of ephedrine hydrochloride (HCl) (the synthetic drug form of ephedrine) and other Ephedra alkaloids such as pseudoephedrine in combination with caffeine. In various exercise modalities, ephedrine and related alkaloids have not been shown to result in any significant performance improvements (Magkos and Kavouras, 2004). The committee identified and reviewed various studies in which the effects of use of Ephedra–caffeine combinations on either performance (Bell et al., 2001; Jacobs et al., 2003), weight loss (Boozer et al., 2002; Coffey et al., 2004; Hackman et al., 2006), or adverse events (Haller et al., 2005; Kalman et al., 2002; Vukovich et al., 2005) were investigated (see Table 45). Caffeine–ephedrine mixtures have been reported to provide a greater ergogenic benefit than either drug alone. However, the published scientific data are too heterogeneous to allow conclusions to be drawn. An increase in athletic performance is a uniform finding observed during submaximal steady-state aerobic exercise, short- and long-distance running, and maximal and supramaximal anaerobic cycling, as well as weight lifting. The ingestion of ephedrine in combination with caffeine increases blood glucose and lactate concentrations during exercise, whereas similar qualitative effects on lipid fuels (free fatty acids and glycerol) are less pronounced. In parallel, epinephrine and dopamine concentrations are significantly increased, while the effects on norepinephrine are not significant. No physiologically significant effects on pulmonary gas exchange were observed during short-term intense exercise following the ingestion of caffeine, ephedrine, or a combination of the two. However, tests during longer and/or more demanding efforts have shown some sporadic enhancements. An increase in heart rate, exceeding that caused by exercise alone, is a relatively consistent concomitant effect of the caffeine-ephedrine mixture. Finally, evidence to date strongly suggests that the combination of caffeine and synthetic ephedrine HCl may be effective in decreasing the rating of perceived exertion; this appears to be independent of the type of activity being performed (Magkos and Kavouras, 2004). Safety Concerns Haller and Benowitz (2000) reviewed 140 case reports of adverse events associated with the use of dietary supplements that were reported to FDA from 1997–1999. Of these reports, 43 cases (31 percent) were considered definitely or probably associated with the use of Ephedra alkaloids (“ephedra”), and another 44 cases (31 percent) possibly related. Of events related to ephedra, 47 percent involved cardiovascular symptoms and 18 percent were central nervous system events. Hypertension was the adverse effect most frequently reported (17 reports), PREPUBLICATION COPY: UNCORRECTED PROOFS

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followed by palpitations, tachycardia, or both (13 reports); stroke (10 reports); and seizures (7 reports). There were 10 events resulting in death, and 13 resulted in permanent disability. Sixtythree percent of ephedra users were under the age of 45 years (Haller and Benowitz, 2000). Use of ephedra-containing supplements is associated with both ischemic and hemorrhagic stroke, cardiac arrhythmias including ventricular tachycardia, coronary vasospasm, acute myocardial infarction, tachycardia-induced cardiomyopathy, and sudden death (Dhar et al., 2005). Increased coronary vasoconstriction, tachycardia, and hypertension reported associated with use of ephedra may be due to induction of myocardial ischemia and infarction. Hemorrhagic stroke is likely secondary to hypertension or cerebral vasculitis (Dhar et al., 2005). Other adverse events such as hearing loss (Schweinfurth and Pribitkin, 2003), psychosis (Jacobs and Hirsch, 2000), rhabdomyolysis (Moawad et al., 2006; Stahl et al., 2006), seizures (Haller et al., 2005), and visual disturbances (Moawad et al., 2006; Simsek et al., 2006) have also been reported. Products containing Ephedra and ephedra alkaloids are contraindicated in patients with coronory thrombosis, diabetes, glaucoma, coronary heart disease, hypertension, thyroid disease, impaired circulation to the cerebrum, pheochromocytoma, or enlargement of the prostate (Mahady et al., 1999). In 2004, because of concerns over cardiovascular effects including increased blood pressure and irregular heart rhythm, FDA banned the sale of dietary supplements containing “ephedra” (ephedrine alkaloids; for simplicity, products containing ephedrine alkaloids will be referred to as “ephedra”). The final FDA rule, published February 6, 2004, became effective on April 12, 2004, and has remained unchanged in spite of attempts by industry to have this ruling overturned (Rados, 2004). Interactions with Other Dietary Supplements or Medications Ephedrine (ephedrine sulfate) is both an D- and E-adrenergic agonist, and also acts as an indirect sympathomimetic drug by enhancing the release of norepinephrine from sympathetic neurons. Indirect sympathomimetic agents given in combination with monoamine oxidase inhibitors (MAOIs) may induce severe hypertension, hyperpyrexia, seizures, arrhythmias, and possibly death (Hansten and Horn, 2000). Ephedra in combination with cardiac glycosides or halothane (anesthesia) may cause heart rhythm disturbances; with guanethidine, it may enhance the sympathomimetic effect; with ergot alkaloid derivatives or oxytocin, it may increase the risk of high blood pressure (Mahady et al., 1999). Considerations Specific to the Military Owing to the strong impetus in the military to maintain prescribed weight and enhance physical performance, past studies reported that the use of ephedra-containing products was high (Brasfield, 2004; Deuster et al., 2003). Although the use of ephedra is currently banned in the United States, the availability of botanicals that are chemically similar to ephedra and might mimic its effects raises safety concerns. The likelihood of adverse events resulting from the misuse of over-the-counter medications containing ephedra might be small, but continues to be of concern. While the effects of ephedra on alertness, physical activity, and caloric intake may be beneficial, the ingestion of products containing ephedra alkaloids is more likely to have negative effects on hydration, thermal regulation, gastrointestinal tract function, kidney stone

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development, liver function, mood, and recovery from injury, and be dangerous to cardiovascular health. Relevant data and conclusions on efficacy and safety reviews and publications identified for ephedra are shown in Table 4-5.

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TABLE 4-5 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Ephedra Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Andraws et al., 2005

Review of clinical trials

Weight loss and athletic performance and cardiovascular risk

Placebo

Doses of ephedrine and related compounds ranged from 60 to 150 mg/d.

Various

Efficacy and safety of ephedra and ephedrine for the treatment of obesity

Boozer et al., 2002

Randomized, double-blind

Weight loss

Placebo

Ephedra 90 mg/day, caffeine 192 mg/day, for 6 mo

None reported

Changes in blood pressure, heart function, body weight, body composition, and metabolic changes.

Weight loss

Placebo

Ephedra product containing 125 mg ma huang (10 mg ephedra at 8%), 250 mg kola nut (60 mg caffeine at 25%), 100 mg white willow bark (15 mg salicin at 15%), 12 wk

None reported

Weight, percent body fat, fat mass, waist circumference, BMI, blood pressure, and pulse measured at 2 days, 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks postrandomization.

n=167 BMI† = 31.8+/4.1 kg/m2

Coffey et al., 2004

Double-blind, randomized, multicenter n=102, age 18–65 y, with 30
†

Body mass index

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Conclusions/Results

Adverse Events Profile

Studies to date have examined small cohorts for relatively short periods of time (usually d 6 months), and have high attrition rates, and most studies have looked at ephedrine in combination with caffeine and, in several cases, aspirin.

Modest incidence of cardiovascular side effects, including mild and transient increases in systolic and diastolic blood pressure, heart rate, and palpitations.

Weight loss due to these products, while statistically significant, may not be clinically relevant (1 kg) with anywhere from a 2- to 4fold increase in side effects compared to placebo. Body weight, body fat, and LDL cholesterol decreased significantly. Increased HDL cholesterol. Small changes in blood pressure variables (+3 to -5 mm Hg), and increased heart rate (4+/-9 vs. -3+/-9 bpm). No increase in cardiac arrhythmias. By self-report, dry mouth, heartburn, and insomnia were increased in the treatment group; the placebo group reported more diarrhea.

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Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

No major adverse cardiovascular events (i.e., stroke, myocardial infarction, or malignant arrhythmias) Adverse event profiles may be different in cohorts with preexisting cardiovascular disease. Reports of irritability, nausea, chest pain, and palpitations did not differ, nor did numbers of subjects who withdrew.

None reported

None reported

None reported

Herbal ephedra/caffeine supplements promoted reduction in body weight and body fat and improved blood lipids without significant adverse events. Additional weight loss (average = 1.5 kg) and greater reductions in BMI and waist circumference in treatment group but may not be clinically significant. No differences observed in percent body fat, fat mass, diastolic or systolic blood pressure, pulse, the occurrence of any adverse event. Testing of the study product by two independent laboratories indicated that it only had approximately half the amount of ephedrine alkaloids and caffeine indicated on the label.

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TABLE 4-5 Continued Review/Clinical Type of Study Indication Trial Reference and Subjects Hackman et al., 2006

Double-blind, randomized

Weight loss

Control

Dose

Product Specification

Outcomes Measured

Placebo

Ephedra/caffeine

Mixture providing 40 mg/day ephedra alkaloids, 100 mg/day caffeine, high-potency mixture of vitamins, minerals, omega-3 fatty acids)

Changes in body weight, body composition, lipids, insulin, leptin, adiponectin, ghrelin, and self-reports of physical activity, diet, and quality-of-life indexes as well as blood pressure, heart rate, electrocardiograms, urinalysis, blood histology, serum chemistry measures, and self-reported symptoms

n=61 healthy premenopausal females, BMI 27–39 kg/ m2

9 mo study

Keisler and Hosey, 2005

Review

Weight loss and athletic performance

Placebo

Various

Various

Athletic performance

Shekelle et al., 2003

Meta-analysis

Weight loss and athletic performance and safety analysis

Placebo/ none

10–20 mg/d low dose, 40–90 mg/d middle dose, 100–150 mg/d high dose Up to 6 mo

Various

Weight loss, heart palpitations, and psychiatric, autonomic, or gastrointestinal symptoms

52 randomized clinical trials 65 case reports

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Conclusions/Results

Adverse Events Profile

The treatment group lost significantly more body weight (7.18 kg) and body fat (-5.33 kg) than the control group (-2.25 and -0.99 kg, respectively), and showed significant declines in serum cholesterol, triglycerides, cholesterol to high-density lipoprotein ratio, glucose, fasting insulin, and leptin.

Dry mouth, insomnia, nervousness, and palpitations

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Blood pressure, electrocardiograms, other clinical chemistry measures, blood histology, urinalysis, and self-reported physical activity were similar in both groups. The treatment group reported more energy and decreased appetite compared with placebo and scored higher on a quality-of-life domain assessing vitality. Low dose (40 mg/d) of ephedra alkaloids plus caffeine appeared safe and effective in causing loss of weight and body fat and improving several metabolic parameters, including insulin sensitivity and lipid profiles, when tested under physician supervision. Ephedra use showed a 0.6 to 0.8 kg per month weight loss compared to placebo.

Myocardial infarction reported in 2 male athletes aged 16–19 y.

Caffeine plus ephedra resulted in a 1.0 kg/mo weight loss compared to placebo, reported only over a 6-mo period. No long-term data exist.

Cardiac arrhythmias, hemorrhagic stroke, and seizures have been reported in young athletes.

The majority of the studies published in the literature show no effect on athletic performance.

Development of psychotic symptoms including decreased sleep, increased agitation, hostility, paranoid delusions, and auditory hallucinations in men aged 19–33 y. Kidney stones have also been reported.

Pooled results for trials with ephedrine (n = 5), ephedrine and caffeine (n = 12), ephedra (n = 1), and ephedra and herbs containing caffeine (n = 4) yielded estimates of weight loss of 0.6, 1.0, 0.8, and 1.0 kg/mo, respectively, greater than placebo.

Psychiatric disturbances, autonomic and gastrointestinal symptoms, and heart palpitations

No trials of ephedra and athletic performance were found; 7 trials of ephedrine were too heterogeneous to analyze.

Data are insufficient to draw conclusions about adverse events occurring at a rate less than 1.0 per thousand.

Ephedrine and ephedra promote modest short-term weight loss (approximately 0.9 kg/mo more than placebo) in clinical trials. No data regarding long-term weight loss and insufficient evidence to support use of ephedra for athletic performance.

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None reported

None reported

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TABLE 4-5 Continued Review/Clinical Type of Indication Trial Reference Study and Subjects Bell et al., 2001 Randomized, Athletic double-blind performance n=24 healthy, untrained males

Control

Dose

Product Specification

Outcomes Measured

Placebo = Metamucil (bulk forming laxative)

Caffeine (5 mg/kg body weight and ephedrine (1.0 mg/kg body weight)

None reported

The trials (3-, 5-, 10-min exercise) commenced 1.5 h treatment or placebo. Anaerobic power and ATP production from anaerobic metabolism ([MAOD‡). Measurement of blood lactate, glucose, and catecholamines (postdrug ingestion just before exercise and 3-, 5-, and 10-min post exercise).

Bell et al., 2002

Jacobs et al., 2003

Controlled n=12

Double-blind

Athletic performance

Athletic performance

n=13 healthy males

Placebo (P) = 300 mg Metamucil (bulk forming laxative)

Caffeine (C) (4 mg/kg body weight and ephedrine (E) (0.8 mg/kg body weight)

None reported

Placebo = 300 mg Metamucil (bulkforming laxative)

Caffeine (4 mg/kg body weight and ephedrine HCl (0.8 mg/kg body weight)

Anhydrous caffeine (Sandoz Canada) and ephedrine hydrochloride (Roberts Pharmaceutica l Canada)

VO2,§ VCO2,** VE,†† heart rate, and ratings of perceived exertion measured during the run. Blood lactate, glucose, and catecholamines.

‡

Maximal accumulated oxygen deficit Oxygen uptake ** Rate of elimination of carbon dioxide †† Pulmonary ventilation during exercise §

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Muscular endurance,

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Conclusions/Results

Adverse Events Profile

Ephedrine increased power output during the early phase of the Wingate test.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Caffeine increased time to exhaustion and O2 deficit during the MAOD test. Caffeine, ephedrine, and a combination increased blood lactate, glucose, and catecholamine levels. Improvement in anaerobic exercise performance may be caused by stimulation of the central nervous system (CNS) by ephedrine and stimulation of skeletal muscle by caffeine. The outcomes and conclusions of this study were challenged by Goldberg et al., 2002, in a letter to the Editor-in-Chief, owing to clinical significance and statistical methods used to analyze the data. Run times in minutes were 46.0 for C, 45.5 for E, 45.7 for C&E, and 46.8 for P . The run times for the E trials (E and C&E) were significantly reduced compared with the non-E trials (C and P). Pace was increased for the E trials compared with the non-E trials over the last 5 km of the run.

None reported

None reported

The E trials (E and C&E) produced significantly faster run times and rate of perceived effort), a reduction of 1.75% than the non-E trials (C and P). VO2 was not affected by drug ingestion. Heart rate was elevated for the ephedrine trials (E and C&E). Caffeine increased the epinephrine and norepinephrine response associated with exercise and also increased blood lactate, glucose, and glycerol levels. Ephedrine reduced the epinephrine response but increased dopamine and free fatty acid levels. The additive nature of E and C was not evident, with the primary ergogenic effect being attributed to E. Ephedrine trials (C&E and E), indicated a transient but significant increase in the mean number of repetitions completed for both the leg-press and benchpress exercises compared with the non-ephedrine trials (C and P), but only during the first SS.

High blood pressure

Total weight lifted during all three sets was greater for the trials involving ephedrine ingestion. Systolic blood pressure was significantly increased with both ephedrine treatment trials when compared with the other trials (C&E = 156 mm Hg; E = 150 mm Hg; C = 141 mm Hg; P = 138 mm Hg. Acute ingestion of E or C&E increases muscular endurance during the first set of traditional resistance-training exercise. The performance enhancement was attributed primarily to the effects of E; there was no additive effect of caffeine.

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None reported

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TABLE 4-5 Continued Review/Clinical Type of Indication Trial Reference Study and Subjects Magkos and Review Athletic Kavouras, 2004 performance

Control

Treatment Dose

Specification

Outcomes Measured

Placebo

Various

Caffeine plus ephedrine

Performance enhancement and metabolic parameters

Various

Various

Various

Weight loss, performance enhancements, and potential health risks

Abourashed et al., 2003

Review of adverse events

Bent et al., 2003

Review of case series and case reports

None

Various

Various

The relative risk and 95% confidence interval (CI) for experiencing an adverse reaction after ephedra use compared with other herbs: This risk was defined as the ratio of adverse reactions to ephedra versus other products, divided by the ratio of their relative use in the United States.

Dhar et al., 2005

Review of adverse events

Various

Various

Various

Cardiovascular adverse events related to ephedra use

Weight loss, performance enhancements

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Conclusions/Results

Adverse Events Profile

Mixtures of caffeine and ephedrine HCl have been reported to confer a greater ergogenic benefit than either drug used alone. Data on increased performance are limited but consistent during submaximal steady-state aerobic exercise, short- and long-distance running, maximal and supramaximal anaerobic cycling, and weight lifting. Blood glucose and lactate concentrations were increased during exercise with ingestion of caffeine and ephedrine in combination; similar effects on lipid fuels (free fatty acids and glycerol) are less pronounced. Concentrations of epinephrine and dopamine are significantly increased though the effects on norepinephrine are less clear. No physiologically significant effects have been reported on pulmonary gas exchange during short-term intense exercise following ingestion of caffeine, ephedrine or their combination; during longer and/or more demanding efforts, some sporadic enhancements have been shown.

Increase in heart rate.

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Of the 140 adverse events submitted to the FDA for dietary supplements between 1997 and 1999, 31% were probably related to ephedra and 31% were deemed possibly related.

Various

None reported

Although products containing ephedra accounted for only 0.82% of sales of herbal products in the United States, they were associated with 64% of all adverse event reports for such products.

Various

None reported

Ephedra use is associated with ischemic and hemorrhagic stroke, cardiac arrhythmias including ventricular tachycardia, coronary vasospasm, acute myocardial infarction, tachycardia-induced cardiomyopathy, and sudden death. Increased coronary vasoconstriction, tachycardia, and hypertension due to ephedra may be the mechanism of induced myocardial ischemia and infarction. Hemorrhagic stroke is likely secondary to hypertension or cerebral vasculitis.

None reported

Despite the type of activity being performed, caffeine and ephedrine combined are quite effective in decreasing the rating of perceived exertion.

The relative risks for an adverse reaction in persons using ephedra were extremely high compared with other herbs, ranging from 100 for kava to 720 for Ginkgo biloba. Use of ephedra is associated with a risk for adverse reactions that is greatly increased compared with other herbal products, and its use should be restricted.

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TABLE 4-5 Continued Review/Clinical Type of Indication Trial Reference Study and Subjects Haller et al., Review of 65 2005 cases (4 MedWatch reports from 1993 to 1999)

Control

Treatment Dose

Specification

Outcomes Measured

None

Various

Ephedra/ caffeine

Probability of causation based on temporal relationship, biological plausibility, and underlying risk factors in supplement-associated seizure cases. Characterization of the patterns of use and types of supplements involved in cases of seizures Identification of trends that may explain potential risks factors for dietary supplement-related seizures

Kalman et al., 2002

Doubleblind, randomized n=27, healthy overweight adults (age 21–60 y)

Maglione et al., 2005

Review

Placebo

Ephedra 335 mg, guarana 910 mg, bitter orange 85 mg, for 14 d

Xenadrine

Systolic and diastolic blood pressure, heart rate, serial electrocardiograms, and Doppler echocardiograms

Various

Various

Serious psychiatric events: psychosis, mania or severe agitation, severe depression, hallucinations, delusions, suicide attempts, paranoia, or violent behaviour

Ma huang, ephedra, ephedrinetype alkaloids, ephedrine, and dietary supplements (doses not reported)

None reported

Weight loss, athletic performance, efficacy, safety

n=1,800 adverse events (from MedWatch reports through September, 2001) Miller, 2004

Review

Weight loss and athletic performances

Various

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4-69

Conclusions/Results

Adverse events profile

Of the 65 cases, 20 seizures were judged to be probably related, 13 possibly related, and 10 unrelated to use of dietary supplements; 5 cases were not seizures, and 17 cases contained insufficient information. In the 20 probably related cases, 19 involved ephedra, 14 involved herbal caffeine, and in 1 case, the supplement contained an array of elemental salts but no herbal constituents. Ephedra was also associated with 7 of the 13 possibly related cases, and caffeine was contained in 5 of these supplement products. Weight loss (45%) and athletic performance enhancement (30%) were the most often cited reasons for supplement use. Ephedra was implicated in 27 of 33 dietary supplementation-associated seizures reported to the FDA over a 7year period.

None reported

No cardiovascular side effects observed.

Interactions with pharmaceuticals, foods, or other dietary supplements None reported

None reported

No significant effects observed in heart rate, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, heart valve function, or in cardiovascular physiology within the parameters measured compared to placebo. Of the almost 1,800 adverse events, 57 were classified as serious psychiatric events. Patients with preexisting psychological/psychiatric conditions and/or use of other moodaltering medications or illicit substances were involved in 2/3 of these psychiatric cases. There was insufficient documentation for the majority of case reports to make an informed judgment about a relationship between the specific adverse event and the use of ephedra. No definitive causal link could be drawn between ephedra and psychiatric complications from the case reports evaluated.

Psychosis

None reported

Few studies support the efficacy or safety of these supplements. Weight loss and athletic performance appear to be only modestly improved, for short durations, in the setting of large numbers of (sometimes serious) adverse event reports.

Seizures, myocarditis, myocardial infarction

None reported

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TABLE 4-5 Continued Review/Clinical Type of Indication Trial Reference Study and Subjects Vukovich et al., Double2005 blind, randomized, crossover

Control

Treatment Dose

Specification

Outcomes Measured

Placebo

20 mg ephedra alkaloids and 150 mg caffeine

Ephedra extract plus caffeine

REE‡‡ Heart rate and blood pressure Blood glucose, caffeine, ephedrine, and free fatty

n= 8 healthy subjects (4 males, 4 females), mean age 23.4± 0.8 y and 22.5± 3.1% body fat

Boerth and Caley, 2003

Case report n=1 female, age 21 y

None

Two supplements containing ephedra

Not specified.

Medical history

Charatan, 2003

Case report n=1, healthy overweight male athlete, age 23 y

None

Ephedra (20 mg ephedrine) 3/day

Xenadrine RFA1

Organ failure

Chen-Scarabelli et al., 2005

Case report n=1 female, age 45 y

None

Ephedra plus other herbs

Xenadrin

Tissue analysis

Chen et al., 2004

Case report n=5 (2 male, 3 female), age 19–45 y

None

Ephedra plus other herbs

Ripped Fuel, Metabolife 356, ma huang, Hydroxycut

Patient-reported symptoms (dizziness, headache, right- or left-side weakness, aphasia and/or slurred speech), MRI§§

‡‡ §§

Resting energy expenditure Magnetic resonance imaging

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Conclusions/Results

Adverse Events Profile

After 3 h, heart rate was 22.7% higher than baseline for the caffeine/ ephedra group compared with 8.9% higher for the placebo group. At 3 h, systolic blood pressure was 9.1% higher than baseline for the caffeine/ephedra trial compared with a difference from baseline of only 1.9% for the placebo trial. There was no effect of the caffeine and ephedra combination on diastolic blood pressure. During the last 30 min, REE was 4.5% higher in the placebo trial and 10.7% higher in the caffeine/ephedra trial; REE was 8.5 % higher in the caffeine/ephedra trial compared with the placebo trial. Free fatty acids increased over time in both the placebo and caffeine/ephedra trials (from 0.5 to 0.63 mEq/L and from 0.48 to 0.8 mEq/L, respectively).

Increases in heart rate, blood pressure

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Conclusion: Caffeine and ephedra, at doses of 150 mg and 20 mg (ephedrine) respectively, result in a significant elevation in REE, heart rate, and blood pressure. Although significant, the increase in energy expenditure is negligible in terms of weight loss. The patient’s medical history was significant for familial bipolar disease. She remained hospitalized for 2 weeks and was treated for acute psychotic disorder; she was discharged with a diagnosis of schizoaffective disorder, bipolar type.

Potential minor role in exacerbating the mania

None reported

Patient died suddenly of heatstroke that resulted in multiorgan failure following a training workout after taking Xenadrine RFA1 for weight loss.

Sudden death due to heatstroke causing multiple organ failure

None reported

Patient died of cardiovascular collapse after taking Xenadrin in combination with aspirin, Nicotrol, and Prozac.

Cardiovascular collapse

Case confounded by concomitant ingestion of aspirin, Prozac, and Nicotrol, and possible marijuana use

Ischemic stroke

Multiple herbal and caffeine use

Tissue analysis revealed nonspecific degenerative alterations in the myocardium such as lipofuscin accumulation, caspase activation, and cleavage of myofibrillary proteins. MRI scans showed single or multiple areas of infarction. Ephedra-containing products appear to have predisposed these five patients to both ischemic and hemorrhagic strokes.

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TABLE 4-5 Continued Review/Clinical Type of Indication Trial Reference Study and Subjects Haller and Review Benowitz, 2000 n=140 case reports (from adverse events reported to FDA from 1997-1999)

Control

Treatment Dose

Specification

Various

Various

Shape-Fast Plus, Ripped Force, Ripped Fuel, Herbalife’s Thermojetics, Metabolife 356, OmniTrim Extra VitaminFortified tea, Ultimate Orange, Purple Blast, Diet Fuel, Fit America Natural Weight Control Aid, PerForm Dieter’s Natural tea, Diet-Phen, Ultimate Nutrition Product Ma Huang, Magic Herb

Outcomes Measured

Haller et al., 2005

Review n=65 case reports (adverse events reported to FDA from 1993–1999)

None

Various

Formula 1, Amp II Pro Drops, Herbalife Thermojetics, Thermochrome 500, Shape–Fast, Power Trim, Metabolift, Victory Turbo Pump

Hypoglycemia, secondary stroke, cardiac arrest, seizure

Jacobs and Hirsch, 2000

Case report n=2 males, age 27 and 20 years

None

Ephedra plus other herbs, creatine, DHEA, ginseng

None reported

Mood, psychosis, agitation

Jordan et al., 2004

Case reports n=13 subjects with impaired baroflex function due to autonomic failure

None

Pseudoephe drine or phenylpropa nolamine (12.5 to 25 mg)

None reported

Systolic blood pressure

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Conclusions/Results

Adverse events profile

Use of ephedra alkaloids was considered definitely or probably associated with 31% of cases, and another 31% possibly related. Of the events related to ephedra, 47% were cardiovascular and 18% central nervous system events. Hypertension was the most frequent adverse event (17 reports); followed by palpitations, tachycardia, or both (13); stroke (10); and seizures (7). There were 10 events resulting in death, and 13 resulted in permanent disability; 63% of patients were under the age of 45 years.

Cardiovascular events, hypertension, seizures

Interactions with pharmaceuticals, foods, or other dietary supplements None reported

Serious events occurred in persons taking low doses of ephedra (12–36 mg/day), and 11 events occurred in healthy individuals; most of the cases were in individuals under the age of 45 years

Of the 65 cases, 20 cases of seizures were judged as probably related, 13 as possibly, and 10 as unrelated; 5 cases were not seizures, and 17 cases did not contain enough information to be analyzed. Of the 20 probable cases, 19 were associated with ephedra, and 14 with herbal forms of caffeine. Of the 13 possible cases, ephedra was associated with 7 and caffeine with 5.

Seizures

None reported

A 27-year-old male presented to ER with suicidal ideation and irritable mood. He had a 2-year history of ephedra use. Once he stopped using ephedra, his mood returned to normal. A 20-year-old male presented with acute psychosis and agitation. He was taking ephedra-containing dietary supplements, ginseng, DHEA, and creatine with caffeine.

Psychosis

None reported

Phenylpropanolamine increased systolic blood pressure by 21 mm Hg after 90 minutes. However, when ingested with 16 oz of roomtemperature tap water, phenylpropanolamine increased systolic blood pressure by 82 mm Hg. When taken with 16 oz of water, 30 mg of pseudoephedrine increased systolic blood pressure 52 mm Hg on average and by as much as 88 mm Hg.

Increased blood pressure when taken with 16 oz of water

None reported

Seizures were associated with hypoglycemia in 3 cases, secondary to stroke in 2 cases, and cardiac arrest in 2 cases. Of the 33 cases of probable and possible seizure associated with ephedra use, 18 were in subjects 18–39 years of age.

Ephedra alkaloids increase blood pressure significantly in individuals with impaired baroreflex function. Concomitant ingestion of ephedra alkaloids and water produced a greater increase in blood pressure.

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TABLE 4-5 Continued Review/Clinical Type of Indication Trial Reference Study and Subjects Libman et al., Case report 2005 n=1 male body builder, age 37 y

LoVecchio et al., 2005

Case report n=1 healthy female, age 20 y

Control

Dose

Product Specification

Outcomes Measured

None

Ephedra

Muscletech Hydroxycut used daily for 3 y and nandrolone and stanazol used weekly for 1 y

Cardiac function, visual disturbances

None

Ephedra plus other herbs; Metabolife 356 contains ma huang (labeled 12 mg ephedrine), guarana extract (labeled 40 mg caffeine), chromium picolinate, and various herbal and vitamin ingredients per tablet

Metabolife 356 (Metabolife International Inc, San Diego, California)

Family history, social history, review of systems

Reported ingestion of 4 tablets of Metabolife 356, 30 min prior to episode and 6–15 tablets/d for 3 d prior. Morgenstern et al., 2003

Casecontrolled study of hemorrhagic stroke between 1994 and 1999 n=702, age 18-49 y

None

Ephedra and various other products

Various

Risk of hemorrhagic stroke

Naik and Freudenberger, 2004

Case report n=2 white male body builders, age 19 and 21 y

None

Ephedra plus other herbs, creatine

Stacker III, Ripped Fuel

Coronary artery disease, heart failure, adverse drug reaction (measured by a causality assessment probability scale)

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Conclusions/Results

Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Patient presented with progressive headaches, blurred vision in left visual field, decreased exercise tolerance, and palpitations. ECG showed right atrial fibrillation, MRI scan confirmed a right middle cerebral artery territorial infarction with minor hemorrhagic transformation.

Visual disturbances and cardioembolic stroke. Case confounded by use of anabolic steroids

Patient experiencing symptoms of a transient ischemic attack (numbness to her left face, arm, and leg that began 1 hr before arrival, mild headache, and nausea). She denied any other similar episodes or prior medical problems. Family history, social history, and review of systems were otherwise negative.

Transient ischemic attack

None reported

No association between the use of ephedra-containing products and increased risk for hemorrhagic stroke were observed

None reported

None reported

A 19-year-old white male presented to the ER complaining of exertional shortness of breath and episodic chest pain radiating to the left arm. Left heart catheterization revealed no significant coronary artery disease, a dilated left ventricle, and global hypokinesis. He died 5 weeks later after returning to the hospital with recurring heart failure.

Cardiomyopathy, heart failure, death, and disability due to longterm product use

None reported

The patient’s symptoms resolved within 4 hours and no rechallenge was performed.

A 21-year-old white male presented to the ER with recurrent chest pain and was diagnosed with myopericarditis. An EC showed global hypokinesis with an ejection fraction of 40–50%. He was treated for myopericarditis with standard therapies for heart failure. An adverse drug reaction was possible between cardiomyopathy and ephedra use in these 2 patients.

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TABLE 4-5 Continued Review/Clinical Type of indication Trial Reference Study and Subjects Peters et al., Case reports 2005 n=6 (4 male, 2 female, age 34–51 y)

Control

Dose

Product Specification

Outcomes Measured

None

Ephedra (unspecified )

Not reported

Clinical and echocardiographic data, ejection fraction, New York Heart Association class

Simsek et al., 2006

Case report n=1 male, age 36 y

None

Ephedra plus other herbs, for 10 d

Xenadrine RFA1

Visual disturbances (measured by fundoscopy)

Schweinfurth and Pribitkin, 2003

Case report n=1 female, age 38 y, with no significant medical or medication history

None

Ephedra plus other herbs, dose not stated

Ripped Fuel (Twin Laboratories, Hauppauge, NY)

Hearing loss

Moawad et al., 2006

Case report n=1 healthy male, age 29 y

None

Ephedra plus other herbs, dose not stated

Stacker 3 and Ripped Fuel Extreme

Cardiac function, neurologic function, visual disturbances, liver function, renal function, blood pressure

Rakovec et al., 2006

Case report n=1 healthy female, age 19 y

None

Ephedrine 50 mg once or twice a day for 10 days

None reported

Cardiac function

Taken 4–6 h prior to onset of symptoms

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Conclusions/Results

Adverse events profile

Patients attending an outpatient department with new onset heart failure were noted to have exposure to ephedra. All 6 patients had left ventricular dysfunction at presentation (mean ejection fraction 20 +/5%) and were treated with conventional heart-failure pharmacotherapy. All patients discontinued ephedra use as advised. New York Heart Association class improved from class III in 5 patients (class II in 1 patient) to class I, within a median of 6 months (range 3–96). Ejection fraction improved to a mean of 47 +/- 6%.

Ephedra may be associated with left ventricular systolic dysfunction.

Patient had loss of lower half of visual field of his right eye, and a history of dyslipidemia. Fundoscopy of the right eye showed a branch retinal artery occlusion with cholesterol embolus at the upper nasal margin of the optic disk, diagnosed as ischemic optic neuropathy.

Visual disturbance in patient with dyslipidemia

None reported

Patient had vertigo and sudden hearing loss in her right ear. Corticosteriod treatment failed to improve hearing. The patient was diagnosed with acute cochlear injury due to a drug-mediated vascular injury.

Hearing loss

None reported

Patient presented with generalized tonic-clonic seizure that occurred while playing basketball. He initially complained of the abrupt onset of a severe headache associated with confusion and lethargy. Initial laboratory values and ECG indicated acute myocardial infarction, fulminant liver failure, acute renal failure, rhabdomyolysis, and transient cortical blindness. Radiographic abnormalities and neurologic dysfunction subsequently resolved with correction of his systolic blood pressure. However, a week later he presented again at the ER with hypertensive crisis without an ephedra rechallenge. Hypertensive crisis may not have been related to ephedra.

Potential hypertensive crisis, posterior reversible encephalopathy syndrome, multiple organ failure

None reported

ECG revealed a typical pattern of idiopathic left-ventricular tachycardia, with an heart rate of 170 beats per minute, narrow QRS complex, right bundle branch block and left axis deviation. Ephedrine alone, or in combination with substances that increase its effects on the cardiovascular system, may also trigger paroxysms of nonischemic ventricular tachycardia. The use of ephedrine carries a risk of development of life-threatening arrhythmias.

Ventricular tachycardia

None reported

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TABLE 4-5 Continued Review/Clinical Type of Study Trial Reference and Subjects Stahl et al., Case report 2006 n=1 male, age 21 y

Indication

Control None

Treatment Dose Ephedrine 20 mg twice daily for 1 mo

Specification

Outcomes Measured

Energel

Muscle function, renal function

Verduin and Labbate, 2002

Case report n=1 male, age 45 y, with schizophrenia, olanzapineinduced obesity and hyperlipidemia

None

Ephedra (12 mg and 40 mg of caffeine) plus other herbs, several ephedra tablets per day for 2 wk

Metabolife

Psychosis, cognition

Walton and Manos, 2003

Case reports n=3 males, age 19, 21, and 33 y

None

Ephedra plus other herbs, dose not stated

Ripped Fuel, Twin labs; Hydroxycut, MuscleTech Research and Development, Inc.; Metabolife

Psychosis, depressive symptoms

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4-79

Conclusions/Results

Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Patient had complete muscle failure after collapsing after a 2-mile run. Patient had tachycardia (heart rate 130+) and was hypotensive. Patient drank very little water over a 2-month period.

Muscle failure likely due to dehydration

Patient was confused and agitated, actively hallucinating and incoherent. After a week of treatment he was able to go back to work.

Case confounded by antipsychotic medications

None reported

Psychosis

None reported

The temporal relationship between initiation of Metabolife and subsequent development of psychosis and delirium strongly suggests that ephedra, was responsible for these symptoms.

A 19-year-old male was referred for psychiatric evaluation due to decreased sleep, increasing aggressive and disorganized behavior, and paranoid delusions. A 21-year-old male experienced a brief psychotic episode after using Hydroxycut for 2 weeks. A 33-year-old male presented with depressive symptoms, suicidal ideation, auditory hallucinations, and paranoid and grandiose delusions. The symptoms in all 3 cases were not abated after discontinuation of the source of ephedra, but did resolve after treatment with antipsychotic drugs, suggesting an underlying pathology.

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Hansten, P. D., and J. R. Horn. 2000. The top 100 drugs interactions: A guide to patient management. Edmonds, WA: H & H Publications. Jacobs, I., H. Pasternak, and D. G. Bell. 2003. Effects of ephedrine, caffeine, and their combination on muscular endurance. Med Sci Sports Exerc 35(6):987-994. Jacobs, K. M., and K. A. Hirsch. 2000. Psychiatric complications of Ma-huang. Psychosomatics 41:5862. Jordan, J., J. R. Shannon, A. Diedrich, B. Black, D. Robertson, and I. Biaggioni. 2004. Water potentiates the pressor effect of ephedra alkaloids. Circulation 109(15):1823-1825. Kalman, D., T. Incledon, I. Gaunaurd, H. Schwartz, and D. Krieger. 2002. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes Relat Metab Disord 26(10):1363-1366. Keisler, B. D., and R. G. Hosey. 2005. Ergogenic aids: An update on ephedra. Curr Sports Med Rep 4(4):231-235. Libman, R. B., B. L. Menna, and S. Gulati. 2005. Case report: Consequences of ephedra use in an athlete. Lancet 366(Suppl 1):S22. LoVecchio, F., B. Sawyers, and P. A. Eckholdt. 2005. Transient ischemic attack associated with Metabolife 356 use. Am J Emerg Med 23(2):199-200. Magkos, F., and S. A. Kavouras. 2004. Caffeine and ephedrine: Physiological, metabolic and performance-enhancing effects. Sports Med 34(13):871-889. Maglione, M., K. Miotto, M. Iguchi, L. Hilton, and P. Shekelle. 2005. Psychiatric symptoms associated with ephedra use. Expert Opin Drug Saf 4(5):879-884. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 1999. Herba Ephedrae. WHO monographs on selected medicinal plants. Volume I. Geneva, Switzerland: World Health Organization. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 2001. Botanical dietary supplements: Quality, safety and efficacy. The Netherlands: Swets and Zeilinger. Miller, S. C. 2004. Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements. Mil Med 169(2):87-93. Moawad, F. J., J. D. Hartzell, T. J. Biega, and C. J. Lettieri. 2006. Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose. South Med J 99(5):511-514. Morgenstern, L. B., C. M. Viscoli, W. N. Kernan, L. M. Brass, J. P. Broderick, E. Feldmann, J. L. Wilterdink, T. Brott, and R. I. Horwitz. 2003. Use of ephedra-containing products and risk for hemorrhagic stroke. Neurology 60(1):132-135. Naik, S. D., and R. S. Freudenberger. 2004. Ephedra-associated cardiomyopathy. Ann Pharmacother 38(3):400-403. ODS (Office of Dietary Supplements). 2003. Ephedra and ephedrine alkaloids for weight loss and athletic performance. http://ods.od.nih.gov/factsheets/ephedraandephedrine.asp (accessed April 17, 2008). Peters, C. M., J. O. O'Neill, J. B. Young, and C. Bott-Silverman. 2005. Is there an association between ephedra and heart failure? A case series. J Card Fail 11(1):9-11. Rados, C. 2004. Ephedra ban: No shortage of reasons. FDA Consum 38(2):6-7. Rakovec, P., M. Kozak, and M. Sebestjen. 2006. Ventricular tachycardia induced by abuse of ephedrine in a young healthy woman. Wien Klin Wochenschr 118(17-18):558-561. Schweinfurth, J., and E. Pribitkin. 2003. Sudden hearing loss associated with ephedra use. Am J Health Syst Pharm 60(4):375-377. Shekelle, P. G., M. L. Hardy, S. C. Morton, M. Maglione, W. A. Mojica, M. J. Suttorp, S. L. Rhodes, L. Jungvig, and J. Gagne. 2003. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: A meta-analysis. JAMA 289(12):1537-1545. Simsek, S., A. Khazen, and P. J. Lansink. 2006. Visual impairment and ephedra. Eur J Intern Med 17(2):147.

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Stahl, C. E., C. V. Borlongan, M. Szerlip, and H. Szerlip. 2006. No pain, no gain—Exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra. Med Sci Monit 12(9):CS81-CS84. Tyler, V. E., L. R. Brady, and J. E. Robbers. 1988. Pharmacognosy, 9th ed. Philadelphia, PA: Lea and Febiger. Verduin, M. L., and L. A. Labbate. 2002. Psychosis and delirium following Metabolife use. Psychopharmacol Bull 36(3):42-45. Vukovich, M. D., R. Schoorman, C. Heilman, P. Jacob III, and N. L. Benowitz. 2005. Caffeine-herbal ephedra combination increases resting energy expenditure, heart rate and blood pressure. Clin Exp Pharmacol Physiol 32(1-2):47-53. Walton, R., and G. H. Manos. 2003. Psychosis related to ephedra-containing herbal supplement use. South Med J 96(7):718-720.

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GARLIC Background *

Garlic is a perennial, erect, bulbous herb, with the bulb giving rise to a number of narrow, keeled, grasslike leaves above the ground (Mahady et al., 1999). Botanical researchers believe that garlic originated in central Asia (Koch and Lawson, 1996; Mahady et al., 1999), but its botanical name, Allium sativum, may have been derived from the Celtic word áll, meaning warm or pungent (Mahady et al., 2001; Srivastava et al., 1995). Botanical synonyms that may appear in the scientific literature include Porvium sativum Rehb. (Mahady et al, 1999). Due to its widespread use throughout the world, there are numerous vernacular (common) names for garlic (for a listing, see Mahady et al., 1999). Currently, garlic is commercially cultivated in Argentina, China, Egypt, France, Hungary, India, Italy, Japan, Mexico, Spain, the United States, and the Czech Republic and Slovakia (Koch and Lawson, 1996; Scientific Technical & Research Commission, 1985). Garlic is one of the earliest documented examples of a food plant that was also used for the prevention and treatment of disease (Mahady et al, 1999; Srivastava et al., 1995). The medical history of garlic dates back approximately 4,000 years, when its medicinal uses were described in Chinese, Indian, and Sumerian literature (Mahady et al., 2001; Srivastava et al., 1995). In 1550 BCE, the importance of garlic in Egyptian medical practice was illustrated in the Codex Ebers, a famous Egyptian papyrus recording over 800 medical formulas. Garlic is contained in 22 of them, for treatment of various ailments including body weakness, headaches, and throat tumors (Srivastava et al., 1995). Cloves of garlic were often found among the ruins of the tombs of Egyptian pharaohs, including Tutankhamen (Mahady et al., 2001). During the first century A.D., the Roman naturalist Pliny the Elder advocated garlic for the treatment of epilepsy, hoarseness, hemorrhoids, and tuberculosis. The Greek physician Dioscorides recommended garlic to clean the arteries, and Hippocrates (460–370 B.C.) prescribed garlic for a wide variety of ailments including infections (Mahady et al., 2001). The therapeutic properties of garlic are also mentioned in the Bible and the Talmud. In medieval Europe, garlic was purported to confer immunity from the bubonic plague, and individual resistance to the plague was often attributed to its consumption (Mahady et al., 2001; Srivastava et al., 1995). Standardized extracts and other commercial products of garlic are prepared from the fresh or dried bulbs of Allium sativum L. (Liliaceae) (European pharmacopoeia, 1996; Mahady et al., 1999; Sendl, 1995). The important chemical constituents of garlic bulbs are organosulfur compounds (Mahady et al, 1999). Approximately 82 percent of the total sulfur content of a garlic bulb is composed of the cysteine sulfoxides (e.g., alliin) and the nonvolatile J-glutamylcysteine peptides. The thiosulfinates (e.g., allicin), ajoenes (e.g., E-ajoene, Z-ajoene), vinyldithiins (e.g., 2-vinyl-(4H)-1,3-dithiin, 3-vinyl-(4H)-1,2-dithiin), and sulfides (e.g., diallyl disulfide, diallyl trisulfide), however, are not naturally occurring compounds. These compounds are degradation products that are produced from the naturally occurring cysteine sulfoxide, alliin. When a garlic bulb is crushed, minced, or otherwise processed, the compartmentalized alliin comes in contact with the enzyme alliinase from the adjacent vacuoles, resulting in hydrolysis and immediate *

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condensation of the reactive intermediate (allylsulfenic acid) to form allicin. Allicin is an unstable compound, and will undergo additional reactions to form other derivatives, depending on environmental or processing conditions (Mahady et al., 1999; Reuter and Sendl, 1994; Sendl, 1995). Analysis of various commercial garlic products shows the variation in sulfur chemical profiles that are reflective of the processing procedure. For example, processed bulb or dried garlic bulb powder products contain mainly alliin and allicin, while the volatile oil contains almost entirely diallyl sulfide, diallyl disulfide, diallyl trisulfide, and diallyl tetrasulfide. Oil macerates, on the other hand, contain mainly 2-vinyl-[4H]-1,3-dithiin; 3-vinyl-[4H]-1,3-dithiin; cis-ajoene; and trans-ajoene (Lawson, 1991; Sendl, 1995; Ziegler and Sticher, 1989). Putative Benefits Modern therapeutic applications for products containing garlic include its use as an adjunct to dietetic management of hyperlipidemia and the prevention of atherosclerotic (age-associated) vascular changes (Mahady et al., 1999). However, results from recent clinical trials that included a low-cholesterol diet for 2 to 4 weeks prior to garlic treatments failed to show any benefits of garlic supplementation when used in conjunction with a cholesterol-lowering diet (Mahady et al., 2001; Pittler and Ernst, 2007). Other reviews of the scientific literature assessing the effectiveness of garlic in reductions in serum cholesterol, low-density lipoproteins oxidation, platelet aggregation, and hypertension show that 44 percent of clinical trials demonstrated a reduction in total cholesterol, with the most profound effect observed in garlic's ability to reduce platelet aggregation. Mixed results have been obtained in the area of blood pressure and oxidative-stress reduction (Ackermann et al., 2001; Rahman and Lowe, 2006). Garlic has been reported to reduce the growth of various antibiotic-resistant microorganisms and reduce the minimum inhibitory concentrations of specific antibiotics in vitro (Cai et al., 2007; Cutler and Wilson, 2004; Tsao and Yin, 2001). Pure compounds from garlic, such as ajoene and allicin, have both antibacterial and antifungal activities in vitro, in vivo, and in human studies; however, these results need to be repeated in controlled clinical trials. One 12-week double-blind clinical trial involving 146 subjects treated daily with garlic or placebo showed a reduction in the symptoms of the common cold and a reduction in the duration of illness in those receiving garlic compared to those receiving placebo (Pittler and Ernst, 2007). Other medical uses claimed for garlic include treatment of asthma, bronchitis, dyspepsia, fever, lower urinary tract infections, ringworm, and rheumatism; however, there are no clinical data to support these claims (Mahady et al., 1999). Safety Concerns Garlic has been reported to reduce the activity of the cytochrome P450 enzyme isomer CYP2E1, thus affecting liver function and health (Hu et al., 2005). Consumption of large doses of garlic-containing dietary supplements may increase the risk of postoperative bleeding (Mahady et al., 1999). Use of supplements containing garlic is contraindicated in patients with a known allergy to garlic, and there is often a cross-sensitivity to onions and tulips (Mahady et al., 1999). Interactions with Other Dietary Supplements or Medications The level of safety for garlic is reflected by its worldwide use as a seasoning in food. However, in therapeutic doses, garlic may cause postoperative bleeding, especially when used in

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combination with anticoagulants such as warfarin. Two case reports suggest that the combination of warfarin and garlic products may increase clotting time and potentially cause postoperative bleeding (Mahady et al., 1999). Therefore, daily use of garlic-containing dietary supplements with concurrent administration of anticoagulants and antiplatelet drugs is not recommended. The possible interaction of garlic with chlorpropamide resulting in hypoglycemia has been reported. Daily administration of garlic-containing supplements has been reported to reduce the plasma concentrations of protease inhibitors, reducing their efficacy and increasing the potential for serious gastrointestinal adverse events. Considerations Specific to the Military The use of supplements containing garlic would likely have no impact on high-intensity physical activity, caloric restriction, hydration, mood, alertness, or ability to function at high altitude or in extreme temperatures. However, garlic supplementation has been reported to cause gastric upset including heartburn, nausea, vomiting, and diarrhea (Mahady et al., 1999). Because of the increased risk of bleeding, especially when taken concurrently with anticoagulants, the use of garlic as a dietary supplement might expose military subpopulations to unnecessary risks when they are in combat situations. Garlic-containing supplements should be discontinued 2 weeks prior to any surgical procedures or combat deployment. Relevant data and conclusions on efficacy and safety reviews and publications identified for garlic are shown in Table 4-6.

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TABLE 4-6 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Garlic Review/Clinical Trial Reference Ankri and Mirelman, 1999

Type of Study and Sample Size Review of in vitro and animal studies

Ledezma and Apitz-Castro, 2006

Review of in vitro and human studies

Antifungal and antiinflammatory

Terbinafine

Topical applications of ajoene for 7–15 d

Pure ajoene extracted from garlic

Martin and Ernst, 2003

Review 1 trial

Anti-Helicobacter pylori activity

None

Raw garlic

Raw garlic cloves

Rahman and Lowe, 2006

Review n=25 clinical studies

Cardiovascular disease

Matching placebo for some studies

None reported

Raw garlic, garlic powder tablets, garlic oil, aged garlic extract (20% ethanol)

Ackermann et al., 2001

Review n=45 randomized trials and 73 additional studies reporting adverse events

Cardiovascular disease

Placebo

Raw garlic, garlic powder tablets, garlic oil, aged garlic extract (20% ethanol)

None reported

Pittler and Ernst, 2007

Double-blind, randomized n=146

Relief of common cold

Placebo-

None reported

Garlic (unspecified), daily for 12 wk

Indication

Control

Dose

Product Specification

Antimicrobial

None

None reported

Pure allicin isolated from garlic bulbs

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Outcomes Measured

Conclusions/Results

Adverse Events Profile

Antibacterial, antifungal and antiparasitic activities

The pure compound, allicin, inhibits the growth of a wide range of gram-negative and gram-positive bacteria, including multidrug-resistant enterotoxigenic strains of Escherichia coli. Allicin has shown antifungal activity against Candida albicans and antiparasitic activity against some major human intestinal protozoan parasites such as Entamoeba histolytica and Giardia lamblia. It has also has antiviral activity.

None reported

Reduction in tinea pedis infections

Treatment produced a clinical cure in 79% of patients treated, with no recurrence 90 days after treatment.

None reported

None reported

Reduction in Helicobacter pylori load and urease activity

A study of garlic to treat Helicobacter pylori infections reported no significant effect on Helicobacter pylori load.

None reported Poor methodology

None reported

Reductions in serum cholesterol, platelet aggregation, blood pressure

A reduction in total cholesterol was indicated in 44% of clinical trials; the most profound effect was observed in garlic's ability to reduce platelet aggregation. Mixed results have been obtained for blood pressure and oxidative-stress reduction

None reported

None reported

Reductions in serum cholesterol, LDL, platelet aggregation, blood pressure, thiglycerides levels

Small reductions in the total cholesterol level at 1 month (range of average pooled reductions, 0.03–0.45 mmol/L [1.2–17.3 mg/dL]) and at 3 months (range of average pooled reductions 0.32–0.66 mmol/L [12.4–25.4 mg/dL]), but not at 6 months. Changes in low-density lipoprotein (LDL) and triglyceride levels paralleled total cholesterol level results; No statistically significant changes in high-density lipoprotein (HDL) levels Significant reductions in platelet aggregation and mixed effects on blood pressure outcomes.

Skin adverse effects: Dermatitis

Reductions in serum cholesterol, LDL, platelet aggregation, blood pressure, thiglycerides levels

Allergic reactions: asthma, rhinitis Cardiovascular dysfunction: myocardial infarction Coagulation dysfunction: bleeding, epidural hematoma, increased international normalized ratio in persons taking warfarin, Gastrointestinal tract dysfunction: smallintestine obstruction, esophageal and abdominal pain, and flatulence.

Duration of the common cold

Significantly fewer colds as well as a shorter duration of symptoms compared to placebo.

None reported

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Interactions with Pharmaceuticals, Foods or other Dietary Supplements One study showed synergistic effects with antibiotics.

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TABLE 4-6 Adverse Events Review/Clinical Trial Reference

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Continued Type of Study and Sample Size Review of 3 meta-analysis of various effects in randomized controlled clinical trials, double-blind

Indication

Control

Dose

Product Specification

Hypercholesterolemia

Placebo

None reported

Garlic (unspecified)

Sengupta et al., 2004

Review of epidemiological studies

Reduced cancer risk

None reported

None reported

None reported

Milner, 2006

Review

Reduced cancer risk

None reported

Various

Various

Pittler and Ernst, 2007

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Outcomes Measured

Conclusions/Results

Adverse Events Profile

Reduction in cholesterol levels

Modest reduction of 15.7 mg/dL compared to placebo over a treatment period of 8–24 weeks.

None reported

Interactions with Pharmaceuticals, Foods or Other Dietary Supplements None reported

In an updated meta-analysis (n=971), including 3 additional trials, the effect was diminished to 13.6 mg/dL. In four new double-blind RCTs (n=3670), no changes were reported in lipid levels for hypercholesterolemic patients. Cancer risk reduction

Higher intake of Allium vegetables is associated with reduced risk of several types of cancers. These epidemiological findings correlate well with laboratory findings. Proposed mechanisms include inhibition of mutagenesis, modulation of enzyme activities, inhibition of DNA adduct formation, freeradical scavenging, and effects on cell proliferation and tumor growth.

None reported

None reported

Cancer risk reduction

Evidence indicates the anticancer properties of fresh garlic extracts, aged garlic, garlic oil, and a number of specific organosulfur compounds generated by processing garlic. These anticarcinogenic and antitumorigenic activities arise through both dose- and temporal-related changes in a number of cellular events involved in the cancer process, including those involving drug metabolism, immune competence, cell-cycle regulation, apoptosis, and angiogenesis. The ability of garlic and related allyl sulfur compounds to block growth of tumors in the colon, lung, breast, and liver suggests general mechanisms that are not tissue specific.

None reported

None reported

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TABLE 4-6 Continued Review/Clinical Trial Reference Hu et al., 2005

Type of Study and Sample Size Review of drug interactions

Indication

Control

Dose

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Product Specification

Garlic extract containing 600 ȝg of allicin per 600 mg extract; garlic oil; aged garlic extract

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Outcomes Measured

Conclusions/Results

Adverse Events Profile

Activity of review of published drug interactions with garlic products

Dextromethorphan and Alprazolam: Administration of 1800 mg of garlic extract twice a day (3 x 600 mg tablets) for 14 days increased the ratio of dextromethorphan to its metabolite; did not alter pharmacokinetics significantly.

Severe gastrointestinal toxicity developed in two HIV-infected patients taking garlic supplements for more than 2 weeks after beginning ritonavir (400 or 600 mg twice daily) therapy. The symptoms resolved after discontinuation of therapy. The symptoms reappeared after rechallenge with garlic, even at a low ritonavir dose of 100 mg twice daily.

Chlorzoxazone: Oral administration of garlic oil to healthy volunteers for 28 days reduced CYP2E1 activity. No alterations were observed with midazolam. Protease inhibitors: Saquinavir—In 10 healthy volunteers, 3-week administration of caplets containing 3.6 mg garlic powder extract twice daily decreased the plasma area under the curve by 51%, plasma concentrations by 49%, and C(max) by 54% of the protease inhibitor. These parameters did not return to baseline values after 10 days of washout. Ritonavir (400 mg single dose)— Administration of two capsules (10 mg Natural Source odorless garlic extract) for 4 days to 10 healthy volunteers did not significantly decrease the area under the curve of the protease inhibitor. Warfarin: Two case reports suggest that the combination of warfarin and garlic products may increase clotting time and potentially cause postoperative bleeding. Chlorpropamide: Possible interaction, causing hypoglycemia Acetaminophen: Administration of aged garlic extract (~6–7 cloves of garlic) for 3 months to 16 healthy volunteers did not alter its metabolism.

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Interactions with Pharmaceuticals, Foods or Other Dietary Supplements Dextromethorphan Saquinavir Warfarin Chlorpropamide

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REFERENCES Ackermann, R. T., C. D. Mulrow, G. Ramirez, C. D. Gardner, L. Morbidoni, and V. A. Lawrence. 2001. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med 161(6):813824. Ankri, S., and D. Mirelman. 1999. Antimicrobial properties of allicin from garlic. Microbes Infect 1(2):125-129. Cai, Y., R. Wang, F. Pei, and B. B. Liang. 2007. Antibacterial activity of allicin alone and in combination with beta-lactams against Staphylococcus spp. and Pseudomonas aeruginosa. J Antibiot (Tokyo) 60(5):335-338. Cutler, R. R., and P. Wilson. 2004. Antibacterial activity of a new, stable, aqueous extract of allicin against methicillin-resistant Staphylococcus aureus. Br J Biomed Sci 61(2):71-74. European pharmacopoeia. 1996. 3rd ed. Strasbourg: Council of Europe. Hu, Z., X. X. Yang, P. C. L. Ho, S. Y. Chan, P. W. S. Heng, E. Chan, W. Duan, H. L. Koh, and S. F. Zhou. 2005. Herb-drug interactions. Drugs 65(9):1239-1282. Koch, H. P., and L. D. Lawson. 1996. Garlic, the science and therapeutic application of Allium sativum L. and related species, 2nd ed. Baltimore: Williams & Wilkins. Lawson, L. 1991. HPLC analysis of allicin and other thiosulfinates in garlic clove homogenates. Planta Medica 57:263-270. Ledezma, E., and R. Apitz-Castro. 2006. Ajoene the main active compound of garlic (Allium sativum): A new antifungal agent. Rev Iberoam Micol 23(2):75-80. Mahady, G. B., H. H. S. Fong, and N. F. Farnsworth. 1999. Bulbus Allii sativi. WHO monographs on selected medicinal plants. Vol. 1. Geneva, Switzerland: World Health Organization. Mahady, G. B., H. H. S. Fong, and N. F. Farnsworth. 2001. Botanical dietary supplements: Quality, safety and efficacy. Lisse, the Netherlands: Swets & Zeitlinger Publishers. Martin, K. W., and E. Ernst. 2003. Herbal medicines for treatment of bacterial infections: A review of controlled clinical trials. J Antimicrob Chemother 51(2):241-246. Milner, J. 2006. Preclinical perspectives on garlic and cancer. J Nutr 136(3):827S-831S. Pittler, M. H., and E. Ernst. 2007. Clinical effectiveness of garlic (Allium sativum). Mol Nutr Food Res 51:1382-1385. Rahman, K., and G. M. Lowe. 2006. Garlic and cardiovascular disease: A critical review. J Nutr 136(3):736S-740S. Reuter, H. D., and A. Sendl. 1994. Allium sativum and Allium ursinum: Chemistry, pharmacology, and medicinal applications. In Economic and medicinal plants research. Vol. 6, edited by H. Wagner and N. R. Farnsworth. London: Academic Press. Pp. 55-113. Scientific Technical and Research Commission. 1985. African pharmacopoeia, 1st ed, Vol. 1. Lagos, Nigeria: Organization of African Unity. Sendl, A. 1995. Allium sativum and Allium ursinum: Part 1. Chemistry, analysis, history, botany. Phytomedicine 4:323-339. Sengupta, A., S. Ghosh, and S. Bhattacharjee. 2004. Allium vegetables in cancer prevention. Asian Pac J Cancer Prev 5(3):237-245. Srivastava, K. C., A. Bordia, and S. K. Verma. 1995. Garlic (Allium sativum) for disease prevention. South African Journal of Science 91:68-77. Tsao, S., and M. Yin. 2001. In vitro activity of garlic oil and four diallyl sulphides against antibioticresistant Pseudomonas aeruginosa and Klebsiella pneumoniae. J Antimicrob Chemother 47(5):665670. Ziegler, S. J., and O. Sticher. 1989. HPLC of S-alk(en)yl-L-cysteine derivatives in garlic including quantitative determination of (+)-S-allyl-L-cysteine sulfoxide (alliin). Planta Medica 55: 372-378.

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GINKGO BILOBA Background *

Ginkgo biloba is a tall, deciduous tree, known to be extremely resistant to insects, bacterial and viral infections, and air pollution (Mahady, 2001, 2002; Major, 1967; Van Beek et al., 1998). The tree is native to China, and the earliest documentation describes the tree as originating in a region south of the Yangtze River (Huh and Staba, 1992). Many specimens of Ginkgo biloba are thought to be over 1,000 years old. Ginkgo biloba was not introduced into Europe and North America until the middle and latter part of the 18th century; it is currently grown as an ornamental shade tree in Europe, Japan, Australia, Southeast Asia, and the United States (Huh and Staba, 1992; Mahady, 2002). It is commercially cultivated in China, France, Korea, and the United States (Mahady, 2002). Medical therapy with ginkgo dates back approximately 5,000 years to the origins of traditional Chinese medicine, when ginkgo was described in ancient Chinese medical texts such as Chen Noung Pen T’sao, Shi Wu Ben Cao, and Ri Yong Ben Cao (Mahady, 2001; 2002). In China, the seeds (nuts) of the ginkgo tree are considered a tonic, and the medicinal uses of ginkgo seeds were reported in the Pen Ts’ao Kang Mu (Great Herbal of 1596) written by Li Shih-Chen (Van Beek et al., 1998). Ginkgo seeds were used for the treatment of alcohol abuse, asthma, bladder inflammation, coughs, and leukorrhoea; in the modern Chinese pharmacopoeia, preparations of the leaves of Ginkgo biloba are official for the treatment of heart and lung diseases (Mahady, 2002; Van Beek et al., 1998). In 1965, the German physician and pharmacist Dr. Willmar Schwabe introduced a standardized Ginkgo biloba leaf extract into Western medical practice (Mahady, 2001). Only a few ginkgo extracts have ever been tested in randomized controlled clinical trials. The most widely investigated ginkgo standardized leaf extract, EGb 761, is manufactured by Dr. Willmar Schwabe BmbH & Company in Karlsruhe, Germany. EGb 761 contains 22–27 percent flavonoid glycosides; 5–7 percent terpene lactones, of which approximately 2.8–3.4 percent consists of ginkgolides A, B, and C, and 2.6–3.2 percent bilobalide; and < 5 ppm of ginkgolic acids (Mahady et al., 1999; Van Beek et al., 1998). Today, EGb 761 is used worldwide for the treatment of memory-related disorders and peripheral arterial occlusive diseases and shows some promise for the treatment and prevention of cardiovascular disease and stroke (Mahady, 2001, 2002). Putative Benefits Results from meta-analysis and reviews of the clinical trials indicate that standardized leaf extracts of Ginkgo biloba may reduce the symptoms of age-associated memory impairment and dementia, including Alzheimer’s disease, and may be of some benefit for the treatment of intermittent claudication (Birks et al., 2002; Mahady, 2001, 2002; Mahady et al., 1999). However, many of the early trials used poor methodology and small sample size, and publication bias could not be excluded. The evidence that ginkgo *

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has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent; the studies would require adequately designed randomized control trials (Birks and Grimley Evans, 2007). The usefulness of ginkgo for the treatment of tinnitus (i.e., ringing in the ears) is limited and thus far unconvincing (Hilton and Stuart, 2004). Its effectiveness in improving cognitive function in healthy subjects has not been well investigated and is also controversial. Ten randomized, placebo-controlled studies involving approximately 1,077 healthy volunteers have measured the effects of various doses of specific Ginkgo biloba extracts on attention, cognition, executive function, reaction times, and quality of life (Burns et al., 2006; Cieza et al., 2003; Elsabagh et al., 2005; Kennedy et al., 2000; Mattes and Pawlak, 2004; Mix and Crews, 2002; Solomon et al., 2002; Stough et al., 2001; Subhan and Hindmarch, 1984; Warot et al., 1991). The dose of ginkgo extract used ranged from 120 mg/d to 720 mg/d and the length of treatment from a single dose to 4 months. In the most recent study by Burns et al. (2006), no statistically significant difference was found between the group receiving a low dose of ginkgo (120 to 180 mg/d) and that receiving placebo for any of the cognition tests performed in either young (18–43 years old) or older (55–79 years old) healthy volunteers. In the acute dosing studies, administration of a single dose of ginkgo extract (120 to 600 mg/d) improved performance on sustained attention tasks and pattern recognition memory task, while administration of chronic doses to healthy individuals showed no effect (Elsabagh et al., 2005; Kennedy et al., 2000; Subhan and Hindmarch, 1984; Warot et al., 1991). These studies presented limitations such as a small subject numbers, a lack of dose response, and lack of standardized tests. Two larger randomized, placebo-controlled studies assessed the effects of ginkgo in healthy adults over 60 years of age (Mix and Crews, 2002; Solomon et al., 2002). Mix and Crews used a standardized Ginkgo biloba extract at a higher dose, 180 mg/d versus 120 mg/d used in the Solomon et al. (2002) study. Salomon et al., (2002) analysed a modified intent-to-treat population and indicated that there were no significant differences between treatment groups on any outcome measure after chronic administration of ginkgo to healthy subjects. In this study, ginkgo did not enhance performance on standard neuropsychological tests of learning, memory, attention, and concentration or naming and verbal fluency (Solomon et al., 2002). Conversely, the results of the study by Mix and Crews (2002) demonstrated that healthy older participants who received 180 mg of the extract EGb 761 daily for 6 weeks exhibited significant improvement on standard recognition test tasks involving 30 minutes of free recall and recognition (P < .01) of noncontextual, auditory–verbal material, as compared with the placebo controls. By treatment end, the follow-up self-report questionnaire showed that significantly more older adults in the ginkgo group rated their overall abilities to remember as “improved” as compared with the placebo controls. The results of this study, from both objective, standardized, neuropsychological tests and a subjective, follow-up self-report questionnaire, suggest that extract EGb 761 is effective in enhancing certain neuropsychological or memory processes of cognitively intact adults 60 years of age and older (Mix and Crews, 2002). Thus, the results of these two studies are conflicting. These two studies measured different outcomes, supporting the need for further studies with larger populations and standardized methodologies and products.

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In summary, for younger healthy subjects, high acute dosing of ginkgo may enhance mental performance for short periods of time, while chronic dosing does not appear to be effective. In older healthy subjects with no cognitive deficits, the data about beneficial effects on mental performance are still conflicting, with one study showing benefits with the chronic use of a higher dose of ginkgo (180 mg/d) and one study showing that a lower dose (120 mg/d) was not effective. The Chinese Pharmacopoeia includes an official monograph on use of Ginkgo biloba for the treatment of cardiovascular disease (Mahady, 2002). In pilot studies, ginkgo is reported to reduce nanoplaque formation in high-risk cardiovascular patients (Rodriguez et al., 2007) and is used in the treatment of acute ischemic stroke (Liu, 2006; Zeng et al., 2005); however, the data are poor, and large-scale randomized controlled clinical trials are needed before any therapeutic recommendations can be made. Ginkgo has been reported to have a protective effect on liver function in various animal models due to its strong antioxidant and anti-inflammatory effects (Harputlougu et al., 2006; Naik and Panda, 2007; Yuan et al., 2007; Zhou et al., 2007). Ginkgo biloba extracts inhibit the activities of cytochrome P450 (CYP) enzymes CYP1A2, CYP2D6, CYP2E1, or CYP3A4 in elderly subjects (Gurley et al., 2005). Ginkgo extracts have been shown to reduce nephrotoxicity due to hypoxic, cisplatin, adriamcin, and diabetic-induced neuropathy in animal models (Abd-Ellah and Mariee, 2007; Gulec et al., 2006; Welt et al., 2007). In one small Chinese clinical study, ginkgo extract was reported to improve the renal function of patients with nephritic syndrome (Zhong et al., 2007). Safety Concerns A recent review of the clinical data has concluded that use of Ginkgo biloba appears to be safe, with no excess side effects compared with placebo (Birks and Grimley Evans, 2007). However, 15 published case reports described a temporal association between the use of ginkgo and bleeding events (Bent et al., 2005). Most cases involved serious medical conditions, including eight episodes of intracranial bleeding. However, 13 of the case reports identified other risk factors for the increased bleeding, and only six reports clearly stated that when subjects stopped using ginkgo, bleeding did not recur. In three reports, bleeding times were increased when patients were taking ginkgo. The review concluded that a structured assessment of published case reports suggests a possible causal association between the use of ginkgo and bleeding events (Bent et al., 2005). Given these data, it is recommended that products containing Ginkgo biloba not be taken with other prescription medications that may also cause bleeding, such as anticoagulants. Interactions with Other Dietary Supplements or Medications Ginkgo biloba extract has been reported to interact with trazodone, warfarin, acetylsalicyclic acid, ibuprofen, ticlopidine, tolbutamide, and chlorpropamide (see Table 4-7). In addition, Ginkgo biloba extract (120 mg/d) decreased plasma insulin by 26 percent in hyperinsulinemic patients with type 2 diabetes mellitus who were taking antihyperglycemic drugs. Ginkgo may increase the hepatic clearance of insulin and antihyperglycemic drugs.

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Ginkgo biloba extracts inhibit cytochrome P450 (CYP) enzymes CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activities in elderly subjects (Gurley et al., 2005). Because many medications, including antiarrhythmics, antibiotics, calcium channel blockers, corticosteroids, immunosuppressants, HMG-CoA reductase inhibitors, anxiolytics, and some neuropsychiatric medications are metabolized in the liver by the cytochrome P450 enzyme complex, Ginkgo biloba has the potential to negatively affect drug metabolism and produce an adverse reaction. Considerations Specific to the Military High acute dosing of ginkgo may enhance mental performance for short periods of time, while chronic dosing does not appear to be effective. Ginkgo extracts have the potential to relieve symptoms of altitude sickness that might result with high-altitude military activities. The clinical trial methodologies from published studies are poor, however, and data are conflicting. The largest clinical study showed no effect on altitude sickness (Gertsch et al., 2004). The ingestion of ginkgo-containing products has been reported to cause bleeding, particularly when used in combination with aspirin or warfarin. Postoperative bleeding has also been reported. Although a recent review of the clinical data has concluded that Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo (Birks and Grimley Evans, 2007), chronic daily use of Ginkgo biloba extracts, in therapeutic doses, may have the potential to cause serious bleeding events postsurgery and in combat situations. Ginkgo extracts have been reported to cause gastrointestinal tract disturbances such as nausea, vomiting, and diarrhea. Upon initiation of ginkgo therapy, transient headaches have also been reported. These headaches are associated with increased blood circulation to the brain and usually resolve over a week of daily administration of the product. Allergic skin reactions have been reported (Mahady et al., 1999). There is no apparent reason to believe that the physiological effects of Ginkgo biloba will be altered by physical activity, diets with caloric restriction, or inadequate hydration. There is also no scientific evidence that Ginkgo biloba would improve other outcomes that are vital to military performance, such as alertness, immune function, or mood. Relevant data and conclusions on efficacy and safety reviews and publications identified for ginkgo are shown in Table 4-7.

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TABLE 4-7 Relevant data and conclusions on efficacy and safety reviews and publications identified for ginkgo Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Burns et al., 2006

Double-blind n=197 (93 aged 55–79 y and 104 aged 18–43 y)

Cognition, attention, executive function, and mood

Placebo

120 mg/d (40 mg 3x/d) for 12 wk

Ginkgoforte (Blackmores Ltd., Australia)

Cognitive abilities test, chronometric testing (speed of information processing) Subjective well-being (mood)

Carlson et al., 2007

Double-blind, randomized, parallel design n=90

Cognitive function, quality of life, and platelet function

Placebo

160 mg/d (1x/d) for 4 mo

Ginkgo biloba-based product containing 160 mg Ginkgo biloba, 68 mg gotu kola (with caffeine), and 180 mg docosahexaenoic acid

Six standardized cognitive function tests SF-36 Quality of Life questionnaire Platelet function adverse events

Cieza et al., 2003

Double-blind, randomized, parallel-group n=66 healthy adults age 50– 65 y

Mental function and quality of life

Placebo

720 mg/d (240 mg, 3x/d) for 4 wk

Ginkgo biloba special extract EGb 761 (SchwabeGermany)

Primary: subjects' judgment of their own mental health, general health, and quality of life based on three different visual analog scales. Secondary: motor performance and emotional evaluation

Chow et al., 2005

Double-blind, randomized n=57 unacclimatized adults

Highaltitude sickness

Placebo

240 mg/d of Ginkgo biloba for 5 d prior to ascent or acetazolami de

Ginkgo biloba product from NOW foods

AMS† symptoms graded based on the LLS‡: Acute Mountain Sickness scoring system. Incidence of AMS was defined as LLS score > or = 3 and headache.

† ‡

Acute mountain sickness Lake Louis Score

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Conclusions/Results

Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Old adult group: significant trend for improvement of longer-term memory with ginkgo (d = 0.52) No statistically significant difference on any other measure. Young adult group: no statistically significant effects with ginkgo

Headaches, sleep disturbances, gastrointestinal symptoms

One of six cognitive tests indicated significant protocol differences for placebo. No significant differences in quality of life, platelet function, or adverse events. High baseline scores may have contributed to the null findings.

No alterations in platelet function observed.

None reported

Significant improvements of self-estimated mental health, selfestimated quality of life with ginkgo extract. No differences of self-estimated general health

None reported

None reported

None reported

None reported

Better motor performance and emotional evaluation with ginkgo extract Findings do not support the use of a ginkgo-containing supplement for improving cognitive function or quality of life in cognitively intact, older, healthy adults. LLS scores: The median score of the acetazolamide group was significantly lower than that of the placebo group (effect size, 2), unlike that of the Ginkgo biloba group (effect size, 0). AMS frequency: less frequently in the acetazolamide group than in the placebo group (effect size, 30%); similar between the ginkgo group and the placebo group (effect size, -5%). The study concluded that prophylactic acetazolamide therapy decreased the symptoms of AMS and trended toward reducing its incidence. No evidence of similar efficacy for Ginkgo biloba NOW product was found. This study was criticized because of small sample size and that ginkgo was not the primary constituent of the product (Betz and Costello, 2006). The products contain two additional plants, 125 mg Eleutherococcus senticosus (Rupr and Maxim) Maxim and 150 mg of Centella asiatica (L) Urb, and only 120 mg of G. biloba L extract.

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TABLE 4-7

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Continued

Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Cochrane review (Birks et al., 2002)

Review n=33 un-confounded, double-blind, randomized, placebocontrolled studies of patients with dementia or cognitive decline

Benefits for dementia or cognitive decline

Placebo

Various

Various

Cochrane review (Birks and Grimley Evans, 2007)

Review n=35 randomized, double-blind studies. Subjects with acquired cognitive impairment, including dementia, of any degree of severity

Assessment of efficacy on cognition

None reported

Various

Various

Various

Cochrane review (Hilton and Stuart, 2004)

Review n=12 clinical studies

Treatment of tinnitus

None reported

Various

Various

Ten trials were excluded on methodological grounds. No trials reached a satisfactory standard for inclusion in the review.

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Clinical Details and Outcomes Measured

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Conclusions/Results

Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Clinical Global Impression (CGI) scale: Dose less than 200 mg/d showed improvements compared with placebo at less than 12 weeks (54/63 showed significant improvement compared with 20/63). Dose of 200 mg/d showed significant improvements at 24 weeks (57/79 compared with 42/77). Cognition shows significant benefit for ginkgo as compared with placebo at 12, 24, and 52 weeks, ginkgo (greater than 200 mg/d) at 12 weeks, ginkgo (any dose) at 12 weeks. Activities of daily living (ADL) shows significant benefit for ginkgo (dose less than 200 mg/d) as compared with placebo at 12 weeks, at 24 weeks, and at 52 weeks. Measures of mood and emotional function show significant benefit for ginkgo (dose less than 200 mg/d) as compared with placebo at less than 12 weeks and at 12 weeks. The review concludes that Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo, and there is promising evidence of improvement in cognition and function associated with ginkgo. However, the three most recent trials show inconsistent results.

Overall, there are no significant differences between ginkgo and placebo in the proportion of participants experiencing adverse events.

Benefits associated with ginkgo (dose greater than 200 mg/d) at 24 weeks (2 studies), but not for a lower dose. Cognition shows benefit for ginkgo (any dose) at 12 weeks (p=5 studies) but not at 24 weeks. Results of 5 studies assessing activities of daily living (ADLs) showed benefit for ginkgo (dose less than 200 mg/d) compared with placebo at 12 weeks (one study) and at 24 weeks (3 studies), but there are no differences at the higher dose. There are no data available on quality of life, measures of depression, or dependency.

No difference above placebo

None reported

Few side effects

None reported

The evidence that ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing. Limited evidence did not demonstrate that Ginkgo biloba was effective for tinnitus. Ten trials were excluded on methodological grounds. No trials reached a satisfactory standard for inclusion in the review.

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TABLE 4-7 Continued Review/Clinical Trial Reference

Type of Study and Subjects Doubleblind, randomized n=92 students, age 18–26 y

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Attention, memory, executive function, and mood

Placebo

120 mg/d (1x/d) and tested after 4 h (experiment 1) or 6 wk of treatment (experiment 2)

Ginkgo onea-day tablets (Lichtwer Pharma UK, Mere Park, Marlow, Bucks, UK)

Mood rating scales, sustained attention, episodic and working memory Mental flexibility and planning.

Gertsch et al., 2004

Prospective, double blind, randomized n=614 healthy males and females

HAS§

Placebo

120 mg ginkgo, 250 mg acetazolamide, combination of 250 mg acetoazolamide and 120 mg ginkgo, or placebo, 2x/d

Ginkgo biloba extract GK 501, Pharmaton, Switzerland

LLSR** score > or = 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome, incidence of headache, and severity of headache. Measured at the approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m.

Gertsch et al., 2002

Doubleblind, randomized n=26 living at sea level.

AMS††

Placebo

180 mg/d (60 mg 3x/d) for 48 h

Ginkgo biloba extract GK 501 (Memfit, Pharmaton SA, Lugano, Switzerland)

The subjects received ginkgo or placebo starting 24 h before ascending Mauna Kea, Hawaii. Subjects were transported from sea level to the summit (4205 m) over a 3 hour period, including 1 hour at 2835 m. LLSR Questionnaire was used as the primary outcome measure at baseline, 2835 m, and after 4 h at 4205 m. AMS was defined as a LLSR > or = 3 with headache.

Kennedy et al., 2000

Doubleblind, matching n=20, age 19–24 y

Cognitive enhancement

Placebo

120 mg/d, 240 mg/d, and 360 mg/d

GK501 standardized Ginkgo biloba extract (Pharmaton, SA, Lugano Switzerland)

Cognitive performance using the CDR computerized test battery immediately prior to dosing and at 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were: speed of attention, accuracy of attention, speed of memory, quality of memory.

Elsabagh et al., 2005

§

High-altitude sickness Lake Louise self-report †† Acute mountain sickness **

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Conclusions/Results

Adverse Events Profile

Experiment 1: Acute dose of ginkgo significantly improved performance on the sustained-attention task and pattern recognition memory task; however, there were no effects on working memory, planning, mental flexibility, or mood.

None reported

Interactions with Pharmaceuticals, Foods, or other Dietary Supplements None reported

Experiment 2: No significant effects on mood or any of the cognitive tests. Acute administration improved performance in tests of attention and memory. Tolerance to the effects may develop in young, healthy participants. Ginkgo at a dose of 240 mg/d, 3– 4 doses prior to ascent, was not significantly different from placebo for any outcome. Acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide, 35% for ginkgo, and 14% for combined ginkgo and acetazolamide. The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazolamide, 18% for ginkgo, and 7% for combined ginkgo and acetazolamide.

Potential worsening of headaches associated with HAS. (Headaches usually resolve within one week of daily use of the product.)

None reported

Median LLSR at 4205 m was significantly lower for ginkgo versus placebo (4, range 1–8 vs. 5, range 2–9). Ginkgo use did not reach statistical significance for lowering incidence of AMS compared with placebo (ginkgo 7/12, 58.3% vs. placebo 13/14, 92.9%). Twenty-one of 26 (81%) subjects developed AMS overall. The results suggest that pretreatment with ginkgo 60 mg three times daily may significantly reduce the severity of AMS prior to rapid ascent from sea level to 4205 m.

None reported

None reported

Ginkgo produced a number of significant changes in performance measures: Dose-dependent improvement of the speed of attention factor following both 240 mg and 360 mg of the extract, which was evident at 2.5 h and still present at 6 h. Other time- and dose-specific changes (both positive and negative) in performance of the other factors.

None reported

None reported

The authors concluded that Ginkgo biloba is capable of producing a sustained improvement in attention in healthy young volunteers after acute dosing.

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Continued Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Mattes and Pawlak, 2004

Type of Study and Subjects Doubleblind, matched n=39, age 23.6 +/–5.4 y

Assessment of amelioration of the postlunch dip

Placebo

4 mg/kg/d for 13 wk

Ginkgo biloba extract

Alertness Performance Affective state, chemosensory tests at weeks 1, 5, 9 and 13.

Roncin et al., 1996

Randomized n=44

AMS and vasomotor changes

Placebo

160 mg/d for 5d

EGb 761

The primary outcomes assessment was based on the Environmental Symptom Questionnaire score and vasomotor changes measured by photoplethysmography and a specific questionnaire.

Solomon et al., 2002

Doubleblind, randomized, parallelgroup n=230, adults, age >60 y

Improvement of memory

Placebo

40 mg, 3x/d for 6 wk

Ginkoba, Boehringer Ingelheim Pharmaceuticals

Standardized neuropsychological tests of verbal and nonverbal learning and memory, attention and concentration, naming, and expressive language. Self-report on a memory questionnaire Caregiver clinical global impression of change

Mix and Crews, 2002

Doubleblind, randomized, fixed-dose n=262 adults, age >60 y

Assessment of memory improvement in older adults

Placebo

180 mg/d

EGb 761

Change in performance scores on standardized neuropsychological measures (Selective Reminding Test [SRT], Wechsler Adult Intelligence Scale-III Block Design [WAIS-III BD] and Digit Symbol-Coding [WAIS-III DS] subtests, and the Wechsler Memory Scale-III Faces I [WMS-III FI] and Faces II [WMS-III FII] subtests) from pretreatment baseline to just prior to termination of treatment. Follow-up self-report questionnaire just prior to termination of the treatment phase

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Conclusions/Results

Adverse Events Profile

Subjects experienced the postprandial affective state decrement (“postlunch dip”) but no performance decrement. Performance on the chemosensory tests improved over the 13week study for all subjects. Ginkgo biloba was ineffective at alleviating the symptoms of the postlunch dip or enhancing taste and smell function.

None reported

No subject in the EGb 761 group developed AMS-cerebral versus 40.9% of subjects in the placebo group; this difference was very significant Three subjects (13.6%) in the EGb 761 group developed AMSrespiratory versus 18 (81.8%) in the placebo group. Ginkgo also decreased vasomotor disorders of the extremities and improved circulation.

None reported above placebo

None reported

No significant differences between treatment groups on any outcome measure. Ginkgo did not facilitate performance on standard neuropsychological tests of learning, memory, attention, and concentration or naming and verbal fluency in adults aged 60 or older without cognitive impairment. There was also no difference between groups in self-reported memory function or global rating by spouses, friends, and relatives.

None reported

None reported

Significantly more improvement on spatial recognition tasks involving delayed (30 min) free recall and recognition of noncontextual, auditory–verbal material, compared with placebo. Significantly greater improvements in the WMS-III FII subtest assessing delayed (30 min) recognition of visual material (i.e., human faces), compared with placebo. However, the significant difference found between the two groups’ pretreatment baseline scores on the WMS-III FII, suggest this result should be interpreted with caution. Follow-up self-report questionnaire also revealed that significantly more adults in the EGb 761 group rated their overall abilities to remember as improved by treatment end compared with placebo. Overall, the results provided complementary evidence of the potential efficacy of Ginkgo biloba EGb 761 in enhancing certain neuropsychological/memory processes of cognitively intact adults 60 years of age and over.

None reported.

None reported.

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Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

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TABLE 4-7 Continued Review/Clinical Trial Reference Stough et al., 2001

Type of Study and Subjects Double-blind, randomized n=61, age 1840 y

Indication

Control

Dose

Memory and executive processing

Placebo

120 mg/d for 30 d

Subhan and Hindmarch, 1984

Double-blind, randomized, crossover n=8, age 25– 40 y

Central nervous system arousal, psychomotor performance, and shortterm memory

Placebo

120, 240 and 600 mg

Tebonin (Germany) Tanakan (France)

Subjects completed a battery of psychological tests including CFF,‡‡ CRT,§§ subjective ratings of drug effects (LARS), and a Sternberg memory scanning test 1 hour after treatment.

Warot et al., 1991

Double-blind n=12

Assessment of vigilance, memory, reaction times

Placebo

600 mg/d

Objective measures of vigilance (critical flicker frequency [CFF], choice reaction time [CRT]), memory tasks (pictures and Sternberg scanning tests), and self-rating evaluation (visual analogue scales). Test administered pre- and 1 hour postdosing.

Bent et al., 2005

15 case reports between 1966 and 2004

None reported

Various

Tanakan (standardized ginkgo extract, France) and ginkgo extract Various

Hu et al., 2005

Review of case studies and clinical trials

None reported

Various

Various

‡‡ §§

Product Specification EGb 761

Clinical Details and Outcomes Measured A battery of validated neuropsychological tests before and after treatment to measure changes in memory and executive processing

Published case reports of bleeding events in persons using ginkgo were queried from MEDLINE, EMBASE, IBIDS, and the Cochrane Collaboration Database from 1966 to October 2004. Two reviewers independently abstracted a standard set of information to assess whether ginkgo caused the bleeding event. A review of drug interactions with herbal products including ginkgo.

Critical flicker fusion Choice reaction time

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Conclusions/Results

Adverse Events Profile

Significant improvements in speed of information processing, working memory, and executive processing were attributable to the ginkgo extract.

None reported.

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

No statistically significant changes from placebo were observed on CFF, CRT, or LARS. However, memory as assessed using the Sternberg technique was found to be significantly improved following treatment with ginkgo at a dose of 600 mg when compared to placebo, and results suggested a localized effect of the extract on the serial comparison stage of the reaction process. These results suggest a specific effect of the extract on central cognitive processes.

Not reported.

None reported

No statistically significant changes from placebo were observed on CFF, CRT or LARS. No differences between treatment were evident on Sternberg scanning test and pictures recognition. Compared to baseline, free recall score, while decreasing under placebo and ginkgo extract, remained the same under Tanakan, indicating that the Tanakan product improved free recall.

None reported.

None reported

A temporal association between use of ginkgo and a bleeding event was described in the 15 published case reports, with most of the cases involving serious medical conditions (with 8 episodes of intracranial bleeding). Other risk factors for bleeding were identified in 13 of the case reports. Six reports clearly described cessation of ginkgo followed by lack of bleeding recurrence. In three reports, bleeding times were elevated when patients were taking ginkgo. The review concluded that a structured assessment of published case reports suggests a possible causal association between using ginkgo and bleeding events.

Potential bleeding due to chronic administration especially in combination with liver cirrhosis or use of nonsteroidal antiinflammatory drugs or warfarin None reported

None reported

One case report of an interaction with ginkgo and trazodone that resulted in coma. However, this case was confounded due to the numerous other drugs that were being taken by the patient. Interactions with warfarin, ticlopidine, and nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen have been reported. Changes in international normalized ratio (INR) and prolonged bleeding times have resulted when ginkgo was combined with these drugs. In healthy subjects, doses of ginkgo up to 480 mg/d did not alter bleeding times or INR. A small clinical trial demonstrated that administration of ginkgo (280 mg/d) for 14 d significantly decreased the plasma concentrations of omeprazole. A reduction in the efficacy of thiazide diuretics in 1 subject was indicated in 1 case report, and rodent studies have indicated that treatment with ginkgo in combination with diltazem inhibited the metabolism of the drug. Ginkgo did not alter the metabolism of midazolam or donepezil in clinical studies. Ginkgo (120 mg/d) decreased plasma insulin by 26% in hyperinsulinemic patients with type 2 diabetes mellitus taking antihyperglycemic drugs. Ginkgo may increase the hepatic clearance of insulin and antihyperglycemic drugs.

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Trazodone, warfarin, aspirin, ibuprofen, ticlopidine, tolbutamide, chlorpropamide

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Continued Type of Study and Subjects Double-blind n=50 in each group, male, age 20–44 y

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Placebo

Aspirin (ASA) followed by aspirin + EGb 761 or aspirin + EGb 761 followed by aspirin 2x/d for 7 d

EGb 761®

Bleeding time, coagulation parameters and platelet activity in response to various agonists were determined. In addition, adverse events, laboratory variables, and vital signs were measured.

Dose/d: 500 mg aspirin or 500 mg aspirin + 240 mg EGb 761®

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Conclusions/Results

Adverse Events Profile

ASA given alone prolonged bleeding time. ASA and the combination of ASA + EGb 761 exerted similar effects on all coagulation parameters measured: Bleeding time (ASA alone: 4.1 min before therapy, 6.2 min after therapy; ASA + EGb 761: 4.2 min before therapy, 6.3 min after therapy Agonist-induced platelet aggregation (collagen-induced platelet aggregation - ASA: 84.5% before therapy, 81.0% after therapy; ASA + EGb 761®: 86.6% before therapy, 81.0% after therapy; adenosine diphosphate-induced platelet aggregation - ASA: 72.6% before therapy, 47.2% after therapy; aspirin + EGb 761: 71.7% before therapy, 44.8% after therapy; ratio of means).

In each group there was at least one adverse effect consisting mainly of coagulation disorders. The pattern of adverse effects matched the effects of aspirin on coagulation parameters. Mild to moderate gastrointestinal adverse effects were also reported in 12–18% of subjects.

Coadministration of aspirin and EGb 761 does not constitute a safety risk. No additive effect was observed.

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REFERENCES Abd-Ellah, M. F., and A. D. Mariee. 2007. Ginkgo biloba leaf extract (EGb 761) diminishes adriamycininduced hyperlipidaemic nephrotoxicity in rats: Association with nitric oxide production. Biotechnol Appl Biochem 46(Pt 1):35-40. Bent, S., H. Goldberg, A. Padula, and A. L. Avins. 2005. Spontaneous bleeding associated with Ginkgo biloba: A case report and systematic review of the literature. J Gen Intern Med 20(7):657-661. Betz, J., and R. Costello. 2006. Studies on natural products. Arch Intern Med 166(3):370-371. Birks, J., and J. Grimley Evans. 2007. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev (2):CD003120. Birks, J., E. V. Grimley, and M. Van Dongen. 2002. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2(4):CD003120. Burns, N. R., J. Bryan, and T. Nettelbeck. 2006. Ginkgo biloba: No robust effect on cognitive abilities or mood in healthy young or older adults. Hum Psychopharmacol 21(1):27-37. Carlson, J. J., J. W. Farquhar, E. DiNucci, L. Ausserer, J. Zehnder, D. Miller, K. Berra, L. Hagerty, and W. L. Haskell. 2007. Safety and efficacy of a Ginkgo biloba-containing dietary supplement on cognitive function, quality of life, and platelet function in healthy, cognitively intact older adults. J Am Diet Assoc 107(3):422432. Chow, T., V. Browne, H. L. Heileson, D. Wallace, J. Anholm, and S. M. Green. 2005. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: A randomized, placebo-controlled trial. Arch Intern Med 165(3):296-301. Cieza, A., P. Maier, and E. Poppel. 2003. Effects of Ginkgo biloba on mental functioning in healthy volunteers. Arch Med Res 34(5):373-381. Elsabagh, S., D. E. Hartley, O. Ali, E. M. Williamson, and S. E. File. 2005. Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers. Psychopharmacology (Berl) 179(2):437-446. Gertsch, J. H., T. B. Seto, J. Mor, and J. Onopa. 2002. Ginkgo biloba for the prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent. High Alt Med Biol 3(1):29-37. Gertsch, J. H., B. Basnyat, E. W. Johnson, J. Onopa, and P. S. Holck. 2004. Randomised, double blind, placebo controlled comparison of Ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: The prevention of high altitude illness trial (PHAIT). BMJ 328(7443):797-802. Gulec, M., M. Iraz, H. R. Yilmaz, H. Ozyurt, and I. Temel. 2006. The effects of Ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malondialdehyde, and nitric oxide in cisplatininduced nephrotoxicity. Toxicol Ind Health 22(3):125-130. Gurley, B. J., S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry, Y. Cui, and C. Y. Ang. 2005. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging 22(6):525-539. Harputluoglu, M. M., U. Demirel, H. Ciralik, I. Temel, S. Firat, C. Ara, M. Aladag, M. Karincaoglu, and F. Hilmioglu. 2006. Protective effects of Ginkgo biloba on thioacetamide-induced fulminant hepatic failure in rats. Hum Exp Toxicol 25(12):705-713. Hilton, M., and E. Stuart. 2004. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev (2):CD003852. Hu, Z. P., X. X. Yang, P. C. Lui, S. Y. Chan, P. W. Heng, E. Chan, W. Duan, H. L. Koh, and S. F. Zhou. 2005. Herb-drug interactions: A literature review. Drugs 65(9):1239-1282. Huh, H., and E. J. Staba. 1992. The botany and chemistry of Ginkgo biloba L. J Herbs, Spices Med Plants 1:91124. Kennedy, D. O., A. B. Scholey, and K. A. Wesnes. 2000. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology (Berl) 151(4):416-423. Liu, J. 2006. The use of Ginkgo biloba extract in acute ischemic stroke. Explore (NY) 2(3):262-263. Mahady, G. B. 2001. Ginkgo biloba: A review of quality, safety and efficacy. Nutr Clin Care 4(3):140-147.

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Mahady, G. B. 2002. Ginkgo biloba for the prevention and treatment of cardiovascular disease: A review of the literature. J Cardiovasc Nurs 16(4):21-32. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 1999. Folium Ginkgo. WHO Monographs on selected medicinal plants. Vol 1. Geneva, Switzerland: World Health Organization. Major, R. T. 1967. The Ginkgo, the most ancient living tree. Science 157(3794):1270–1273. Mattes, R. D., and M. K. Pawlik. 2004. Effects of Ginkgo biloba on alertness and chemosensory function in healthy adults. Hum Psychopharmacol 19(2):81-90. Mix, J. A., and W. D. Crews Jr. 2002. A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: Neuropsychological findings. Hum Psychopharmacol 17(6):267-277. Naik, S. R., and V. S. Panda. 2007. Antioxidant and hepatoprotective effects of Ginkgo biloba phytosomes in carbon tetrachloride-induced liver injury in rodents. Liver Int 27(3):393-399. Rodriguez, M., L. Ringstad, P. Schafer, S. Just, H. W. Hofer, M. Malmsten, and G. Siegel. 2007. Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients. Atherosclerosis. 192(2):438-444. Roncin, J. P., F. Schwartz, and P. D'Arbigny. 1996. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med 67(5):445-452. Solomon, P. R., F. Adams, A. Silver, J. Zimmer, and R. DeVeaux. 2002. Ginkgo for memory enhancement: A randomized controlled trial. JAMA 288(7):835-840. Stough, C., J. Clarke, J. Lloyd, and P. J. Nathan. 2001. Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol 4(2):131-134. Subhan, Z., and I. Hindmarch. 1984. The psychopharmacological effects of Ginkgo biloba extract in normal healthy volunteers. Int J Clin Pharmacol Res 4(2):89-93. Van Beek, T. A., E. Bombardelli, P. Morazzoni, and F. Peterlongo. 1998. Ginkgo biloba L. Fitoterapia 69(3):195-244. Warot, D., L. Lacomblez, P. Danjou, E. Weiller, C. Payan, and A. J. Puech. 1991. Comparative effects of Ginkgo biloba extracts on psychomotor performances and memory in healthy subjects. Therapie 46(1):3336. Welt, K., J. Weiss, R. Martin, T. Hermsdorf, S. Drews, and G. Fitzl. 2007. Ginkgo biloba extract protects rat kidney from diabetic and hypoxic damage. Phytomedicine 14(2-3):196-203. Wolf, H. R. 2006. Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily? Drugs R D 7(3):163-172. Yuan, G., Z. Gong, J. Li, and X. Li. 2007. Ginkgo biloba extract protects against alcohol-induced liver injury in rats. Phytother Res 21(3):234-238. Zeng, X., M. Liu, Y. Yang, Y. Li, and K. Asplund. 2005. Ginkgo biloba for acute ischaemic stroke. Cochrane Database Syst Rev (4):CD003691. Zhong, Z. M., L. Yu, Z. Y. Weng, Z. H. Hao, L. Zhang, Y. X. Zhang, and W. Q. Dong. 2007. Therapeutic effect of Ginkgo biloba leaf extract on hypercholestrolemia in children with nephrotic syndrome. Nan Fang Yi Ke Da Xue Xue Bao 27(5):682-684. Zhou, J. B., X. K. Yang, Q. F. Ye, Y. Z. Ming, and Z. J. Xia. 2007. Effect of extract of ginkgo biloba leaves on the precondition of liver graft in rat liver transplantation. Zhong Nan Da Xue Xue Bao Yi Xue Ban 32(1):5458.

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PANAX GINSENG Background Some of the most popular and well-known dietary supplements come from a group of plants known generically as ginseng*. The primary commercial species (scientific name, Panax ginseng C.A. Meyer), is commonly referred to as Korean or Asian ginseng. The plant is indigenous to the mountainous regions of Korea, Japan, China (Manchuria), and Russia (eastern Siberia) (Hu, 1976; Mahady et al., 1999). However, most commercial ginseng is now cultivated, as wild Panax ginseng is a protected species in both Russia and China (Carlson, 1986). Commercial products are prepared from cultivated ginseng imported from China and Korea (Hu, 1976; Mahady et al., 1999). In China, the root or rhizome (underground stem) and other parts of the plant have been used medicinally (Hu, 1976). However, the root is certainly the most prominent part and sales of root-derived products dominate the commercial market. The plant is a slow-growing perennial herb, and the roots are usually not harvested until the fifth or sixth year of growth, when the ginsenosides (the active constituents) are at their highest concentration (Hu, 1976; Mahady et al., 2001). After harvesting, Panax ginseng roots are prepared for commercial use by one of two methods to prevent rotting and microbial contamination. Ginseng root prepared by drying and bleaching the roots using sulfur dioxide is called “white ginseng.” The root is also sometimes peeled to remove the outer coating (skin). “Red ginseng” is prepared by steaming the root for 3 hours and then air-drying it. The steamed root turns a caramel color and is resistant to invasion by fungi and pests (Hu, 1976; Mahady et al., 2001; Shibata et al., 1985). The main active chemical constituents of Panax ginseng include the triterpene saponins, known as the ginsenosides (Mahady et al., 1999). More than 30 are based on the dammarane structure, with one, ginsenoside Ro, being an oleanolic acid derivative (Cui, 1995; Mahady et al., 1999; Shibata et al., 1985). The ginsenosides are derivatives of either protopanaxadiol or protopanaxatriol. The most important constituents are the ginsenosides Rb-1, -2, Rc, Rd, Rf, Rg1, and Rg-2 (Mahady et al., 1999, 2001). Putative Benefits While the genus name Panax derives from the Greek word panacea, meaning “cure-all,” its application according to traditional Chinese medicine is actually very specific (Hu, 1976; Mahady et al., 2001; Sonnenborn and Proppert, 1991). Panax ginseng is used to treat older patients with chronic illnesses, especially given during periods of convalescence, to restore the person to a normal state of good health (Hu, 1976; Mahady et al., 2001). Up until 1937, Panax ginseng was an official compendial drug in the United States, listed in the The Dispensatory of the United States of America. The U.S. Food and Drug Administration (FDA) currently regards ginseng as a food and ginseng-containing products as dietary supplements (Mahady et al., 2001). According to the World Health Organization’s (WHO) Monographs on Selected Medicinal Plants, Panax ginseng is used as a tonic or

*

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

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immune stimulant for enhancement of mental and physical capacity during fatigue, chronic illness, and convalescence (Mahady et al., 1999). The hypothesis that Panax ginseng might be used as an ergogenic agent in healthy subjects is a more modern idea; in 2001 and 2003, two small controlled clinical trials investigated the ergogenic effects of standardized Panax ginseng extract G115 in healthy subjects (Engels et al., 2001, 2003). Both studies failed to find ergogenic benefits in the recovery from short, supramaximal exercise or in the Wingate Anaerobic test (an all-out-effort, 30-second leg cycle test). These studies confirm the lack of ergogenic effects for Panax ginseng in healthy subjects seen in previous studies (Lieberman, 2001). Thus, to date, there are no compelling data that suggest that Panax ginseng has any positive effects on physical performance in healthy individuals. One randomized placebo-controlled clinical trial assessed the effects of Panax ginseng extract G115 at a dose of 200 to 400 mg/day on mood and other psychological parameters in 83 young healthy subjects (Cardinal and Engels, 2001). After 8 weeks of treatment, no improvements were observed in any measured parameter, indicating that ginseng has no beneficial effects on mood or memory in young healthy subjects (Cardinal and Engels, 2001). Two smaller clinical studies assessed the cognitive effects of Panax ginseng extract G115 at a dose of 200 mg or 400 mg in 30 or 27 healthy young adults respectively (Reay et al., 2005, 2006). The 2006 study showed that both Panax ginseng or glucose enhanced the performance of a mental arithmetic task and ameliorated the increase in subjective feelings of mental fatigue experienced by participants during the later stages of the sustained, cognitively demanding task performance. No evidence of synergistic effects was observed when glucose and Panax ginseng G115 were administered together (Reay et al., 2006). The 2005 trial showed that improvements in behavioral effects were associated with the oral administration of 200 mg of Panax ginseng G115 extract, and included significant improvements (P < .05) in the Serial Sevens subtraction task performance and a significant reduction in the subjective mental fatigue test throughout all of the postdose completions of the 10-minute battery (with the exception of one time point in each case) (Reay et al., 2005). The study concluded that Panax ginseng may improve performance and subjective feelings of mental fatigue during sustained mental activity and that these effects may be related to the acute gluco-regulatory properties of the extract (Reay et al., 2005). Some of the problems with these investigations include the small sample sizes, lack of dose response, poor methodology, and the short delay between intake and testing, all making the studies difficult to interpret. The effects of a combination of Panax ginseng extract G115 and Ginkgo biloba extracts look more promising in terms of improving mood and memory in healthy subjects. In four randomized placebo-controlled trials, the combination of ginkgo plus Panax ginseng was investigated in one large (n=256) and three small (n=20) clinical studies (Kennedy et al., 2001, 2002; Scholey and Kennedy, 2002; Wesnes et al., 2000). Results from the smaller studies suggest an enhancement in quality of memory and improvements in secondary memory and accuracy as well as improvements in mood in healthy subjects (Kennedy et al., 2001, 2002; Scholey and Kennedy, 2002). However, the quality of these studies is low due to the small number of subjects and poor methods. In the larger study, treatment of healthy volunteers with a combination of ginseng and ginkgo significantly improved the Index of Memory Quality (IMQ) (Wesnes et al., 2000). Improvements averaging 7.5 percent were seen in a number of aspects of memory, including working and long-term memory. These memory enhancements were observed throughout the 12-week dosing period as well as after a 2-week washout

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(Wesnes et al., 2000). Panax ginseng extracts, particularly the water-soluble polysaccharides from these extracts, are reported in animals to have immune-stimulating effects against infections (Lee and Han, 2006; Quan et al., 2007; Song et al., 2003) and radiation damage (Han et al., 2005; Kim et al., 2007). Five clinical trials assessed the effects of ginseng on immune function (reviewed in Kaneko and Nakanishi, 2004; Mahady et al., 2001). The studies in general used poor methods and had few subjects, but showed an increase in immune function via an increase in natural killer cell activity, T cell ratios, phagocytosis by macrophages, and antibody titres when administered in addition to an anti-influenza polyvalent vaccination (Kaneko and Nakanishi 2004; Mahady et al., 2001). Safety Concerns With few exceptions, Panax ginseng appears to be safe if administered in recommended therapeutic doses (Mahady et al., 1999). In a 2-year uncontrolled study involving 133 patients who were taking large doses of ginseng (up to 15 g/d compared to a normal dose of 2 g/d), 14 patients presented with symptoms of hypertension, nervousness, irritability, diarrhea, skin eruptions, and insomnia, which were collectively called ginseng abuse syndrome (GAS) (Coon and Ernst, 2002; Mahady et al., 2001). Critical analysis of this report has shown that there were no controls, nor was there analysis to determine the type of ginseng being ingested or the constituents of the preparation taken. Additionally, the authors of this improperly designed study did not take into account the concomitant ingestion of prescription drugs and/or alcohol by the subjects. In a follow-up study, when the ginseng dose was decreased to 1.7 g/d, the symptoms of GAS were rare, indicating that excessive and uncontrolled intake of ginseng products should be avoided. One case of ginseng-associated cerebral arteritis has been reported in a patient consuming a high dose of a rice-wine extract of ginseng root (approximately 6 g in one dose). Two cases of mydriasis and disturbance in accommodation as well as dizziness have been reported after ingestion of large doses (3–9 g) of an unspecified type of ginseng preparation (Coon and Ernst, 2002; Mahady et al., 2001). Mahady et al., (2001) indicated that ginseng supplementation has also been reported to cause estrogenic-like adverse effects in both pre- and postmenopausal women, including seven cases of mastalgia and one case of vaginal bleeding in a postmenopausal woman. These effects have not been confirmed. Ginseng supplementation was associated with the development of Stevens-Johnson syndrome (SJS) in one patient, but the type of the ginseng was not identified, and the patient had been taking both acetylsalicylic acid and unspecified antibiotics 6 days prior to the development of SJS (Mahady et al., 2001). In one human study, administration of Panax ginseng to elderly subjects was followed by a statistically significant inhibition of cytochrome 2D6; however, the magnitude of the effect (approximately 7 percent) was not clinically relevant (Gurley et al., 2005). Interactions with Other Dietary Supplements or Medications Panax ginseng reduces the blood concentrations of alcohol and warfarin, induces mania when used concomitantly with phenelzine (a monoamine oxidase inhbitor), and may increase the efficacy of influenza vaccination (Hu et al., 2005). While coadministration of ginseng with warfarin did not appear to alter the International Normalized Ratio or platelet aggregation in one clinical trial (Jiang et al., 2004), alterations were observed in another study (Yuan et al.,

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2004). Considering the potential seriousness of this interaction, coadministration of warfarin with products containing Panax ginseng is not recommended. With few exceptions, Panax ginseng appears to be safe if administered in recommended therapeutic doses (Mahady et al., 1999). Considerations Specific to the Military. Although there is no evidence to believe that Panax ginseng would have different effects under the extreme conditions of military operations (e.g., high physical activity, caloric restriction, or high altitude), there are no data available from which to draw conclusions. According to Coon and Ernst (2002), the most commonly experienced adverse events are headache, sleep disorders, and gastrointestinal disorders. Although the consumption of Panax ginseng might not cause dehydration per se, some adverse gastrointestinal effects (e.g., vomiting, diarrhea) might result in dehydration. Panax ginseng has been shown to have vasodilating effects in animal models and in one human study. Administration of Panax ginseng to volunteers subjected to cold stress increased tolerability in the ice water tolerance test (Kaneko and Nakanishi, 2004). This effect was thought to be due to dilation of the blood vessels, increased blood flow under cold stress, decreased pain from ischemia, and protection from local tissue damage. Relevant data and conclusions on efficacy and safety reviews and publications identified for ginseng are shown in Table 4-8.

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TABLE 4-8 Ginseng

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Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for

Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Cardinal and Engels, 2001

Prospective, double-blind, randomized

Enhancement of mental performance

Placebo (lactose)

200 or 400 mg/d (2 or 4 capsules/d) for 60 d

Standardized extract Panax ginseng G115, 100 mg capsules

Positive affect, negative affect, and total mood disturbance. Measures were obtained pre- and postintervention.

Exercise performance and shortterm recovery

Placebo

400 mg/d (4 capsules/d) for 8 wk

Standardized extract Panax ginseng G115, 100 mg capsules

Peak anaerobic power output, mean anaerobic power output, rate of fatigue (as measured by a Wingate ergonomic protocol), and recovery heart rates

Exercise performance and shortterm recovery

Placebo

400 mg/d (4 capsules/d) for 8 wk

Standardized extract Panax ginseng G115, 100 mg capsules

Exercise performance (as measured by consecutive Wingate tests), absolute SigA,† salivary protein concentrations, SIgA secretion rate (S-SIgA), the relation of SIgA to total protein, peak and mean mechanical power output, and heart rate during exercise recovery

Mood and cognitive performance

Placebo

320 mg (120 mg ginkgo, 200 mg ginseng), 640 mg (240 mg ginkgo, 400 mg ginseng), or 960 mg (360 mg ginkgo, 600 mg ginseng)

Ginkgo biloba standardized extract GK 501; 60 mg capsules; Panax ginseng standardized extract G115, 100 mg capsules

Effect on mood and aspects of cognitive performance (quality of memory, secondary memory, working memory, speed of memory, quality of attention and speed of attention)

n= 40 healthy females and 43 males, mean age 25.7 y, with relatively normal psychological profiles Engels et al., 2001

Double-blind, randomized n=24 females

Engels et al., 2003

Double-blind, randomized n=38 active, healthy adults

Kennedy et al., 2001

Balanced crossover, double-blind, randomized n=20 healthy, young adults

†

Secretory immunoglobulin A

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Conclusions/Results

Adverse Events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

No psychological benefits observed after 8 weeks of chronic ginseng supplementation at its clinically recommended dose (200 mg/d) or at 400 mg/d compared to placebo.

None reported

No significant difference found for peak anaerobic power output, mean anaerobic power output, rate of fatigue, and immediate postexercise recovery heart rates. Prolonged supplementation with ginseng provided no ergogenic benefits during and in the recovery from short supramaximal exercise.

A single case of stomach upset associated with ginseng

None reported

Compared with resting levels, S-SIgA, SIgA:protein ratio, and SFR were significantly lower after exercise at baseline. Significant decline seen in both peak and mean mechanical power output across consecutive Wingate tests. Few changes seen in scores for salivary parameters, exercise performance, and HRR between ginseng- and placebo-treated groups. Mucosal immunity was not affected as indicated by changes in secretory IgA at rest and after an exercise-induced state of homeostatic disturbance; neither did it improve physical performance or heart rate recovery for individuals undergoing repeated periods of exhausting exercise.

None reported

None reported

A dose-dependent improvement in performance on the "quality of memory" factor was observed for the highest dose (960 mg). This effect was differentially targeted at the secondary memory rather than the working memory component. Also a dose-dependent decrement was seen in performance of the "speed of attention" factor for both the 320 and 640 mg doses.

None reported

None reported

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TABLE 4-8 Continued Review/Clinical Type of Study Indication Trial Reference and Subjects Kennedy et al., 2002

Balanced crossover, double-blind, randomized

Mood and cognitive performance

Control

Dose

Product Specification

Outcomes Measured

Placebo

360 mg of ginkgo, 400 mg of ginseng, 960 mg of a product combining the two extracts

Ginkgo biloba standardized extract GK 501; Panax ginseng standardized extract G115

Cognitive testing (using the CDR‡ computerized assessment battery and two serial subtraction mental arithmetic tasks)

n=20

Mood testing (Bond-Lader visual analogue scales) Measured 1, 2.5, 4, and 6 h posttreatment dose

Lieberman, 2001

Review of 7 clinical trials

Physical performance and wellbeing

Placebo

Various

Various

Physical performance, cognitive performance, immune function, disease state

Reay et al., 2006

Balanced crossover, double-blind

Cognition and glucose tolerance

Placebo

Standardized ginseng extract, 200 mg/d (2 capsules/day)

Panax ginseng standardized extract G115, 100 mg capsules

Cognitive function (as measured by Serial Threes subtraction task, Serial Sevens task, and RVIP§ performance task), mental fatigue (visual analogue scale), blood glucose levels

n=27 healthy, young adults

Reay et al., 2005

Balanced crossover, double-blind

200 mg G115/0 mg glucose (ginseng); 0 mg G115/25 g glucose (glucose); or 200 mg G115/25 g glucose (ginseng/glucose combination) Cognition and glucose tolerance

n=30

Placebo

Standardized ginseng extract, 100 mg capsules, 2 or 4 per day

Measured 60 min posttreatment dose

Panax ginseng standardized extract G115

Cognitive function (as measured by Serial Threes subtraction task, Serial Sevens task, and RVIP performance task), mental fatigue (as measured by a visual analogue scale), blood glucose levels. Measured 60 min posttreatment dose, 6 times in immediate succession

‡ §

Cognitive Drug Research Rapid visual information processing

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Conclusions/Results

Adverse Events Profile

All three treatments were associated with an improvement of secondary memory performance on the CDR battery, with ginseng treatment showing some improvement in the speed of performing memory tasks and in accuracy of attention-related tasks. Ginkgo and the ginkgo/ginseng combination improved performance of the Serial Threes and Serial Sevens subtraction tasks. No modulation of the speed of performing attention tasks was evident. Ginkgo improved self-rated mood; lesser improvements with the combination product.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

No compelling evidence that ginseng had any positive effects on physical or cognitive performance, immune function, or any specific disease state.

None reported

None reported

Panax ginseng and glucose enhanced the performance of mental arithmetic tasks and ameliorated the increase in participants’ subjective feelings of mental fatigue during performance of the sustained, cognitively demanding task performance. Glucose improved accuracy in performance of the RVIP. No evidence in any cognitive outcome measure of a synergistic relationship was found. A reduction in blood glucose levels was seen 1 hour following consumption of Panax ginseng without glucose. Panax ginseng may have glucoregulatory properties and can enhance cognitive performance.

Not reported, poor methodology

Insulin and prescription medications to treat type 2 diabetes

None reported

None reported

Conclusions from this study are limited due to poor methodology.

Treatment with both 200 mg and 400 mg dosage led to significant reductions in levels of blood glucose levels at all three posttreatment measurements. Administration of 200 mg of ginseng significantly improved performance on the Serial Sevens subtraction task and significantly reduced subjective mental fatigue throughout all (with the exception of one time point in each case) of the postdose completions of the 10 min battery. Panax ginseng can improve performance and subjective feelings of mental fatigue during sustained mental activity. This effect may be related to the acute glucoregulatory properties of the extract.

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TABLE 4-8 Review/Clinical Trial Reference Scholey and Kennedy, 2002

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Continued

Type of Study and Subjects Balanced crossover, double-blind

Indication

Control

Dose

Product Specification

Outcomes Measured

Cognition

Placebo

320 mg (120 mg ginkgo and 200 mg ginseng)

Ginkgo biloba standardized extract GK 501; Panax ginseng standardized extract G115

Cognitive function (as measured by Serial Three and Serial Seven subtraction tasks)

Ginkgo biloba standardized extract GK 501; Panax ginseng standardized extract G115

Attention and memory (as measured by the Cognitive Drug Research computerized cognitive assessment system) Measured prior to receiving their first daily dose and repeated 1, 3, and 6 h later.

n=20

640 mg (240 mg ginkgo and 400 mg ginseng)

Measured before treatment and 1, 2.5, 4, and 6 h thereafter.

960 mg (360 mg ginkgo and 600 mg ginseng) Given daily Wesnes et al., 2000

Multicenter trial, doubleblind

Memoryenhancement

Placebo

n=256, age 38-66 y

160 mg (60 mg ginkgo and 100 mg ginseng) 2x/d or 320 mg (120 mg ginkgo and 200 mg ginseng), 1x/d For 14 wk

Mood states, quality of life and sleep quality (as measured by questionnaire)

Cheng, 2005

Review of interactions with warfarin n=3

None

Various

Various

Anticoagulant effects of warfarin

Hu et al., 2005

Review of drug interactions with ginseng

None

Various

Various

Blood concentrations of alcohol and warfarin, mania, efficacy of the influenza vaccination

Jiang et al., 2004

Randomized, crossover

St John’s wort

Extract equivalent to 0.5 g Panax ginseng root and 8.93 mg ginsenosides as ginsenoside Rg1, given as 2 capsules 2x/d

Golden Glow Korean ginseng

Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma, and S-7hydroxywarfarin concentration in urine

n=12 healthy males

for 7 days 25 mg warfarin

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Conclusions/Results

Adverse Events Profile

Ginseng: Dose-dependent improvement in speed of response during Serial Threes, depending on dosage. Ginkgo-ginseng combination (320 mg) resulted in the most significant and sustained increase in the number of Serial Sevens responses at all posttreatment testing times. Ginkgo-ginseng combination (640 and 960 mg): improved accuracy on performance of the Serial Seven and Serial Three tasks with 640 and 960 mg, respectively.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Ginkgo/ginseng combination significantly improved the Index of Memory Quality. Average improvement was 7.5%; this reflected improvements to different aspects of memory including working and long-term memory. Benefit was seen throughout the 12-week dosing period as well as after a 2-week washout.

None reported

None reported

In three reports, ginseng reduced the anticoagulant effects of warfarin.

Reduced anticoagulant effects when used in combination with warfarin

Ginseng affects the anticoagulant properties of warfarin.

Panax ginseng was seen to reduce the blood concentrations of alcohol and warfarin, induce mania when used concomitantly with phenelzine, and increase the efficacy of the influenza vaccination.

None reported

Ginseng influences the effects of alcohol, warfarin, phenelzine, and influenza vaccine.

No effect on INR (International Normalization Ratio) and platelet aggregation by St John’s wort or ginseng. No effect on the apparent volumes of distribution or protein binding of warfarin enantiomers. St John’s wort significantly induced the apparent clearance of both Swarfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of warfarin. Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin.

None reported

Ginseng does not appear to affect the pharmacokinetics of warfarin.

Panax ginseng should not affect bleeding times during injury or in patients treated with warfarin.

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Continued

Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Rosado, 2003

Case report n=1 male, age 58 y with a thrombosis on a mechanical bileaflet aortic valve prosthesis admitted to hospital with diagnosis of acute anteroseptal myocardial infarction and diabetic ketoacidosis

None

Yuan et al., 2004

Double-blind, randomized n=20

Placebo

Dose

For 2 wk

Product Specification

Outcomes Measured

Ginseng product obtained overseas

International normalized ratio (INR) and coronary angiography

Panax quinquefolius (American ginseng)

International normalized ratio (INR) and plasma warfarin concentrations as measures of interactions of ginseng with warfarin

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Conclusions/Results

Adverse Events Profile

Thrombosis was thought to be caused through an interaction with ginseng and warfarin that produced a reduction in his INR.

Thrombosis

Peak INR significantly decreased compared to placebo (difference between ginseng and placebo. Significant reduction in the INR area under the curve (AUC), peak plasma warfarin level, and warfarin AUC. Peak INR and peak plasma warfarin level were positively correlated.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements Ginseng interaction with warfarin

Ginseng interaction with warfarin

Ginseng may reduce the efficacy of warfarin.

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REFERENCES Cardinal, B. J., and H. J. Engels. 2001.Ginseng does not enhance psychological well-being in healthy, young adults: Results of a double-blind, placebo-controlled, randomized clinical trial. J Am Diet Assoc 101(6):655-660. Carlson, A. W. 1986. Ginseng: America’s botanical drug connection to the Orient. Econ Bot 40(2):233249. Cheng, T. O. 2005. Ginseng and other herbal medicines that interact with warfarin. Int J Cardiol 104(2):227. Coon, J. T., and E. Ernst. 2002. Panax ginseng: A systematic review of adverse effects and drug interactions. Drug Saf 25(5):323-344. Cui, J. F. 1995. Identification and quantification of ginsenosides in various commercial ginseng preparations. Eur J Pharm Sci 3(2):77-85. Engels, H. J., I. Kolokouri, T. J. Cieslak II, and J. C. Wirth. 2001. Effects of ginseng supplementation on supramaximal exercise performance and short-term recovery. J Strength Cond Res 15(3):290295. Engels, H. J., M. M. Fahlman, and J. C. Wirth. 2003. Effects of ginseng on secretory IgA, performance, and recovery from interval exercise. Med Sci Sports Exerc 35(4):690-696. Gurley, B. J., S. F. Gardner, M. A. Hubbard, D. K. Williams, W. B. Gentry, Y. Cui, and C. Y. Ang. 2005. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging 22(6):525539. Han, S. K., J. Y. Song, Y. S. Yun, and S. Y. Yi. 2005. Ginsan improved Th1 immune response inhibited by gamma radiation. Arch Pharm Res 28(3):343-350. Hu, S. Y. 1976. The genus Panax (ginseng) in Chinese medicine. Econ Bot 30(1):11-28. Hu, Z., X. Yang, P. C. Ho, S. Y. Chan, P. W. Heng, E. Chan, W. Duan, H. L. Koh, and S. Zhou. 2005. Herb-drug interactions: A literature review. Drugs 65(9):1239-1282. Jiang, X., K. M. Williams, W. S. Liauw, A. J. Ammit, B. D. Roufogalis, C. C. Duke, R. O. Day, and A. J. McLachlan. 2004. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 57(5):592-599. Kaneko, H., and K. Nakanishi. 2004. Proof of the mysterious efficacy of ginseng: Basic and clinical trials: Clinical effects of medical ginseng, korean red ginseng: Specifically, its anti-stress action for prevention of disease. J Pharmacol Sci 95(2):158-162. Kennedy, D. O., A. B. Scholey, and K. A. Wesnes. 2001. Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/Panax ginseng combination to healthy young volunteers. Nutr Neurosci 4(5):399-412. Kennedy, D. O., A. B. Scholey, and K. A. Wesnes. 2002. Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ginseng combination to healthy young adults. Physiol Behav 75(5):739-751. Kim, H. J., M. H. Kim, Y. Y. Byon, J. W. Park, Y. Jee, and H. G. Joo. 2007. Radioprotective effects of an acidic polysaccharide of Panax ginseng on bone marrow cells. J Vet Sci 8(1):39-44. Lee, J. H., and Y. Han. 2006. Ginsenoside Rg1 helps mice resist to disseminated candidiasis by Th1 type differentiation of CD4+ T cell. Int Immunopharmacol 6(9):1424-1430. Lieberman, H. R. 2001. The effects of ginseng, ephedrine, and caffeine on cognitive performance, mood and energy. Nutr Rev 59(4):91-102. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 1999. WHO monographs of selected medicinal plants. Vol. 1. Geneva, Switzerland: World Health Organization. Mahady, G. B., H. H. S. Fong, and N. R. Farnsworth. 2001. Botanical dietary supplements: Quality, safety and efficacy. The Netherlands: Swets and Zeilinger.

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Quan, F. S., R. W. Compans, Y. K. Cho, and S. M. Kang. 2007. Ginseng and salviae herbs play a role as immune activators and modulate immune responses during influenza virus infection. Vaccine 25(2):272-282. Reay, J. L., D. O. Kennedy, and A. B. Scholey. 2005. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol 19(4):357-365. Reay, J. L., D. O. Kennedy, and A. B. Scholey. 2006. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained “mentally demanding” “tasks. J Psychopharmacol 20(6):771-781. Rosado, M. F. 2003. Thrombosis of a prosthetic aortic valve disclosing a hazardous interaction between warfarin and a commercial ginseng product. Cardiology 99(2):111. Scholey, A. B., and D. O. Kennedy. 2002. Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: Differential interactions with cognitive demand. Hum Psychopharmacol 17(1):35-44. Shibata, S., O. Tanaka, J. Shoji, and H. Saito. 1985. Chemistry and pharmacology of panax. In Economic and medicinal plants research. Vol. 1, edited by H. Wagner and N. R. Farnsworth. London-San Diego-New York: Academic Press. Pp. 217-284. Song, Z., C. Moser, H. Wu, V. Faber, A. Kharazmi, and N. Hoiby. 2003. Cytokine modulating effect of ginseng treatment in a mouse model of Pseudomonas aeruginosa lung infection. J Cyst Fibros 2(3):112-119. Sonnenborn, U., and Proppert, Y. 1991. Ginseng (Panax ginseng C. A. Meyer). Brit J Phytotherapy 2:3-14. Wesnes, K. A., T. Ward, A. McGinty, and O. Petrini. 2000. The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharm (Berl) 152(4):353-361. Yuan, C. S., G. Wei, L. Dey, T. Karrison, L. Nahlik, S. Maleckar, K. Kasza, M. Ang-Lee, and J. Moss. 2004. Brief communication: American ginseng reduces warfarin's effect in healthy patients: A randomized, controlled trial. Ann Intern Med 141(1):23-27.

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Ǻ-HYDROXY-Ǻ-METHYLBUTYRATE (HMB) Background *

ȕ-Hydroxy-ȕ-methylbutyrate (HMB) is a metabolic derivative of the amino acid leucine. The first step of catabolism of leucine is transamination to Į- ketoisocaproate, followed by production of HMB via KIC-kioxygenase. Under normal conditions, approximately 5 percent of leucine is converted to HMB (Baxter et al., 2005). There have been over 20 human clinical trials investigating the effects of HMB on body composition, muscle function, and safety factors concerning HMB intake (Alon et al., 2002; Bohn et al., 2002; Nissen and Sharp, 2003; Nissen et al., 2000; Palisin and Stacy, 2005; Slater and Jenkins, 2000; van Someren et al., 2005). The mechanism of action appears to be primarily via reduction in muscle protein catabolism. Specifically, HMB has been shown in vitro to attenuate the protein degradation induced by proteolysis-inducing factor (PIF) through the ubiquitin-proteasome proteolytic pathway by inhibition of protein kinase C (PKC) and resulting stabilization of the INB/NFNB complex (Smith et al., 2004). This is compatible with the finding that HMB is most effective in individuals undergoing substantial muscle catabolism (e.g., elderly people, AIDS and cancer patients, untrained individuals beginning a resistance exercise program). HMB’s role as precursor for cholesterol synthesis in muscle cells has been suggested as a mechanism for an effect of HMB of decreasing muscle damage following strenuous exercise (Baxter et al., 2005). Putative Benefits Altogether, the literature supports the value of HMB to increase fat-free mass gain in untrained subjects undergoing resistance training (Alon et al., 2002; Bohn et al., 2002; Nissen and Sharp, 2003; Palisin and Stacy, 2005; Slater and Jenkins, 2000) and in elderly or clinically catabolic subjects (e.g., patients with cancer or AIDS) without resistance training (Alon et al., 2002; Palisin and Stacy, 2005). One meta-analysis of nine studies determined that the net increase in lean mass gain in untrained men consuming 3 g/d of HMB during resistance training was 0.28 percent/wk greater than in those consuming a placebo (Nissen and Sharp, 2003). Some studies support an increase in muscle function (e.g., strength) as well as mass (Slater and Jenkins, 2000). One meta-analysis calculated a net increase in strength gain of 1.40 percent/wk for subjects consuming HMB compared to placebo (Nissen and Sharp, 2003). The value of HMB for well-trained athletes is less often observed than for individuals initiating a resistance training program (Palisin and Stacy, 2005). Several studies reported reduction in markers of muscle damage and/or soreness following strenuous exercise associated with the use of HMB (Bohn et al., 2002; van Someren et al., 2005). However, the majority of studies do not support a unique value of this supplement for reduction of markers (e.g., serum creatine kinase) or functional impairment (strength, soreness, range of motion) associated with skeletal muscle injury following resistance exercise (Bloomer, 2007). Almost all human clinical trials that supported a benefit of HMB used a dose of 3 g/d for 4 to 24 weeks. None of the studies involving shorter periods of supplementation (e.g., 6 to 10 days) reported any benefits (Palisin and Stacy, 2005). Most studies used between 28–35 subjects, with *

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. PREPUBLICATION COPY: UNCORRECTED PROOFS 4-126

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9 to 18 subjects per group. Some of the studies used HMB in combination with arginine and lysine in elderly or clinically catabolic subjects (Palisin and Stacy, 2005). Those studies reported anabolic effects of the combination supplement compared to placebo, but as the isoenergetic placebo was not isonitrogenous, it is not possible to attribute the benefits to HMB per se. Safety Concerns for HMB Toxicological studies in rats show no negative effects for HMB given at up to 5 percent of the diet for 91 days (Baxter et al., 2005). Many of the human studies of HMB ingestion measured health-related blood factors, psychological function, and frequency of adverse events. There was virtually no indication of negative side effects of the supplement, with several suggestions of improvement in some measures of blood cholesterol and blood pressure, especially in those who began with elevated levels. However, the long-term effects of chronic ingestion are not known, as most of the studies were performed for relatively brief periods (up to 12 weeks). A minority of studies used doses greater than 3 g/d (i.e., 6 g/d). There were no clear benefits or side effects associated with this higher dose compared to 3 g/d. No interactions with food components or drugs were noted, and none would be expected based on the theoretical metabolism of the compound. There is no evidence to support a safety concern for this supplement taken in doses of 3 g/d for up to 24 weeks. Considerations Specific to the Military HMB may help to slightly increase lean tissue gains for new military recruits undergoing vigorous resistance training but is less likely to be of value for well-trained individuals, and its high cost relative to other potentially anabolic supplements (e.g., creatine) may reduce the practicality of HMB use. Although negative effects on liver or kidney function have not been reported in any study, individuals with compromised function of either of these organs are advised not to use these supplements. Relevant data and conclusions on efficacy and safety reviews and publications identified for HMB are shown in Table 4-9.

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TABLE 4-9 HMB Review/Clinical Trial Reference Slater and Jenkins, 2000

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Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Type of Study and Subjects Review, included 84 references with at least 10 describing human clinical trials with HMB

Indication

Control

Dose

Muscle growth and strength

Placebo

Typically 3 g/d, a minority 1.5 or 6 g/d

Product Specification Various

Clinical Details and Outcomes Measured Total lean mass, strength gains, muscle protein breakdown, muscle soreness and damage indicators

n=20–41

Nissen et al., 2000

Nine clinical trial studies that included safety data

Muscle growth and strength

Placebo

3 g/d for 3– 8 wks

Data provided on health-related blood measures, emotional profiles (Circumplex test of emotion), and adverse events reported via questionnaire

Bohn et al., 2002

Review of several strength-enhancing supplements including HMB; Four were not part of Slater and Jenkins, 2000, review

Muscle growth and strength

Placebo

2–3 g/d

(See Slater and Jenkins above): Reduction in markers of muscle damage following 2-mile run reported in one study; beneficial effects on body composition observed in men and women 70 years of age and older.

Alon et al., 2002

Review of human studies; only additional clinical trial not included in reviews above was one on effect on body composition in cancer patients (May et al., 2002)

Body composition

Placebo

9 cancer patients received 3 g/d HMB+14 g/d arginine and 14 g/d glutamine

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Conclusions/Results

Adverse Events Profile

Most studies with HMB supplementation of 3 g/d paired with resistance training observed enhanced lean tissue and strength gains; a minority of studies showed no effect. Evidence was reviewed suggesting that the benefits are primarily observed in untrained individuals with less response for trained subjects. The mechanism was suggested to be reduction in muscle protein catabolism.

Some studies performed routine blood screens for hepatic, renal, or immune effects or had surveys regarding adverse effects; none reported serious negative clinical effects. Similarly, none of the animal studies (most on lambs, chickens, and steers) have reported adverse effects with doses up to 100 g/d.

Emotional profiles: Only significant change was decrease in “unactivated unpleasant affect” (associated with reduced sensation of sluggish, bored, tired) Blood measures: Significant 3.7% decrease in serum cholesterol and 5.7% in LDL (effect was greater in subjects who began with elevated lipids). There was also less increase in HDL in response to exercise for HMB group, but this was eliminated when expressed relative to total cholesterol. Systolic blood pressure fell 3% more for the HMB than placebo group. None of the indicators of liver function nor traditional blood chemistries were altered by HMB with the exception of a significant (2%) drop in blood potassium, a significantly greater increase in albumin/globulin ratio, and a significantly lower (0.5%) hematocrit in HMB.

No difference observed between placebo and HMB treatments.

None reported

One study beyond Slater and Jenkins, 2000, studied variety of markers of hematology as well as renal, hepatic function.

None reported

None reported

Questionnaire on adverse events indicated no effect of HMB on adverse events in the patients; no effects on serum chemistries with exception of increase in blood urea nitrogen, sodium, phosphorus, and uric acid contrasted to reduction in placebo group

None reported

None reported

The treated cancer group had a greater increase in fat-free mass compared to placebo group over the 24-week trial. Body fat was not different. There was no evaluation of HMB alone.

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Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

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TABLE 4-9

Continued

Review/Clinical Trial Reference Nissen and Sharp, 2003

Type of Study and Subjects Meta-analysis of nine HMB studies; two were not included in above reviews (Jowko et al., 2001 and Panton et al., 2000)

Indication

Palisin and Stacy, 2005

Review with 20 references; 6 were not included in above reviews

Various

Control

Dose

Placebo

3 g/d (8 studies) or 38 mg/kg/d + resistance exercise

Placebo

2 or 3 g HMB/d (Depending on the study) alone or combined with creatine, arginine or lysine, or glutamine or arginine for 10 d to 12 wk

Product Specification

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Clinical Details and Outcomes Measured Net increase in lean mass gain of 0.28%/wk during resistance training with effect size of 0.15. Net increase in strength gain of 1.40%/wk and effect size of 0.19.

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Conclusions/Results

Adverse Events Profile

HMB was one of few supplements reviewed that had anabolic effects when paired with resistance training.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Consensus of studies show that HMB alone or in combination with other amino acids: - reduced loss of muscle mass and function in elderly, - improved fat-free mass gains in AIDS and cancer patients, -may improve fat-free mass and muscle strength gains in untrained better than in trained individuals, - is effective if consumed 4–8 weeks but not briefly, and - does not cause adverse effects.

None reported

None reported

The effect to reduce muscle damage is provocative but needs to be confirmed. The effects of longer treatments and higher doses need to be studied. Effect of HMB alone is not possible to determine in those studies that used it in combination with arginine and lysine (and the placebos in those cases were not isonitrogenous) Ransone et al., 2003: 35 football players consumed HMB or placebo for 4 weeks; no difference in muscular strength or body composition Crowe et al., 2003: 6 weeks HMB (3 g) or HMB (3 g)+creatine (3 g) or control (received nothing) in 28 trained male rugby players; no effects were observed on health-related blood measures with exception of reduced bicarbonate and higher lymphocyte and monocyte counts in HMB (all still in normal range) Hoffman et al., 2004: No effect of 10 days of HMB in 26 players during preseason 2-a-day football practice on anaerobic power, hormones, or markers of muscle damage Flakoll et al, 2004: 57 elderly women given 2 g HMB + 5 g arginine + 1.5 g lysine or placebo for 12 wk; supplement increased fat-free mass, whole body protein synthesis, limb circumferences, strength and functionality compared to placebo (not isonitrogenous placebo) Rathmacher et al., 2004: 3 studies, one on 34 healthy males, one on 43 HIV patients, one in 32 cancer patients; combination of 3 g HMB + 14 g arginine + 14 g glutamine; no adverse effects on blood chemistries (with exception that blood urea nitrogen increased), emotional profile or adverse events; in fact, positive effects on emotional profile, reduced feeling of weakness, and increased red blood cells and lymphocytes

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TABLE 4-9 Continued Newer or military-relevant studies not included in reviews, listed chronologically Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Baxter et al., 2005

Dietary toxicity of calcium HMB

van Someren et al., 2005

Effects on muscle damage caused by exercise

Control

Placebo

Dose

Product Specification

Clinical Details and Outcomes Measured

0, 1, 2, 5% of diet as CaHMB for 91 days

Ca HMB

Mortality, clinical observations, body weight, food consumption, clinical and anatomic pathology evaluation

3 g/d HMB + 0.3 g/d Įketoisocaproic acid

Maximuscle HMB 1000, Maximuscle Ltd., Watford U.K.

Subjects consumed either HMB + Įketoisocaproic acid or placebo for 14 days followed by performance of exercise designed to cause muscle damage.

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Conclusions/Results

Adverse Events Profile

No effect on body weight, food intake, no meaningful hematological changes (some inconsistent effects on hematocrit), organ weights, micro or macroscopic pathology. The only clinical chemistry measure changed was increase in inorganic phosphorus in 5% group.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported.

None reported.

None reported.

HMB was well tolerated up to 5% of the diet for 91 days

Combination supplement reduced the increase in marker of muscle damage, muscle soreness, percentage decrement in muscle strength, and increase in limb girth compared to placebo.

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REFERENCES Alon, T., D. Bagchi, and H. G. Preuss. 2002. Supplementing with beta-hydroxy-beta-methylbutyrate (HMB) to build and maintain muscle mass: A review. Res Comm Mol Path Pharma 111(1-4):139152. Baxter, J. H., J. L. Carlos, J. Thurmond, R. N. Rehani, J. Bultman, and D. Frost. 2005. Dietary toxicity of calcium ȕ-hydroxy-ȕ-methyl butyrate (CaHMB). Food Chem Toxic 43(12):1731-1741. Bloomer, R. J. 2007. The role of nutritional supplements in the prevention and treatment of resistance exercise-induced skeletal muscle injury. Sports Med 37(6):519-532. Bohn, A. M., S. Betts, and T. L. Schwenk. 2002. Creatine and other nonsteroidal strength-enhancing aids. Curr Sports Med Rep 1(4):239-245. Crowe, M. J., D. M. O'Connor, and J. E. Lukins. 2003. The effects of beta-hydroxy-beta-methylbutyrate (HMB) and HMB/creatine supplementation on indices of health in highly trained athletes. Int J Sport Nutr Exerc Metab 13(2):184-197. Flakoll, P., R. Sharp, S. Baier, D. Levenhagen, C. Carr, and S. Nissen. 2004. Effect of beta-hydroxy-betamethylbutyrate, arginine, and lysine supplementation on strength, functionality, body composition, and protein metabolism in elderly women. Nutrition 20(5):445-451. Hoffman, J. R., J. Cooper, M. Wendell, J. Im, and J. Kang. 2004. Effects of beta-hydroxy betamethylbutyrate on power performance and indices of muscle damage and stress during high-intensity training. J Strength Cond Res 18(4):747-752. May, P. E., A. Barber, J. T. D'Olimpio, A. Hourihane, and N. N. Abumrad. 2002. Reversal of cancerrelated wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg 183(4):471-479. Nissen, S., and R. L. Sharp. 2003. Effect of dietary supplements on lean mass and strength gains with resistance exercise: A meta-analysis. J Appl Physiol 94(2):651-659. Nissen, S., R. L. Sharp, L. Panton, M. Vukovich, S. Trappe, and J. C. Fuller. 2000. ȕ-Hydroxy-ȕMethylbutyrate (HMB) supplementation in humans is safe and may decrease cardiovascular risk factors. J Nutr 130(8):1937-1945. Palisin, T., and J. J. Stacy. 2005. ȕ-Hydroxy-ȕ-Methylbutyrate and its use in athletics. Curr Sports Med Rep 4(4):220-223. Ransone, J., K. Neighbors, R. Lefavi, and J. Chromiak. 2003. The effect of beta-hydroxy betamethylbutyrate on muscular strength and body composition in collegiate football players. J Strength Cond Res 17(1):34-39. Rathmacher, J. A., S. Nissen, L. Panton, R. H. Clark, P. Eubanks May, A. E. Barber, J. D'Olimpio, and N. N. Abumrad. 2004. Supplementation with a combination of beta-hydroxy-beta-methylbutyrate (HMB), arginine, and glutamine is safe and could improve hematological parameters. J Parenter Enteral Nutr 28(2):65-75. Slater, G. J., and D. Jenkins. 2000. ȕ-Hydroxy-ȕ-Methylbutyrate (HMB) supplementation and the promotion of muscle growth and strength. Sports Med 30(2):105-116. Smith, H. J., S. M. Wyke, and M. J. Trisdale. 2004. Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by ȕ-Hydroxy-ȕ-Methylbutyrate Cancer Res 64(23):8731-8735. van Someren, K. A., A. J. Edwards, and G. Howatson. 2005. Supplementation with ȕ-Hydroxy-ȕMethylbutyrate (HMB) and Į-ketoisocaproic acid (KIC) reduces signs and symptoms of exerciseinduced muscle damage in man. Int J Sport Nutr Exerc Metab 15(4):413-424.

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MELATONIN Background *

Melatonin is a light-sensitive hormone synthesized from tryptophan (i.e., it is a metabolite of 5-hydroxytryptamine). It is secreted by the pineal gland, and is a mediator in circadian processes. Because the pineal gland is neurobiologically part of the endogenous circadian system in humans and many other complex animals, the secretory profile of melatonin is circadian (i.e., about a day in length). Plasma levels of melatonin peak during the period of darkness (nighttime) in all mammal species (Arendt and Skene, 2005). A 10- to 50-fold increase in blood melatonin concentration occurs 1 to 2 hours after dusk (Lewy et al., 1992), suggesting that endogenous melatonin has a role in facilitating sleep (e.g., it lowers core body temperature by increasing heat loss prior to sleep). Similarly, exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during “biological daytime.” The half-life of endogenous melatonin in the bloodstream is less than 1 hour, making hangover effects in the morning relatively rare (Morin et. al., 2007). Due to widespread belief that endogenous melatonin has a key role in the “natural” promotion or regulation of sleep, exogenous melatonin has become one of the most frequently requested over-the-counter sleep aids (Wagner et al., 1998). Among 31,044 people who completed the 2002 Alternative Health/Complementary and Alternative Medicine (CAM) supplement to the National Health Interview Survey, 5.2 percent reported using melatonin. Of those users, 27.5 percent reported insomnia as a reason for taking the supplement (Bliwise and Ansari, 2007). Women were five times as likely to report melatonin use as men, and 13.9 percent of them described taking melatonin for anxiety and/or depression. Putative Benefits Laboratory studies of melatonin in treating sleep disorders have shown mixed results in various measures of sleep quality. Melatonin is typically administered orally, with dosages ranging from 0.3 to 5 mg in both regular and time-release capsules. In one placebo-controlled study of patients with primary insomnia, melatonin treatment reduced sleep onset latency by an average of 4.0 minutes, increased sleep efficiency by 2.2 percent, and increased total sleep duration by 12.8 minutes (Brzezinski et al., 2005). Another meta-analysis found that melatonin decreased sleep-onset latency by an average of 7.2 minutes in insomniacs and by an average of 38.8 minutes in patients with delayed sleep phase syndrome (Buscemi et al., 2005). However, there was no significant difference between melatonin and placebo. Most reviews of the effects of exogenous melatonin on insomnia conclude that the consensus is that the majority of studies find no benefits of melatonin for insomnia, and/or that the studies are inadequate, and that larger, long-term studies are needed to determine efficacy (Buscemi et. al., 2005; Turek and Gillette, 2004). In contrast to the absence of evidence that exogenous melatonin administration can improve physiological signs and subjective symptoms of insomnia, an extensive scientific literature shows that exogenous melatonin can be an effective chronobiotic (Arendt and Skene, 2005). That is, when its ingestion is timed appropriately (i.e., most effective around dusk and *

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dawn), it will shift the phase of the human circadian clock (i.e., recalibrate sleep, core body temperature, and endogenous production of melatonin and cortisol) to earlier or later times. Thus, the literature reveals that ingestion of melatonin 1 hour before the desired sleep time can be effective for insomnia associated with jet lag (Morin et. al., 2007). Exogenous melatonin has also been tested in several different ways to facilitate adjustment to night-shift work. Although exogenous melatonin has been shown to have some benefit in adjustment to jet lag when used prior to the desired sleep time, there is considerably less scientific evidence for its efficacy in promoting adjustment to night-shift work, perhaps because circadian synchronizers such as bright light also promote phase adjustment to jet lag, while they promote no adjustment to night work. The authors of the leading scientific review on the effects of exogenous melatonin concluded that due to the large number of poorly controlled studies, use of melatonin for adaptation to night-shift work is unproven but promising (Arendt and Skene, 2005). Safety Concerns Although available as an over-the-counter product in the United States, melatonin is classified as a drug in Canada and is available only by prescription in the UK. One recent review concluded that there is no long-term safety data on the use of exogenous melatonin or on the optimal dose and formulation for any application (Arendt and Skene, 2005). Another review concluded that melatonin is generally regarded as safe in recommended doses for short-term use, and is likely safe when taken orally for up to 2 years at a maximum dose of 5 mg/d (Morin et. al., 2007). A placebo-controlled study showed that the occurrence of adverse events was similar for melatonin and placebo. The most commonly reported adverse effects were headaches, dizziness, nausea, and drowsiness (Buscemi et al., 2006). Exogenous melatonin is a vasodilator—it lowers core body temperature, and it can affect skin blood flow, which suggests it is not advisable in cold environments, where it may accelerate heat loss (Weekley, 1993). While one study reported a case of exogenous melatonin being linked to psychosis, other case reports suggest it helps prevent psychotic symptoms from severe reactions to jet lag (Katz et al., 2001). Interactions with Other Dietary Supplements or Medications To the extent that melatonin is sedating, it has the potential for unwanted synergy with other sedating agents. Therefore, in people engaged in safety-sensitive activities that require alertness and quick responses, this supplement should not be taken in conjunction with other sedating or hypnotic substances. Of the 109 medications most frequently prescribed for military personnel, 13 are hypnotics, anxiolytics, antidepressants, opioids, and so on, which have sedating side effects. Considerations Specific to the Military Although there is evidence that exogenous melatonin has chronobiotic effects—helping to phase shift circadian rhythms in jet lag and night-shift work—the timing of intake in relation to the effect (i.e., phase response curve) is essential. The decrease in core body temperature seen as a common effect of melatonin poses a risk to military personnel in cold environments, and drowsiness can adversely effect both physical and mental performance. However, melatonin could counteract disruptions in sleep and the thermoregulatory and central nervous systems,

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which would be of benefit for active duty military personnel. Therefore, consideration should be given to the tasks performed and circumstances; for instance, its use might be limited to the needed adjustment to jet lag and/or night-shift work and in a thermal environment that is above freezing. Relevant data and conclusions on efficacy and safety reviews and publications identified for melatonin are shown in Table 4-10.

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TABLE 4-10 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Melatonin Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Arendt and Skene, 2005

Review of 14 studies

Jet lag and shift work

Variable

1.8 mg sustained release or 5 mg fast release

Brzezinski et al., 2005

Meta-analysis of 7 studies, n=284 subects

Insomnia

Placebo

Variable

None reported

Polysomnography (PSG) and actigraphy used to measure sleep onset latency, total sleep duration, sleep efficiency

Buscemi et al., 2005

Meta-analysis

Insomnia and delayed sleep phase syndrome

Placebo

None reported

None reported

Sleep onset latency, sleep efficiency, wakefulness after sleep onset, total sleep time, REM sleep percentage

of 14 randomized controlled trials

Product Specification

Clinical Details and Outcomes Measured Sleep phase shifts

Buscemi et al., 2006

Meta-analysis

Secondary sleep disorders or sleep disorders accompanying sleep restriction

Placebo

Variable; 0.5 mg to 7.5 mg

Variable; mostly oral capsules and tablets

Sleep onset latency, sleep efficiency, wakefulness after sleep onset, total sleep time, REM sleep percentage

Morin et al., 2007

Review

Insomnia, delayed sleep phase syndrome, jet lag

Varies

Variable, ranges from 0.3 mg to 5 mg

None reported

Sleep latency, sleep duration, sleep quality

Wagner et al., 1998

Review

Insomnia and circadian disorders

Varies

0.3 mg to 10 mg

Variable

Many, including sleep quality, sleep latency, EEG, sleep duration

Bliwise and Ansari, 2007

Database evaluation n=31,044 adults (ages 18–61+); representative U.S. sample

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Conclusions/Results

Adverse Events Profile

11 of 14 placebo controlled studies on the use of melatonin for jet lag found at least some benefit. The benefits included reduction in subjective jet lag, and improvements in sleep and alertness. The evidence for using melatonin to adapt to nightshift work was inconclusive.

Exogenous melatonin is a vasodilator—it lowers core body temperature, and it can affect skin blood flow. Therefore, if taken in a cold environment it may accelerate heat loss.

Melatonin treatment reduced sleep onset latency by an average of 4.0 minutes, increased sleep efficiency by 2.2%, and increased total sleep duration by 12.8 minutes.

None reported

None reported

Melatonin decreased sleep onset latency by an average of 7.2 minutes in insomniacs and by an average of 38.8 minutes in patients with delayed sleep phase syndrome. Some evidence that melatonin is not effective in treating primary sleep disorders over the short term (less than 4 weeks)

No significant difference observed between melatonin and placebo.

None reported

Change in sleep onset latency was not statistically significant. Although the increase in sleep efficiency in people with secondary sleep disorders was statistically significant with melatonin, the effect was small—1.9%—an increase of less than 10 minutes if the amount of time spent asleep for 8 hours spent in bed.

The occurrence of adverse events was similar for melatonin and placebo. The most commonly reported adverse events were headaches, dizziness, nausea, and drowsiness.

None reported

Although there is some evidence supporting the use of melatonin in treating jet lag and sleep disturbance caused by shift work, more research is needed before melatonin can be recommended as a treatment for insomnia.

Common: fatigue, dizziness, headache, irritability, and drowsiness Less common: mood changes, hypotension, atherosclerotic plaques, hyperglycemia, mild GI distress, increased intraocular pressure, fluctuations in reproductive and thyroid hormones

Potential synergy with other sedative hypnotics.

The evidence may support melatonin use for circadian rhythm disorders and in patients with low melatonin levels such as the elderly; more evidence is needed before it can be recommended for insomnia in the general population.

Fatigue, headache, dizziness, irritability

None reported

Data from 2002 Alternative Health/Complementary and Alternative Medicine supplement to the National Health Interview Survey. 5.2% of the survey sample used melatonin of which 27.5% (SE = 3.93) endorsed insomnia as one reason for use. 5.8% of the survey sample mentioned insomnia in association with valerian and melatonin use. Women used it more than men (5.5:1). Melatonin showed a 13.9% usage rate in association with anxiety/depression.

None reported

None reported

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REFERENCES Arendt, J., and D. J. Skene. 2005. Melatonin as a chronobiotic. Sleep Med Rev 9(1):25-39. Bliwise, D. L., and F. P. Ansari. 2007. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep 30(7):881-884. Brzezinski, A., M. G. Vangel, R. J. Wurtman, G. Norrie, I. Zhdanova, A. Ben-Shushan, and I. Ford. 2005. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 9(1):41-50. Buscemi, N., B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, G. Baker, T. P. Klassen, and S. Vohra. 2005. The efficacy and safety of exogenous melatonin for primary sleep disorders—A meta-analysis. J Gen Intern Med 20(12):1151-1158. Buscemi, N., B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, S. Vohra, T. P. Klassen, and G. Baker. 2006. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep-restriction: Meta-analysis. BMJ 332(7538):385-393. Katz, G., R. Durst, and H. Y. Knobler. 2001. Exogeneous melatonin, jet lag, and psychosis: Preliminary case results. J Clin Psychopharmacol 21(3):349-351. Lewy, A. J., S. Ahmed, J. M. Jackson, and R. L. Sack. 1992. Melatonin shifts human circadian rhythms according to a phase–response curve. Chronobiol Int 9(5):380-392. Morin, A. K., C. I. Jarvis, and A. M. Lynch. 2007. Therapeutic options for sleep-maintenance and sleeponset insomnia. Pharmacotherapy 27(1):89-110. Turek, F. W., and M. U. Gillette. 2004. Melatonin, sleep and circadian rhythms: Rationale for development of specific melatonin agonists. Sleep Med 5(6):523-532. Wagner, J., M. L. Wagner, and W. A. Hening. 1998. Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother 32(6):680-686. Weekley, L. B. 1993. Effects of melatonin on pulmonary and coronary vessels are exerted through perivascular nerves. Clin Auton Res 3(1):45-47.

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QUERCETIN Background There are more than 5,000 different flavonoid compounds in plants that can be subdivided into six major subclasses. One subclass is the flavonols, which include quercetin*, myricetin, and kaempferol. Flavonols are three-ring compounds chemically characterized as flavan-3,4-diols. These compounds are especially prevalent in onions, kale, broccoli, apples, and berries (Ross and Kasum, 2002). Quercetin is the most frequently studied of all flavonoids (Formica and Regelson, 1995). The absorption and bioavailability of quercetin has been extensively studied. Recent reviews point to evidence that quercetin is readily absorbed from foods or supplements, although there is some variability depending on the specific food matrix in which it is consumed and whether the molecule has a glycoside linkage (Erdman et al., 2007; Ross and Kasum, 2002). The maximal blood concentration of quercetin is reached within a few hours of ingestion with reported halflives of between 11 and 28 hours. Results from several studies suggest that repeated consumption of foods containing quercetin will maintain blood concentrations of this flavonol (Ross and Kasum, 2002). In persons consuming their habitual diets blood concentrations ranging between about 15-24 μg/L (50-80 nmole/L) were noted compared to about 42 μg/L (140 nmole/L) after a diet high in vegetables, fruits, and berries, respectively, and have been noted (Erlund, 2004). Long-term feeding of quercetin to rats leads to accumulation in many tissues including lungs, testes, kidney, heart, liver, thymus, and muscle (de Boer et al., 2005). Putative Benefits A variety of in vitro trials have provided support for antioxidant activity of quercetin and other flavonoids. It is quite difficult, however, to demonstrate that specific food components in isolation such as flavonoids have biologically important antioxidant effects in vivo. These flavonols have also been reported to have utility as antibiotic, antiallergenic, antidiarrheal, antiulcer, and anti-inflammatory agents. Other studies of these compounds have shown inhibition of cellular proliferation in a variety of cancer cell models, although some studies have used concentrations of the flavonoids that are 100 times or higher than achieved by eating diets high in flavonoid-containing foods. Epidemiological evaluations of diets high in flavonoids provide some support of the theory that flavonoid intake is related to reduction in risk factors of cardiovascular disease. Most recently, an ILSI-North America (International Life Sciences Institute-North America) workshop group concluded that “[d]ata presented support the concept that certain flavonoids in the diet can be associated with significant health benefits, including heart health” (Erdman et al., 2007). For example, Lotito and Frei (2006) demonstrated that quercetin and some other flavonols were able to inhibit endothelial adhesion molecule expression in human aortic endothelial cells. There is also a great deal of interest in the role of flavonoids in the reduction of inflammation and inflammatory states that are thought to be related to a variety of diseases such as cardiovascular disease. *

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The effects of quercetin on immunological responses have been studied in several testing systems. For example, Formica and Regelson (1995) stated that flavonoids appear to inhibit enzyme pathways involved in lymphocyte activation via their ability to scavenge free radicals. In a double-blind, randomized, crossover study, MacRae and Mefferd (2006) investigated whether 6 weeks of supplementation with an antioxidant would enhance the performance of elite male cyclists in 30 km time trials. The supplement contained a variety of nutrient and nonnutrient antioxidants, and included a total of 600 mg of quercetin. The results showed that the supplement improved the time trial performance and enhanced power output. These findings could not be attributed to quercetin, however, as there was no quercetin-only supplement. Nieman et al. (2007) tested whether 1,000 mg/d of quercetin would have an effect on upper respiratory tract infections (URTI) and exercise-induced changes in immune function in trained male cyclists (n=40). Participants were randomized to receive quercetin or placebo supplements twice daily under double-blind conditions for 3 weeks prior to, during, and 2 weeks following a 3-day period in which subjects cycled at high output for 3 hours per day. The results of this trial showed no effects on natural killer cell activity, PHA-stimulated lymphocyte proliferation, polymorphonuclear oxidative burst activity, or salivary IgA output. However, the incidence of URTI during the 2-week postexercise period differed significantly between groups (P = .004), with quercetin resulting in only 1 versus 9 episodes of URTI in the placebo group. Interestingly, plasma quercetin was increased from 113 μg/L in the placebo group to 1,158 μg/L in supplemented groups. The authors concluded that even in the absence of demonstrated effects of the supplement on multiple measures of immune function, quercetin may have a direct antiviral mechanism. Davis et al. (2007) evaluated the effects of 7 days of an oral gavage of quercetin (either 12.5 or 25 mg/kg body weight) on tissue mitochondrial enzymes and performance on a treadmill in previously sedentary mice. Both dose levels of quercetin were associated with significant increases in mitochondrial content in skeletal muscle and brain cells as well as increased endurance capacity in the mice. Safety Concerns The safety of quercetin was extensively reviewed by Okamoto (2005). He notes that although the National Toxicology Program had reported some studies showing carcinogenic effects in rats, most in vivo studies indicated that quercetin is not carcinogenic. Moreover, in 1999, the International Agency for Research on Cancer (IARC) concluded that quercetin is not classifiable as to its carcinogenicity to humans (IARC, 1999). One phase I clinical trial of the effects of quercetin on the inhibition of tyrosine kinase activity has been completed, and antitumor activity was shown (Ferry et al., 1996). Numerous published in vitro trials have reported the effects of querctin on a variety of cell culture types and a wide range of outcomes. Many have focused on cell proliferation in cancer cell lines. There is a clear, though not consistent, effect of dose level on whether quercetin inhibits cancer cell growth or causes cellular damage. For example, van der Woude et al. (2005) showed a biphasic effect of quercetin in several breast cancer cell lines in which, at a low dose level (10–20 μmol/L), quercetin increases cell proliferation, while at higher doses (40–80 μmol/L), there is decreased proliferation. In contrast, Watjen et al. (2005) showed in a rat hepatoma cell line that lower concentrations of quercetin (as low as 10–25 μmol/L) and other flavonoids protected against DNA strand breaks and induced apoptosis, but at higher

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concentrations (between 50–250 μmol/L) caused DNA damage. Thus, dose level may play a critical role in whether quercetin supplementation has helpful or adverse outcomes. To put the concentrations used in typical cell culture studies into perspective, it was estimated that blood concentrations of quercetin ranging between about 50 nmol/L and about 140 nmol/L are reached for persons consuming their habitual diets and diets high in vegetables, fruits, and berries, respectively (Erlund, 2004). Nieman et al. (2007) reported achieving levels of 1158 μg/L, or about 3.8 μmol/L, in test subjects receiving 1,000 mg of quercetin daily for several weeks. These blood levels are substantially below those of most in vitro trials. It is not known whether concentrations of quercetin higher than plasma levels might be achieved in other tissues after consuming quercetin. However, it appears that the majority of in vitro studies have involved quercetin levels that are not achieved even with high-dose dietary supplements. The applicability of the findings of these high-dose in vitro studies to human health and safety is questionable. Overall, Okamoto (2005) concluded that it is unlikely that administration of quercetin at a typical dosage could cause any adverse effect. There do not appear to be any safety concerns about quercetin supplements at doses of 1,000 mg daily or less. However, most dietary supplements currently on the market contain mixtures of compounds, not just quercetin in isolation. There are no clear interactions of quercetin with other dietary supplements or medications. Considerations Specific to the Military There are no clear indications that quercetin supplements have adverse effects upon issues of military concern (e.g., high-intensity physical activity; injury/bleeding; temperature extremes; high altitude; dehydration; diarrhea; infectious disease; risk of kidney stones; weight considerations). Relevant data and conclusions on efficacy and safety reviews and publications identified for quercetin are shown in Table 4-10.

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TABLE 4-11 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Quercetin Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Lotito and Frei, 2006

Pharmacologic study

Inflammation and atherosclerosis

Nieman et al., 2007

Double-blind, randomized, controlled

Upper respiratory infections and immune function after exercise

n=40 males

Control

Placebo

Dose

Product Specification

Clinical Details and Outcomes Measured

Quercetin

Inhibition of endothelial molecule expression

1,000 mg/day twice daily for 3 wk prior and 2 wk after the 3 d period of exercise

Quercetin

Upper respiratory tract infections (URTI) and changes in immune function after cycling at high output for 3 hours per day

12.5 or 25 mg/kg body weight for 7 d

Quercetin

Mitochondrial content in muscle and brain Endurance capacity

Davis et al., 2007

Animal study

Okamoto, 2005

Review

Quercetin

Carcinogenicity

IARC, 1999

Review

Quercetin

Carcinogenicity

van der Woude et al., 2005

Tissue culture: breast cancer cells

Quercetin

Cell proliferation

Watjen et al., 2005

Tissue culture: hepatoma rat cells

Quercetin

Effects on DNA

10–80 μmol/L

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Conclusions/Results

Adverse Events Profile

Quercetin, among other hydroxyl flavones, was able to inhibit endothelial adhesion molecule expression.

None reported

No effects on natural killer cell activity, PHA-stimulated lymphocyte proliferation, polymorphonuclear oxidative burst activity, or salivary IgA output. Incidence of URTI during the 2-week postexercise period differed significantly between groups Quercetin might have antiviral effect.

None reported

None reported

Significant increases in mitochondrial content in skeletal muscle and brain Increased endurance capacity observed in the mice.

None reported

None reported

Quercetin is not carcinogenic.

None reported.

None reported

Quercetin is not carcinogenic.

None reported

None reported

Biphasic effect: increase in cell proliferation at a low dose level (10–20 μmol/L) and a decreased proliferation at higher doses (40–80 μmol/L)

None reported

None reported

Biphasic effect: lower doses of 10–25 μmol/L protect against DNA strand breaks and induced apoptosis, but 50–250 μmol/L caused DNA damage.

None reported

None reported

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REFERENCES Davis, J. M., E. A. Murphy, M. D. Carmichael, J. B. Davis, J. D. Gangemi, and E. P. Mayer. 2007. Effect of quercetin feedings on tissue mitochondrial enzymes and performance in mice. Am Coll Sports Med Abstract. de Boer, V. C. J., A. A. Dihal, H. van der Woude, I. C. W. Arts, S. Wolffram, G. M. Alink, I. M. C. M. Rietjens, J. Kiejer, and P. C. H. Hollman. 2005. Tissue distribution of quercetin in rats and pigs. J Nutr 135(7):1718-1725. Erdman, J. W. Jr., D. Balentine, L. Arab, G. Beecher, J. T. Dwyer, J. Folts, J. Harnly, P. Hollman, C. L. Keen, G. Mazza, M. Messina, A. Scalbert, J. Vita, G. Williamson, and J. Burrowes. 2007. Flavonoids and heart health: Proceedings of the ILSI North America flavonoids workshop, May 31–June 1, 2005. Washington, DC. J Nutr 137(3):718S-737S. Erlund, I. 2004. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res 24(10):851-874. Ferry, D. R., A. Smith, J. Malkhandi, D. W. Fyfe, P. G. de Takats, D. Anderson, J. Baker, and D. J. Kerr. 1996. Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2(4):659-668. Formica, J. V., and W. Regelson. 1995. Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol 33(12):1061-1080. IARC (International Agency for Research on Cancer). 1999. IARC monographs on the evaluation of carcinogenic risks to humans. IARC 73:497-515. Lotito, S. B., and B. Frei. 2006. Dietary flavonoids attenuate tumor necrosis factor Į-induced adhesion molecule expression in human aortic endothelial cells. J Biol Chem 281(48):37102-37110. MacRae, H. S. H., and K. M. Mefferd. 2006. Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance. Int J Sport Nutr Exerc Metab 16(4):405-419. Nieman, D. C., D. A. Henson, S. J. Gross, D. P. Jenkins, J. M. Davis, E. A. Murphy, M. D. Carmichael, C. L. Dumke, A. C. Utter, S. R. Mcanulty, L. S. Mcanulty, and E. P. Mayer. 2007. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc 39(9):1561-1569. Okamoto, T. 2005. Safety of quercetin for clinical application (Review). Int J Molec Med 16(2):275-278. Ross, J. A., and C. M. Kasum. 2002. Dietary flavonoids: Bioavailability, metabolic effects and safety. Annu Rev Nutr 22:19-34. van der Woude, H., G. M. Alink, and I. M. C. M. Rietjens. 2005. The definition of hormesis and its implications for in vitro to in vivo extrapolation and risk assessment. Crit Rev in Tox 35(6):603-607. Watjen, W., G. Michels, B. Steffan, P. Niering, Y. Chovolou, A. Kampkooter, Q-H. Tran-Thi, P. Proksch, and R. Kahl. 2005. Low concentrations of flavonoids are protective in rat H411E cells whereas high concentrations cause DNA damage and apoptosis. J Nutr 135(3):525-531.

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SPORTS BARS Background *

Sports bars are a vehicle for provision of calories, macronutrients, and micronutrients for active individuals. Although more concentrated and thus a lighterweight form of energy than sports drinks, they do not contribute to hydration. This category cannot be easily summarized—there is a very broad range of sports bars commercially available. Most bars contain substantial amounts of carbohydrate and protein, moderate to low amounts of fat, and a total of 100–300 kcal/bar. Most companies fortify these products with vitamins or minerals, and some add herbs or other compounds purported to improve health or performance (e.g., creatine, antioxidants). Sports bars can serve as a snack contributing to the overall carbohydrate and protein needs of service members, especially those with higher energy demands. For example, the Military Dietary Reference Intake for protein is 91 g/d for an 80 kg male. For sustained operations, the carbohydrate and protein needs for an 80 kg male have been estimated at 450 g/d and 100–120 g/d, respectively (IOM, 2005). A more detailed review of the value of protein and carbohydrate for military personnel is presented in the previous IOM report, Nutrient Composition of Rations for Short-term, High-intensity Combat Operations (2005). Energy supplements in the form of gels are another vehicle for ingestion of carbohydrate during activity. The energy in these products (approximately 100 kcal) typically comes only from carbohydrate, but they may be fortified with electrolytes or other micronutrients. They are intended to serve as a concentrated source of carbohydrate (one or two packages per hour is the suggested rate of ingestion) during prolonged periods of exertion. Putative Benefits Very few published studies have examined the effect of sports bars on physical performance. One study observed that consumption of a bar containing a mix of macronutrients (7 g fat, 14 g protein, 19 g carbohydrate) increased use of fat during exercise of 330 minutes in duration, but reduced ability to complete a high-intensity time trial following the submaximal exercise bout compared to ingestion of an equal amount of energy as carbohydrate (glucose polymer) alone (Rauch et al., 1999). Thus, if carbohydrate and fluids are the limiting factor for physical performance, consumption of a sports drink would likely be a better choice during exercise than a sports bar. However, sports bars may be especially valuable after exercise when a concentrated source of energy and carbohydrate is beneficial, and adequate fluids are available and ingested. These products can also serve to boost energy (and nutrient) intake between meals in individuals with high energy demand.

*

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy.

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Safety Concerns Sports bars, like sports gels, need to be ingested with copious amounts of water since they do not provide sufficient fluid to prevent dehydration. Research shows that ingestion of gels with a small amount of water impaired endurance exercise performance in a hot environment relative to ingestion of the same amount of carbohydrate in a sports drink (Ebert et al., 2007). Some individuals may experience gastrointestinal distress when using gels during exercise (Burke et al., 2005). A minor safety concern is the potential for excess energy intake from the additional calories provided to those whose activity level or environment does not require additional energy. Many bars are highly fortified, so there is potential for overconsumption of micronutrients, including the potential to exceed the upper limit for some minerals. It is valuable to train personnel to read the labels of the bars so users are aware of the unique composition, energy, and nutrient value of the product and how it fits into their daily diet. The safety of added ingredients other than macronutrients and required micronutrients cannot be summarized but needs to be assessed individually. Considerations Specific to the Military Sports bars are a convenient vehicle to carry fuel for active individuals. These bars typically have long shelf lives so can be transported and stored without refrigeration until needed. This may be important for various military environments and circumstances. If consumed during exercise, they should be consumed with sufficient water to maintain hydration. Relevant data and conclusions on efficacy and safety reviews and publications identified for sports bars are shown in Table 4-12.

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TABLE 4-12 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Bars Review/Clinical Trial Reference Burke et al., 2005

Type of Study and Subjects Crossover n=18 highly trained marathon runners

Ebert et al., 2007

Randomized, crossover, not blinded n=8 welltrained male cyclists

Indication

Control

Dose

Product Specification

Outcomes Measured

Athletic performance (marathons)

Placebo (426 +/- 227 mL) or water (386 +/185 mL)

Commercial gel providing 1.1 +/- 0.2 g/kg body mass carbohydrate

Powergel, Nestle Australia

Body mass, performance on 2 half marathons

Athletic performance (cycling in a warm environment )

No placebo

0.4 L water and a sport gel

Gu Energy Gel, Sports Street Marketing, Berkeley, CA

Maximal aerobic power (MAP), hydration status, body mass changes, sweat rate, blood glucose, blood lactose, rating of exertion, thermal sensation, and stomach fullness

None reported

Maximal oxygen consumption, respiratory exchange ratio, heart rate, fat oxidation, perceived exertion

or 2.4 L of a 7% carbohydrateelectrolyte drink Sport gel had same carbohydrate content as carbohydrateelectrolyte drink

Rauch et al., 1999

2 random order trials n=6 male highly trained endurance cyclists, mean age 31

Ultraendurance athletic performance (cycling)

No placebo

Trial 1: 1.5 energy bars and 700 mL water every hr. Each bar has 19 g carbohydrate, 7 g fat, 14 g protein, 200 mg sodium, 50 mg potassium, <1 g fiber, and trace amounts of vitamins A, B, C, and E. Trial 2: 700 mL of a 100 g/L glucose polymer solution every hr similar energy ingestion during both trials 330 min cycling per trial

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Conclusions/Results

Adverse Events Profile

Mean body mass change of approximately 2.4%. Three runners reported gastrointestinal discomfort after consuming gel, which impaired marathon performance. The effect of gel on performance was insignificant (time was improved by 0.3% or 14 seconds compared with placebo). No benefits of carbohydrate gel intake on half marathon performance.

Gastrointestinal discomfort

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

No differences in bicycle treadmill speed, blood glucose, blood lactose, hydration status, perceived exertion, thermal sensation, or stomach fullness.

None reported

None reported

None reported

None reported

Significantly lower absolute power output in water plus gel group to maintain same speed as carbohydrate-electrolyte drink group during treadmill test. Time to exhaustion was significantly shorter in water plus gel group. Ingestion of water and a sport gel reduced the exercise capacity of trained cyclists during laboratory cycling hill-climbing. Fat oxidation rates were greater in subjects who ingested energy bar compared to those ingesting carbohydrate gel. Ingestion of a sports bar significantly enhanced fat metabolism during prolonged submaximal exercise. Ingestion of sports bar containing carbohydrate, fat, and protein during exercise, led to impaired performance on subsequent high-intensity exercise.

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REFERENCES Burke, L. M., C. Wood, D. B. Pyne, D. R. Telford, and P. U. Saunders. 2005. Effect of carbohydrate intake on half-marathon performance of well-trained runners. Int J Sport Nutr Exerc Metab 15(6):573-589. Ebert, T. R, D. T. Martin, N. Bullock, I. Mujika, M. J. Quod, L. A. Farthing, L. M. Burke, and R. T. Withers. 2007. Influence of hydration status on thermoregulation and cycling hill climbing. Med Sci Sports Exerc 39(2):323-329. IOM. 2005. Nutrient composition of rations for short-term, high-intensity combat operations. Washington, DC: The National Academies Press. Rauch, H. G., J. A. Hawley, M. Woodey, T. D. Noakes, and S. C. Dennis. 1999. Effects of ingesting a sports bar versus glucose polymer on substrate utilisation and ultra-endurance performance. Int J Sports Med 20(4):252-257.

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SPORTS DRINKS Background *

Sports drinks were developed to supply carbohydrate as a fuel and maintain hydration or enhance rehydration in response to the stresses of exercise. Most sports drinks contain 6–8 percent carbohydrate (as combinations of various forms including glucose, fructose, sucrose, high-fructose corn syrup, multidextrans) and electrolytes (10–25 mmol/L sodium and 3–5 mmol/L potassium) (Maughan and Murray, 2001). They are typically used prior to exercise to ensure fluid balance and to top off carbohydrate stores; during exercise to maintain hydration and provide carbohydrate fuel; and after exercise to replace body fluids, electrolytes, and carbohydrate. Some newer sports drinks have protein added, with the claim that this will enhance hydration and muscle protein balance. Some newer beverages marketed to active individuals also include additional compounds such as vitamins, minerals, herbs, and stimulants. These products contributed to a recent broad market for “energy drinks” or “functional beverages.” Some of these products are claimed to improve mood, athletic performance, or health. These products blur the line between foods and supplements. Some manufacturers may attempt to sell functional beverages as supplements because of the differences in regulation between supplements and foods. Very little research has been done to validate the effects of these beverages on health or performance. Putative Benefits Much research has been performed using traditional sports drinks with virtually no evidence of harm. On the contrary, there is much research that demonstrates evidence of benefit of carbohydrate ingestion for prolonged, moderately intense endurance exercise (especially in a hot environment). Most studies demonstrate that consumption of sports drinks (at up to 1 g/min carbohydrate) can improve endurance performance of exercise at 70 percent of aerobic capacity for 60 min or more (Jeukendrup, 2004; Maughan and Murray, 2001). Some studies support a benefit for exercise bouts of approximately an hour, but this finding is not consistent. More recent studies performed simulating sport activities such as soccer or basketball report improved performance and/or perception of effort (Winnick et al., 2005). The fluids and electrolytes provided by sports drinks can maintain plasma volume during exercise better than plain water and more rapidly rehydrate the body following dehydration. The electrolytes in these drinks help maintain the drive to drink such that more total fluid volume is typically ingested than if water alone is provided. There is some evidence that consumption of carbohydrate during exercise reduces the immune suppression that can occur with strenuous exercise (Nieman, 2007) . As reviewed by Gibala (2007), addition of protein to a carbohydrate beverage ingested during endurance exercise improves protein balance but does not consistently affect performance. Additional well-designed research is necessary to confirm the effects of protein on health and performance during exercise. Several studies suggest that sports beverages containing protein may improve muscle protein balance after strenuous exercise (Gibala, 2007), which also *

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requires additional validation. Enhancement of muscle protein balance by protein ingestion following resistance exercise has been repeatedly observed, but most hydration-type sports beverages that do contain protein would not provide the amount observed to have a substantial effect. Protein-carbohydrate products marketed specifically for recovery following resistance exercise typically have the recommended 6 g or more of protein per serving that may improve acute muscle balance. Very limited research suggests that consumption of these products or foods containing carbohydrate and protein shortly after every resistance workout will enhance lean tissue gains (Koopman et al., 2007). Safety Concerns There is little reason to be concerned about harm from the various “traditional” sports drinks containing electrolytes and 6–8 percent carbohydrate, other than provision of extra calories to those whose physical activities and environment do not warrant the additional hydration and energy. Substantial overconsumption of any hypotonic fluid, including sports drinks, could cause hyponatremia (blood sodium <135 mmol/liter), a very rare but potentially fatal condition caused by retention of fluids in vascular space in spite of efflux of blood sodium (Gardner, 2002; Montain et al., 2001). Data from the military estimated this risk to be very low, at 0.10 per 1,000 soldier-years (Craig, 1999). The risk may be higher for very salty sweaters and for those drinking extreme amounts of fluid. Evaluation of cases of hyponatremia among military personnel showed that all had consumed more than 5 liters (usually 10–20 liters) of water during a period of a few hours (Gardner, 2002). The incidence of hyponatremia is higher in female marathon runners than in male marathon runners, but the reported incidence in the military is similar to the gender distribution of the Army (15 percent female and 85 percent male) (Montain et al., 2001). Weight gain during prolonged exercise suggests evidence of possible hyponatremia. The risk of hyponatremia can be reduced by consuming an appropriate amount (not to exceed 150 percent of losses during exercise, typically not greater than 1.5 liters/h) of sodium-containing fluid. The value of ingestion of an electrolyte-containing beverage compared to water for superior maintenance of blood sodium during exertion has been shown in experimental studies (Barr et al., 1991) and with theoretical models (Montain et al., 2006). Considerations Specific to the Military Sports drinks are most likely to be of benefit for military personnel working in hot, humid environments where sweat loss is substantial. In addition, those personnel who are doing considerable amounts of exercise (> 1 hour per day) as part of their duties may perform better, feel better, and become less dehydrated if they consume a sports drink at regular intervals. The amount consumed should attempt to match the loss of body weight (i.e., sweat loss) and/or provide aproximately 1 g/min carbohydrate. Relevant data and conclusions on efficacy and safety reviews and publications identified for sports drinks are shown in Table 4-13.

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TABLE 4-13 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Sports Drinks Review/Clinical Trial Reference Gibala, 2007

Type of Study and Subjects Review

Indication

Control

Dose

Product Specification

Outcomes Measured

Protein metabolism

Various

Various

None reported

Endurance performance, repair and synthesis of muscle proteins, synthesis of muscle glycogen

Jeukendrup, 2004

Review

Exercise performance

Various

Various

None reported

Endurance capacity and performance

Maughan and Murray, 2001

Review

Exercise performance

Various

Various

None reported

Various

Nieman, 2007

Review

Immune function

None reported

None reported

None reported

Immune dysfunction

Winnick et al., 1995

Doubleblind, randomized, counterbalanced

Peripheral and central nervous system function

Placebo

6% carbohydrate solution:

Gatorade Sports Science Institute, Barrington, IL

Tests of peripheral and central nervous system function (sprints, jumping, mood evaluation, cognitive function, force sensation, motor skills tests, and target jumping accuracy)

n=20 active adults (10 male, 10 female), mean age 23.9 y

5 mL/kg before exercise 3 mL/kg after exercise 8 mL/kg during exercise

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Conclusions/Results

Adverse Events Profile

One study found that ingestion of a sport drink with added protein provided no additional benefit on athletic performance. There is no established mechanism by which protein intake during exercise should improve acute endurance performance.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

None reported

None reported

None reported

None reported

None reported

None reported

Ingestion of protein with carbohydrate improves net protein balance during exercise and recovery compared with carbohydrate alone, but it remains to be determined whether this practice facilitates the adaptive response to chronic training. Ingestion of small amounts of carbohydrate (16 g/h) during exercise has positive ergogenic effects on performance. Larger amounts do not show any further benefits. Rehydration with sports drinks can restore the negative fluid balance caused by exercise. Sports drinks can also restore muscle glycogen after exercise. Ingestion of a sport drink at regular intervals during physical activity may enhance performance. Ingestion of carbohydrate beverages during exercise is an effective countermeasure to exercise-induced immune suppression in marathon athletes. Carbohydrate supplementation decreases exerciseinduced increases in plasma cytokines and stress hormones, but is largely ineffective against other immune components including natural killer cell function and salivary IgA, with an undetermined influence on incidence of upper respiratory tract infections. Carbohydrate intake during exercise resulted in significantly faster 20-m sprint times and higher average jump height at the end of the exercise period. Carbohydrate intake also reduced force sensation, enhanced motor skills, and improved mood late in exercise. Carbohydrate intake during intermittent highintensity exercise similar to that of team sports improved peripheral and central nervous system function late in exercise.

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REFERENCES Barr, S.I., D.L. Costill, and W. Fink. 1991. Fluid replacement during prolonged exercise: Effects of water, saline, or no fluid. Med Sci Sports Exerc 23:811-817. Craig, S. C. 1999. Hyponatremia associated with heat stress and excessive water consumption: The impact of education and a new Army fluid replacement policy. MSMR 5:1-9. Gardner, J. W. 2002. Death by water intoxication. Military Med 5:432-434. Gibala, M. 2007. Protein metabolism and endurance exercise. Sports Med 37(4-5):337-340. Jeukendrup, A. 2004. Carbohydrate intake during exercise and performance. Nutrition 20(7-8):669-677. Koopman, R., W. H. Saris, A. J. Wagenmakers, and L. J. van Loon. 2007. Nutritional interventions to promote post-exercise muscle protein synthesis. Sports Med 37(10):895-906. Maughan, R., and R. Murray. 2001. Sports drinks: Basic science and practical aspects. Boca Raton, FL: CRC Press. Montain, S. J., M. N. Sawka, and C. B. Wenger. 2001. Hyponatremia associated with exercise: Risk factors and pathogenesis. Exerc Sports Sci Rev 29(3):113-117. Montain, S. J., S. N. Cheuvront, and M. N. Sawka. 2006. Exercise associated hyponatremia: Quantitative analysis to understand the etiology. Brit J Sports Med 40:98-105. Nieman, D. C. 2007. Marathon training and immune function. Sports Med 37(4-5):412-415. Winnick, J. J., J. M. Davis, R. S. Welsh, M. D. Carmichael, E. A. Murphy, and J. A. Blackmon. 2005. Carbohydrate feedings during team sport exercise preserve physical and CNS function. Med Sci Sports Exerc 37(2):306-315.

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TYROSINE Background *

Tyrosine , a large neutral amino acid found in most protein-containing foods, is the metabolic precursor for the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. These neurotransmitters play a significant role in mediating neural functions such as attention, arousal, and mood. Under normal conditions, the brain receives sufficient quantities of tyrosine from the diet to provide adequate amounts of these neurotransmitters. However, in stressful situations in which there are increases in the activity of catecholaminergic neurons and subsequent depletion of these neurotransmitters, tyrosine supplementation may prove useful. Both norepinephrine and dopamine play an important role in the performance of cognitive tasks involving psychomotor skills, decision making, vigilance, and memory. Decrements in these tasks are often observed in stressful situations resulting from conditions such as extremes in environmental temperature, sleep deprivation, and high altitudes. It has been hypothesized that these stress-induced decrements in cognitive performance are the result of increased activity within catecholaminergic neurons, and the consequent reduction of norepinephrine and dopamine within the central nervous system. It has been further suggested that increasing the synthesis of these neurotransmitters could ameliorate stress-induced deficits in mental functioning. Putative Benefits One way to increase levels of dopamine, epinephrine, and norepinephrine is to provide more of their metabolic precursor, tyrosine. Indeed, research using young military and nonmilitary personnel of normal weight has shown that tyrosine supplements can reverse a portion of the deficits in cognitive performance observed in cold environments (Ahlers et al., 1994; Mahoney et al., 2007; O’Brien et al., 2007; Shurtleff et al., 1994), at high altitudes (Bandertet and Lieberman, 1989), as a function of sleep deprivation (Magill et al., 2003; Wiegmann et al., 1993), after extensive combat training (Deijen et al., 1999), and in a multitasking environment (Thomas et al., 1999). Tasks involving memory and attention particularly benefited by tyrosine supplementation. Additionally, relative to placebo, tyrosine may alleviate stress-induced decrements in performance of psychomotor skills such as marksmanship (O’Brien et al., 2007). Tyrosine might also reduce negative mood states including fatigue, confusion, and tension that accompany environmental stressors (Bandertet and Lieberman, 1989). Safety Concerns Studies investigating the effects of tyrosine on cognitive behavior and psychomotor performance have examined doses of the amino acid ranging between 50 and 300 mg/kg body weight. The majority of these studies have used healthy, young, military personnel of normal weight as participants. The number of participants in these studies ranges from 8 to 75. *

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Participants reported no adverse consequences of tyrosine supplementation. However, it is important to note that in all of these studies, only a single trial of tyrosine supplementation was examined. There are no data on the effects of chronic tyrosine supplementation on cognitive function, or on the actions of tyrosine in individuals over the age of 35. A review of the literature on the use of tyrosine supplements did not find any studies indicating significant interactions between tyrosine and medications. Considerations Specific to the Military There is no indication that tyrosine will impart benefits to military personnel under normal garrison situations. However, tyrosine could benefit military personnel experiencing stressful environmental conditions that are typically associated with decrements in cognitive behavior, such as intense combat, exposure to extreme heat or cold, high altitudes, and sleep deprivation. Additionally, tyrosine could potentially improve mental performance when military personnel are required to respond to multiple demanding cognitive and psychomotor tasks. The scientific evidence for these putative effects, however, is still preliminary and lacks confimation. Relevant data and conclusions on efficacy and safety reviews and publications identified for tyrosine are shown in Table 4-14.

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TABLE 4-14 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Tyrosine Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Banderet and Lieberman, 1989

Double-blind, crossover n=23 male U.S. soldiers, age 18– 20 y

Mood, physical condition, and cognitive performance under environmental stress

Placebo

2 gelatin capsules adjusted to contain 50 mg/kg tyrosine

None reported

Mood states, sustained attention, vigilance, processing spatial and verbal information, math skills, number coding, pattern recognition

Wiegmann et al., 1993

Controlled n=20 male U.S. Marines, age 21– 27 y

Cognitive performance after sleep loss and sustained work

Placebo

2 doses of 75 mg/kg tyrosine

Ajinomoto Company, Inc.

Eye-hand coordination, shortterm memory, dichotic listening, mood, sleepiness, blood pressure, heart rate

Deijen and Orlebeke, 1994

Double-blind, randomized n=9 male and 7 female healthy subjects, age 25– 35 y

Cognitive performance

Placebo

100 mg/kg Ltyrosine

Country Life, Hauppauge, NY

Perceptual motor tasks, vigilance task, short-term memory test, Stroop task, and adjective checklist of mood

Shurtleff et al., 1994

Controlled 8 males

Cognitive performance

Placebo

Applesauce adjusted to contain 150 mg/kg tyrosine

Tysons & Assoc., Santa Monica, CA –crystalline tyrosine

Performance on delayed matching to sample test of working memory

Neri et al., 1995

Double-blind n=20 male U.S. marines, age 21– 27 y

Cognitive performance after sleep loss

Placebo

150 mg/kg tyrosine

None reported

Performance on psychomotor tasks, and mood scales

Deijen et al., 1999

Double-blind, randomized n=20 male and 1 female military cadets, age 18–27 y

Cognitive performance

Carbohy drate rich drink

2 g tyrosine in a protein-rich drink

PROTIFAR powder

Memory perceptual motor, vigilance tasks, and mood scales

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Conclusions/Results

Adverse Events Profile

Individuals were exposed to environmental stressors: Two levels of decreased temperature and reduced atmospheric pressure versus normal temperature and pressure. Relative to placebo, tyrosine significantly reduced symptoms of headache, coldness, distress, fatigue, muscular discomfort, and sleepiness in subjects who responded adversely to environmental stress. Tyrosine also reduced dizziness, feelings of confusion, unhappiness, hostility, and tension, and reversed the adverse effects of environmental stressors on cognitive performance on tasks measuring math skills, pattern recognition, vigilance, and coding.

None reported

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

Participants tested under conditions with noise stressor. Across night performance on cognitive tasks decreased. However, tyrosine administration led to smaller decrements in performance in eye-hand coordination, and short-term memory than placebo. Additionally, participants reported being less sleepy after tyrosine than placebo.

None reported

None reported

Relative to placebo, tyrosine improved performance on shortterm memory and Stroop task.

None reported

None reported

Tested at ambient temperatures of 4°C and 22°C. Relative to placebo, tyrosine prevented cold-induced memory deficit.

None reported

None reported

Tyrosine prevented performance decline on a psychomotor task and exhibited reduction on lapse responses on a vigilance task in sleep-deprived participants.

None reported

None reported

Tyrosine supplementation reduced cognitive deficits associated with psychosocial stress and fatigue associated with combat training. Tyrosine did not affect mood. Study design does not eliminate the possibility that other amino acids contributed to the observed results.

None reported

None reported

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TABLE 4-14

Continued

Review/Clinical Trial Reference

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Clinical Details and Outcomes Measured

Thomas et al., 1999

Double-blind, crossover n=10 male and 10 female active duty personnel and civilians, age 20–38 y

Cognitive performance under stress condition

Placebo

Applesauce adjusted to contain 150 mg/kg tyrosine

None reported

Simple task battery measuring working memory and multiple task battery consisting of four simultaneously occurring tasks measuring memory; math skills, visual monitoring, auditory monitoring

Chinevere et al., 2002

Double-blind, randomized, counterbalanced n=9 male competitive cyclists

Endurance exercise performance

Polydextrose solution or aspartame solution

25 mg/kg tyrosine dissolved in a polydextrose solution or water

None reported

Time trial performance test on a stationary bicycle

Magill et al., 2003

Double-blind, randomized n=76 males, age 18–35 y

Cognitive performance when sleep deprived

Placebo

150 mg/kg

None reported

Visual scanning, memory, logical reasoning, mathematical processing, reaction time, vigilance, pursuit tracking

O’Brien et al., 2007

Double-blind n=15 soldiers (14 male, 1 female)

Cognitive and psychomotor performance after cold water immersion

Placebo

2 energy bars adjusted to each contain 150 mg/kg tyrosine

None reported

Skin folds, U.S. Special Operations Command standardized tests of cognitive and physical performance evaluating short-term spatial memory and pattern recognition, complex reaction time, visual vigilance, mathematic reasoning, logical reasoning, psychomotor performance, marksmanship, grip strength, pull ups, cycle ergometer, step ups

Mahoney et al., 2007

Double-blind n=19 military members

Cognitive performance and mood after acute cold stress

Placebo

2 energy bars adjusted to each contain 150 mg/kg tyrosine

None reported

Visual vigilance, reaction time, short-term memory, mood state, muscle discomfort, alertness

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Conclusions/Results

Adverse Events Profile

Tyrosine improved performance on multiple task battery, but not on simple task battery. Tyrosine might be beneficial to memory under conditions of increased cognitive stress (e.g., multiple cognitive demands placed on military personnel).

None reported

Interactions with Pharmaceuticals, Foods, or other Dietary Supplements None reported

Tyrosine, either alone or with carbohydrates, did not improve cycling time trial performance.

None reported.

None reported.

Tyrosine showed positive effects for overcoming performance deficits due to prolonged sleep deprivation. Effects most pronounced for deficits in tasks measuring memory and mathematical processing.

None reported

None reported

Tyrosine mitigated cold-induced decrements in performance on tasks measuring short-term memory, pattern recognition, and marksmanship.

None reported

None reported

Tyrosine reduced cold-induced decrements in working memory and mitigated coldinduced increased score on tension subscale of mood test.

None reported

None reported

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REFERENCES Ahlers, S. T., J. R. Thomas, J. Schrot, and D. Shurtleff. 1994. Tyrosine and glucose modulation of cognitive deficits resulting from cold stress. In: Food components to enhance performance. Edited by B. M. Marriott. Washington, DC: National Academy Press. Pp. 301-320. Bandertet, L. E., and H. R. Lieberman. 1989. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull 22(4):759-762. Chinevere, T. D., R. D. Sawyer, A. R. Creer, R. K. Conlee, and A. C. Parcell. 2002. Effects of l-tyrosine and carbohydrate ingestion on endurance exercise performance. J Appl Physiol 93(5):1590-1597. Deijen, J. B., and J. F. Orlebeke. 1994. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull 33(3):319-323. Deijen, J. B., C. J. E. Wientjes, H. F. M. Vullinghs, P. A. Cloin, and J. J. Langefeld. 1999. Tyrosine improves cognitive performance and reduces blood pressure in cadets after one week of a combat training course. Brain Res Bull 48(2):203-209. Magill, R. A., W. F. Waters, G. A. Bray, J. Volaufova, S. R. Smith, H. R. Lieberman, N. NcNevin, and D. H. Ryan. 2003. Effects of tyrosine, phentermine, caffeine, d-amphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation. Nutr Neurosci 6(4):237-246. Mahoney, C. R., J. Castellani, F. M. Kramer, A. Young, and H. R. Lieberman. 2007. Tyrosine supplementation mitigates working memory decrements during cold exposure. Physiol Behav 92(4):575-582. Neri, D. F., D. Wiegmann, R. R. Stanny, S. A. Shappell, A. McCardie, and D. L. McKay. 1995. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med 66(4):313-319. O’Brien, C., C. Mahoney, W. J. Tharion, I. V. Sils, and J. W. Castellani. 2007. Dietary tyrosine benefits cognitive and psychomotor performance during body cooling. Physiol Behav 90(2-3):301-307. Shurtleff, D., J. R. Thomas, J. Schrot, K. Kowalski, and R. Hardford. 1994. Tyrosine reverses a coldinduced working memory deficit in humans. Pharmacol Biochem Behav 47(4):935-942. Thomas, J. R., P. A. Lockwood, A. Sing, and P. A. Deuster. 1999. Tyrosine improves working memory in a multitasking environment. Pharmacol Biochem Behav 64(3):495-500. Wiegmann, D. L., D. F. Neri, R. R. Stanny, S. A. Shappell, A. H. McCardie, and D. L. McKay. 1993. Behavioral effects of tyrosine during sustained wakefulness. Pensacola, FL: Naval Aerospace Medical Research Laboratory.

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VALERIAN Background *

Valerian is an herbal product made from the roots of the plant Valeriana officinalis that has been used for hundreds of years as a mild hypnotic. Over 150 individual compounds can be found in valerian, and although the exact mechanism by which it works is unknown, valepotriates and valerenic acid have been proposed as active ingredients (Houghton, 1999). One study found that valerian extracts bind to benzodiazepine receptors in vitro (Holzl and Godau, 1989). It was subsequently reported that valerian extract increased gamma aminobutyric acid (GABA) concentrations in the synaptic cleft, but this was complicated by the presence of endogenous GABA in the aqueous extract used (Gyllenhaal et al., 2000; Santos et al., 1994). Among the 31,044 people who completed the 2002 Alternative Health/Complementary and Alternative Medicine (CAM) supplement to the National Healthy Interview Survey, 5.9 percent reported using valerian. Of those users, 29.9 percent reported insomnia as a reason for taking the supplement (Bliwise and Ansari, 2007). Women reported using it more than men (2.6:1 ratio), and 23.4 percent reported using it to treat anxiety and/or depression. Putative Benefits Despite published literature and widespread belief that valerian has positive effects on sleep, the lack of scientifically sound clinical trials and longer-term studies investigating valerian makes it inappropriate to attribute any sleep-promoting efficacy to valerian. The available evidence suggests, but does not clearly demonstrate, the possibility that valerian may improve sleep quality (Bent et al., 2006), but this is not an outcome recognized by FDA. Recent reviews suggest that valerian generally produced decreased sleep latency, fewer nocturnal awakenings, and improved subjective sleep quality. However, in some studies the placebo effect was large, and in others the beneficial effects of valerian were not seen until after 2 to 4 weeks of therapy (Beaubrun and Gray, 2000). Five studies of valerian for sleep that included polysomnographic (PSG) recordings revealed no consistent, statistically significant changes in any PSG outcome measures (i.e., in sleep-onset latency, sleep efficiency index, sleep period time, time in each sleep stage, and number of arousals). Six randomized trials showed no difference between valerian and placebo groups in terms of sleepiness the next morning (Bent et al., 2006). Safety Concerns Despite recommended dosages for valerian, there may be significant differences in effective dose among the many commercially available products. First, the number and amount of active chemicals can vary greatly within individual species and between different species of plants used to produce a valerian dietary supplement (Hobbs, 1989), though most reputable distributors use the level of valerenic acid in their product for standardization (Gyllenhaal et al., 2000). Second, since valerian is considered an over-the-counter supplement by FDA, its contents and manufacturing process are not strictly regulated. Third, valerian products come in a variety of forms and dosages. Adult dosages for insomnia range from 1.5–3 g of actual herb or root, which *

The monographs were developed in order to evaluate the review process outlined in Chapter 5. The monographs present scientific reviews of safety and efficacy, but do not attempt to provide a final assessment of safety or efficacy. PREPUBLICATION COPY: UNCORRECTED PROOFS 4-167

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roughly corresponds to 400–900 mg of an aqueous extract, taken 30–60 minutes before bedtime (Morin et al., 2007). Owing to the lack of comprehensive randomized, double-blind, placebocontrolled trials (Stevinson and Ernst, 2000), valerian is not recommended for subjects under the age of 18 years. FDA generally regards valerian as safe, but some studies have reported concerns about toxicity. One study reported hepatoxicity in four women using a combination of valerian and another herbal product called skullcap (Scutellaria spp.) (MacGregor et al., 1989). Concern has also been expressed about the cytotoxicity of valepotriates, constituents found in negligible amounts in most valerian preparations. Valepotriates contain an epoxide group and were found to act as alkylating agents in vitro. However, this property was not found in vivo, presumably because of the poor absorption and distribution of valepotriates (Tortarolo et al., 1982; Wagner et al., 1998). Most studies reporting on the side effects of valerian found them to be mild and generally not more common than the placebo condition. In a placebo-controlled study of 128 subjects, one person experienced nausea and withdrew from the study. However, it was not possible to attribute the nausea definitively to valerian (Leathwood et al., 1982). Another placebo-controlled study found more adverse events with placebo than with valerian (Donath et al., 2000). Some evidence suggests that valerian does not have measurable hangover effects (Leathwood et al., 1982) or adverse effects on cognitive or psychomotor performance (Hallam et al., 2003), but further studies are needed to confirm these claims. Considerations Specific to the Military Valerian has the potential for unwanted synergy with other sedating agents that may be ingested. Therefore, people engaged in safety-sensitive activities that require alertness and quick responses should not take valerian in conjunction with other sedating substances, especially not in conjunction with prescription medications having sedating effects. Thirteen (12 percent) of the 109 medications most frequently prescribed for military personnel (e.g., hypnotics, anxiolytics, antidepressants, opioids) have sedating side effects. Relevant data and conclusions on efficacy and safety reviews and publications identified for valerian are shown in Table 4-15.

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See Next Page for Table 4-15

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TABLE 4-15 Relevant Data and Conclusions on Efficacy and Safety Reviews and Publications Identified for Valerian Review/ Clinical Trial Reference Leathwood et al., 1982

Type of Study and Subjects

Indication

Control

Dose

Product Specification

Outcomes Measured

Randomized, controlled n=128

Improvement of sleep quality and latency

Placebo

400 mg

Valerian aqueous extract

Subjective ratings of sleep quality, sleep latency, night awakenings, dream recall, next morning sleepiness

Donath et al., 2000

Randomized, doubleblind, crossover n=16 (4 male, 12 female), age 22–55 y, with psychophysiological insomnia

Sleep quality and structure

Placebo

600 mg for 8/d

Valerian extract (300 mg) pills as Sedonium

Sleep structure changes as measured by EEG,† EOG,‡ EMG,§ and ECG.** Subjective sleep quality

Beauburn and Gray, 2000

Review

Sleep latency, nocturnal awakenings, and subjective sleep quality

Placebo

400 mg to 900 mg

Valerian extract

Sleep latency, nocturnal awakening, subjective sleep quality

Bent et al., 2006

Review n=16 studies

Improving sleep quality

Placebo

Variable

Variable

Sleep quality

Diaper and Hindmarch, 2004

Double-blind, crossover n=16 (5 male, 11 female) sleep disturbed patients

Insomnia and improving sleep quality

Placebo

300 mg and 600 mg for 1 d

Valerian extract (300 mg) Sedonium

Time in bed, total sleep time, sleep latency, number of awakenings, total slow-wave sleep

Hallam et al., 2003

Randomized, doubleblind, crossover n=9 (5 male, 4 female) healthy subjects

Cognitive and psychomotor effects of valerian

Placebo

500 mg and 1000 mg for 1 d

Valerian extract (500 mg) Herb Valley

Critical flicker fusion, choice reaction time, digit symbol substitution test, symbol search test, digit span test, and visual analogue scales of mood.

†

Electroencephalography is the technique of using electrodes placed on the scalp to measure electrical activity of the brain. Electro-oculography is a technique for measuring the resting potential of the retina. § Electromyography is a technique for evaluating physiologic properties of muscles. ** Electrocardiogram is a recording of the electrical activity of the heart over time. ‡

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Conclusions/Results

Adverse events Profile

Interactions with Pharmaceuticals, Foods, or Other Dietary Supplements None reported

The aqueous extract of valerian produced a significant improvement in sleep quality in young, poor sleepers as well as a significant improvement in sleep quality in women who were poor sleepers. There were no differences between placebo and valerian in dream recall, night awakenings, or next morning sleepiness.

One person withdrew from the study because they experienced nausea. However, it was not possible to attribute the nausea definitively to valerian.

In insomnia patients, valerian had positive effects on sleep structure and sleep perception. It can be recommended for the treatment of patients with mild psychophysiological insomnia.

More adverse events were seen under the placebo condition (18 vs. 3).

None reported

Valerian generally produced decreased sleep latency and nocturnal awakenings and improved subjective sleep quality. However, in some studies the placebo effect was large and in others the beneficial effects of valerian were not seen until after 2 to 4 weeks of therapy.

Rare, but may include headache, restless sleep, allergies, gastrointestinal problems, and mydriasis.

Potential interaction with other sedative hypnotics

No significant difference was found between either dose of valerian and placebo. Valerian is ineffective as an acute treatment for sleeping problems at these doses.

None reported

None reported

Valerian was without effect on either cognitive or psychomotor performance at the doses used in this study.

None reported

None reported

Valerian may be an effective treatment for insomnia; larger studies needed.

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REFERENCES Beaubrun, G., and G. E. Gray. 2000. A review of herbal medicines for psychiatric disorders. Psychiatr Serv 51(9):1130-1134. Bent, S., A. Padula, D. Moore, M. Patterson, and W. Mehling. 2006. Valerian for sleep: A systematic review and meta-analysis. Am J Med 119(12):1005-1012. Bliwise, D. L., and F. P. Ansari. 2007. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. Sleep 30(7):881-884. Diaper, A., and I. Hindmarch. 2004. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res 18(10):831-836. Donath, F., S. Quispe, K. Diefenbach, A. Maurer, I. Fietze, and I. Roots. 2000. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry 33(2):47-53. Gyllenhaal, C., S. L. Merritt, S. D. Peterson, K. I. Block, and T. Gochenour. 2000. Efficacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Med Rev 4(3):229-251. Hallam, K. T., J. S. Olver, C. McGrath, and T. R. Norman. 2003. Comparative cognitive and psychomotor effects of single doses of Valeriana officianalis and triazolam in healthy volunteers. Hum Psychopharmacol 18(8):619-625. Hobbs, C. 1989. Valerian: A literature review. HerbalGram 21:19-34. Holzl, J., and P. Godau. 1989. Receptor binding studies with Valeriana officinalis on the benzodiazepine receptor. Planta Medica 55:642. Houghton, P. J. 1999. The scientific basis for the reputed activity of valerian. J Pharm Pharmacol 51(5):505-512. Leathwood, P. D., F. Chauffard, E. Heck, and R. Munoz-Box. 1982. Aqueous extract of valerian root (Valeriana officinalis L) improves sleep quality in man. Pharmacol Biochem Behav 17(1):65-71. MacGregor, F. B., V. E. Abernathy, S. Dahabra, I. Cobden, and P. C. Hayes. 1989. Hepatotoxicity of herbal remedies. Br Med J 299(6708):1156-1157. Morin, A. K., C. I. Jarvis, and A. M. Lynch. 2007. Therapeutic options for sleep-maintenance and sleeponset insomnia. Pharmacotherapy 27(1):89-110. Santos, M., F. Ferreira, A. T. Cunha, A. P. Carvalho, and T. Macedo. 1994. An aqueous extract of valerian influences the transport of GABA in synaptosomes. Planta Medica 60(3):278-279. Stevinson, C., and E. Ernst. 2000. Valerian for insomnia: A systematic review of randomized clinical trials. Sleep Med 1(2):91-99. Tortarolo, M., R. Braun, G. E. Hübner, and H. R. Maurer. 1982. In vitro effects of epoxide-bearing valepotriates on mouse early hematopoietic progenitor cells and human T-lymphocytes. Arch Toxicol 51(1):37-42. Wagner, J., M. L. Wagner, and W. A. Hening. 1998. Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother 32(6):680-686.

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5 Framework to Review the Safety of Dietary Supplements for Use by Military Personnel

BACKGROUND The increasing popularity of dietary supplements among civilians and military personnel has raised questions about their safety and efficacy for both populations. In the United States, various government agencies are charged with ensuring the safety of consumable products by developing and implementing policy according to their legal authority. Decisions regarding the safety of ingested substances in the United States are made using three models, based on the nature and intended use of each substance. The basic models are the food model (based on the assumption, derived from historic consumption, that all foods are safe and therefore, no premarket safety assessment is necessary), the food additive model (based on premarket safety assessments submitted to the U.S. Food and Drug Administration [FDA] by manufacturers), and the drug model (based on risk-benefit assessments submitted to the FDA by manufacturers). The Dietary Supplement Health and Education Act (DSHEA) of 1994 designated the FDA as the agency responsible for determining whether a marketed dietary supplement is unsafe (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress, October 25, 1994). The unique nature of dietary supplements (i.e., they are legally categorized as foods but are used to enhance health) and their history of use (i.e., some have been used as medicines for centuries by other cultures) have resulted in difficulty and confusion in establishing and implementing policies to address their safety. Despite wide concurrence that, given the nature of these products, a premarket approval process would be appropriate to address their safety, there is no such process in place. While the DSHEA mandates that manufacturers wishing to market new dietary supplement ingredients inform the FDA of their intention, this notification is often not accompanied by a safety profile of the product. The FDA relies on a postmarket adverse-event surveillance system to monitor adverse effects and, along with other supporting scientific data, to take action against any dietary supplement identified as unsafe after it has been marketed. However, the voluntary nature of reports by consumers or others to the FDA presents important limitations, such as low reporting rate or poor data quality (see Chapter 6). The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act represents a step forward in ensuring safety by mandating that companies report to the FDA any serious adverse event derived from the use of dietary supplements, but the success of this act in establishing an effective signaling system to identify supplement

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

ingredients particularly in need of safety evaluation is still unknown. The act defines the term serious adverse event as an adverse event that (A) results in (i) death; (ii) a life-threatening experience; (iii) inpatient hospitalization; (iv) a persistent or significant disability or incapacity; (v) a congenital anomaly or birth defect; or (B) requires, based on reasonable medical judgment, a medical or surgical intervention to prevent a previously listed outcome described under subparagraph (A). Also, in 2007, the FDA published the final rule, stipulated under the DSHEA, establishing the minimum current good manufacturing practices (cGMP) required for activities related to manufacturing, packaging, labeling, and storing dietary supplements to ensure their quality. This rule ensures consistency in product composition, but not the safety or efficacy of that product. The FDA is empowered to initiate regulatory action (e.g., banning a dietary supplement, taking an enforcement action [e.g., seizure or injunction] against a product or firm, or alerting the public) when the agency has evidence a product violates a provision of the Federal Food, Drug, and Cosmetic Act (FFD&C Act). Evidence that a product may be unsafe could include postmarket reports of severe adverse events, reports in the scientific literature of harm associated with exposure to a particular product or ingredient, or evidence of the presence of an adulterant such as an unforeseen contaminant or a purposeful adulterant. In light of the growing use of dietary supplements, the FDA requested in 2002 that the Institute of Medicine (IOM) provide a process or framework for evaluating the safety of dietary supplement ingredients. Highlights of the IOM report Dietary Supplements: A Framework for Evaluating Safety (2005) were presented at the February 2007 workshop (see Jeffery in Appendix B). The 2005 IOM report recognizes that the potential for a significant or unreasonable risk resulting from consumption of a dietary supplement varies depending on the specific circumstances of its use (e.g., under temperature extremes) or for specific populations (e.g., military personnel; see also Chapter 9 of the 2005 IOM report for a discussion of vulnerable groups). Thus, a vulnerable group may be at far greater risk from adverse effects of a given supplement than the general public. An example would be persons operating motor vehicles, who should not take sedative supplements such as valerian. Because neither federal dietary supplement policies nor the safety framework outlined in the 2005 IOM report was created with the specific needs (e.g., unique policies, behaviors, environmental stresses, and performance requirements) of the military population in mind, the U.S. Department of Defense (DoD) requested that this committee assess the applicability of the 2005 IOM report framework to a military setting and establish how it could be modified to determine which supplements need active management by the military. The committee concluded that the 2005 IOM report’s framework for the general population is not directly applicable to military personnel for reasons that include the military’s need for optimal health and performance as well as the high demands for readiness and success in military operations. Benefits and/or risks to military personnel from use of a particular dietary supplement might also differ from those of the general population owing to specific unit missions and environments; for example, the thermoregulatory effects of some dietary supplements could be critical for military personnel operating in extreme temperatures, while

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FRAMEWORK

5-3

they would be less important for the general population or for military personnel deployed to a more temperate area. Some groups of military personnel might experience risks and benefits from the use of dietary supplements different from those of other military personnel because of their unique responsibilities and tasks (e.g., aviators, those with access to nuclear weapons, or those conducting special operations). The U.S. regulatory model to manage the use of dietary supplements may also be inadequate for certain military populations (see Chapter 1, Box 1-3). For example, because of the potentially life-threatening consequences of being in suboptimal mental or physical health while conducting military operations, military leadership might need to develop an active monitoring system, rather than basing decisions only on the passive system of voluntarily reported adverse events now in use (see Chapter 6). Furthermore, the potential gains in health or performance from the use of some dietary supplements need to be considered in managing their use. For instance, if dietary supplement X causes slight dehydration but substantially improves alertness, the management of X by military leadership might be different from that of dietary supplement Y, which induces a similar level of dehydration but imparts little benefit. To summarize, this IOM committee was asked to review the 2005 IOM report’s framework for evaluating the safety of dietary supplements and assess whether modifications are necessary for its application to the military. This chapter does not enumerate the specific series of in vitro and in vivo toxicological and clinical tests that would be required to evaluate the safety of a dietary ingredient; these will vary with the specific ingredient(s), the users, and other circumstances. Instead, the chapter includes a framework to review the available scientific evidence and determine the level of concern; this is to be used as a tool to help military decision makers establish policies on the use of dietary supplements. In contrast to the 2005 IOM report framework, which—in accordance with the FDA’s mandate—focused only on safety, this committee has provided general guidance for the military on integrating considerations of efficacy and safety when making policy on dietary supplement use. The development of a framework to perform a complete risk-benefit analysis is beyond the scope of this report. It is also beyond the scope of this report to recommend definitive management actions. Examples are provided of possible actions (e.g., restricting or recommending the use of specific dietary supplements, developing educational programs) based on the level of concern (and the potential for benefit). To demonstrate application of the framework recommended, the committee reviewed a number of dietary supplements on the basis of published safety and efficacy reports (see Chapters 3 and 4) and identified those that might pose concerns or be of benefit. In addition, the committee’s overall approach (i.e., including application of the framework and recommendations for action) was applied to a subset of those dietary supplements (Appendix D). It was outside the committee’s task to provide a review of all dietary supplements. These monographs and case studies should be considered as examples; as recommended below, determining the specific actions to take in response to a dietary supplement review should be the prerogative of military leadership.

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5-4

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

SAFETY FRAMEWORK FOR DIETARY SUPPLEMENTS: MODIFICATIONS FOR MILITARY USE The committee’s recommended approach to manage the use of dietary supplements in a military context comprises four related components: 1) improving monitoring of the use of dietary supplements by military personnel, 2) using a framework to determine the level of concern for dietary supplements in a military context, 3) implementing a system to report adverse events associated with dietary supplements, and 4) expanding education on dietary supplements. This section describes the second component, that is, elements of the safety framework outlined in the 2005 IOM report that are particularly useful to the military in its need to understand the safety (and possible benefits) of the use of dietary supplements by military personnel. (For greater detail on the regulatory background and the statement of task of the 2005 IOM Committee on the Framework for Evaluating the Safety of Dietary Supplements, see Jeffery in Appendix B). The 2005 IOM report framework consists of a process for prioritizing, evaluating, and describing available information to establish risk of harm, together with a second, supportive component: a set of science-based principles that serve as guidelines for evaluating risk to human health (see Jeffery, Figure B-24, in Appendix B) . It characterizes the nature of the scientific evidence that is likely to be available to the FDA and describes a process for organizing this evidence to assess the level of concern for a dietary supplement ingredient. A “significant or unreasonable risk of illness or injury” is the standard that warrants regulation by the FDA under the FFD&C Act, as amended by the DSHEA. The process outlined in the 2005 IOM report is divided into three steps: signal detection, initial signal review to determine a preliminary level of concern, and integrated safety evaluation of dietary supplements. This process provides a basis for determining whether a dietary supplement is unsafe and for translating a serious concern into safety management actions. For example, a high level of initial concern based on a signal that leads to a high potential for a “significant or unreasonable risk of illness or injury” warrants a full evaluation of safety. Proving that a dietary supplement presents an unreasonable risk is a substantial undertaking requiring valuable time and resources. The FDA, which bears responsibility for the safety of all dietary supplements on the market, is presently limited to responding to reports of serious adverse events as the primary signal for action. The DoD could take a more proactive stance, choosing to evaluate the effects of a dietary supplement and take management actions based on criteria pertinent to the demands of military service. Thus, the military may choose to focus attention on determining the safety of those dietary supplements with the highest volume of sales, even if there have been no adverse events reported for the general population. Furthermore, the scientific basis for concern may be more stringent and may include evidence of more subtle effects than those causing concern for the general public. For these reasons, the 2005 IOM report framework has been adapted to meet the specific needs of the military. Described below are the three steps (i.e., signal detection, initial review of signals, and integrated safety evaluation) described in the 2005 IOM report, followed by their adaptation for the military.

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Signal Detection The 2005 IOM Safety Framework for Dietary Supplements: Adverse Event Monitoring The 2005 IOM report suggested that, given the limited resources available to the FDA, a supplement should undergo a safety review only when the signal of a serious adverse event indicates the need. However, should resources permit, it was proposed that the FDA’s attention should focus on signals that indicate a serious health problem may result from ingestion of a dietary supplement ingredient. The 2005 IOM report framework suggested that if the FDA were able to operate proactively, a review of a dietary supplement ingredient should be initiated on the basis of either a high prevalence of use in the general population, or a high level of use by a particularly vulnerable population. As Modified for the Military: Adverse Events and Frequency of Use Monitoring The military should proactively concern itself not only with dietary supplements associated with an adverse event but also with those most commonly sold on base, and with consideration for the safety of those military personnel who, because of their duties, would be particularly vulnerable to the adverse effects of specific supplements. For example, pilots might be susceptible to effects including hypoxia, cognitive decrements, or loss of spatial orientation. Similarly, those on active duty in adverse environments might be particularly vulnerable to supplements causing loss of thermal regulation (see Chapter 1, Box 1-3 for a list of special military populations). Conversely, if there were supplements that could aid in prevention of these adverse effects, this information might be of considerable benefit to the military. Initial Review of Signals The 2005 IOM Safety Framework for Dietary Supplements: Severity of Adverse Events The second step in the process outlined in the 2005 IOM framework is the initial review of available information on the signal (i.e., adverse event reports). First, the nature of the signal information is examined to determine the preliminary level (low, moderate, or high) of concern about a potential risk to human health. This is not a detailed analysis of data, but rather an assessment to determine whether further evaluation of the supplement is indicated. If review of the reports show an isolated case lacking reliable evidence that the supplement was likely to be a cause, the resulting low level of concern would indicate no further need for action at that time. If signal review results in even a moderate level of concern traced directly to the supplement, then other criteria, such as prevalence of use or potential to adversely affect vulnerable subpopulations, should be considered, which might result in elevation of the signal concern level to high. Signal review would typically be triggered by an adverse event report of medium or high concern.

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As Modified for the Military: Severity of Adverse Events and Frequency of Use Recommendation 4: The decision to initiate a review of a dietary supplement should be based on two criteria: severity and number of adverse events, and prevalence of use. The selection of dietary supplements for review should consider the particular vulnerabilities of the military subpopulations, which would depend on their missions and mission environments. Severity and number of adverse events As with the general population, one set of criteria relies on adverse event(s) reported by military or nonmilitary personnel. (See Chapter 6 for recommendations on a system to monitor adverse events for the military). Military health care professionals should identify any adverse events associated with dietary supplement use that might compromise the performance or survivability of military personnel. Such adverse events would include those that affect vigilance; have a significant adverse impact on alertness, mood, or cognitive performance; cause hypoxia; or affect balance or spatial orientation. They would also include impairment of clotting, hydration, immune function, or thermoregulation. Conditions to help categorize adverse events as high, moderate, low, and minimal are listed in Box 5-1. Summaries of adverse event reports should be submitted to the military committee or entity designated to oversee dietary supplements (herein referred to as the designated oversight committee; see Chapter 6), who will identify a signal of concern for a dietary supplement and determine whether a review is appropriate. When the adverse event reported is serious or might compromise performance or survivability, the committee proposes a two-part response. The first step is to determine whether urgent action (e.g., new policies; see Figure 5-1) is warranted. Second, in conjunction with policy implemention and enforcement, a safety and efficacy review should be conducted. Adverse events of moderate concern might not signal the need for new policy, although the military should initiate a safety review (Figure 5-1). If no adverse effects are being noted from the use of a specific supplement and its safety review reveals no concern, then the determination would be made that the dietary supplement is of minimal concern and no further evaluation would be needed. Nevertheless, due to low rates of adverse event reporting, the lack of such reports does not necessarily mean that the dietary supplement is safe. Further, the committee believes that because these products are bioactive, high frequency of use calls for a review of safety, unless the dietary supplement has already been declared to be of minimal concern. The committee cautions that the linking of an adverse event to a dietary supplement ingredient might be confounded if the product contains multiple ingredients, adulterants, or adventitious contaminants. In the case of multiple ingredients, determination of causation for a particular substance requires careful review of all the individual ingredients in a product or the combination product itself. If contamination is the issue, then attribution of the source of the event is even more challenging. In either case, and until the cause of the adverse event is determined, the military might need to apply policies for the use of the suspect product as well as for any other product containing any of the ingredients found in the suspect product.

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BOX 5-1 Description of Concern Levels Specific to Use of Dietary Supplements by Military Personnel High concern x Human epidemiological studies or adverse effects signaling: o Product has been found responsible for a serioussevere adverse event1 o Performance degradation (e.g., for those deployed, in training, or in combat settings) from: ƒ Product significantly affects vigilance ƒ Product has significant adverse impact on alertness/drowsiness, mood alteration, cognitive performance ƒ Product significantly induces hypoxia ƒ Product significantly affects balance and spatial orientation A decrease in survivability (e.g., for those deployed, in training, or in combat settings) from:(particular concern in combat or deployed settings) ƒ Product significantly inhibits clotting time ƒ Product significantly promotes dehydration ƒ Product significantly inhibits immune system Product significantly disrupts affects body’s ability to maintain thermal regulation x Animal data signaling: o Severe adverse events as described above for human data, seen in animals at doses 10x recommended exposure for humans o Neoplasia o Severe organ toxicity (necrosis/dysplasia) o Reproductive failure/developmental effects o Severe neurological/behavioral changes o

x

In vitro data signaling: o Multiple different assays suggest the same pathological condition related to severe adverse events described for human data above. o Concentrations of the dietary supplement causing severe adverse effects in vitro are similar to reported blood or plasma levels in humans following consumption of this dietary supplement. o Chemical or plant species are similar to known toxic compound and/or banned dietary supplement, or similar to products having adverse effects described above in humans.

1

The 2007 Dietary Supplement and Nonprescription Drug Consumer Protection Act defines the term “serious adverse event” as an adverse event that (A) results in (i) death; (ii) a life-threatening experience; (iii) inpatient hospitalization; (iv) a persistent or significant disability or incapacity; (v) a congenital anomaly or birth defect; or (B) requires, based on reasonable medical judgment, a medical or surgical intervention to prevent a previously listed outcome described under subparagraph (A).

continued

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

BOX 5-1 Continued Moderate Concern Human epidemiological studies or adverse events signaling: o Performance degradation (e.g., for those deployed, in training, or in combat): ƒ Product has moderate impact on hydration, gastrointestinal function (e.g., diarrhea, nausea), shortness of breath, syncope, thermal regulation, alertness/drowsiness, mood, or cognitive performance.

x

o

A decrease in survivability (e.g., for those deployed, in training, or in combat): ƒ Product has moderate impact on clotting time. ƒ Product has moderate or low ability to inhibit immune system.

x

Animal data signaling: o Moderate organ toxicity (atrophy, hyperplasia) o Reduced reproductive capacity/mild developmental effects o Altered clinical chemistry outside the reference range o Those adverse effects listed above as severe in humans, occurring at 100x the recommended dose range Low Concern x Human epidemiological studies or adverse events signaling: o Performance degradation: ƒ Product has low impact on hydration, gastrointestinal function (e.g., diarrhea, distress, nausea), alertness/drowsiness, thermal regulation, mood, or cognitive performance. o x

No decrease in survivability (product has no known impact on immune response or bleeding/clotting time).

Animal data signaling: o Reduced food intake o Enzyme changes o Reversible degenerative changes

Minimal Concern x Human epidemiological studies or adverse events signaling: o No serious adverse events o No performance degradation (product has no known impact on hydration, gastrointestinal function, thermal regulation, alertness/drowsiness, mood, or cognitive performance) o

No decrease in survivability (product has no known impact on immune response or bleeding/clotting time)

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Copyright © National Academy of Sciences. All rights reserved. Moderate Concern

Low Concern

Integrate Data from A, B, C and Decide on Lev el of Concern (See Box 5-1)

Minimal Concern

C. Review of Interactions with Medications

Proactive Initiative

5-9

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FIGURE 5-1 Framework to review the safety of dietary supplements

Footnote: 1High Physical Activity; Calorie Restriction; Hydration; GI Tract (diarrhea/nausea); Liver Health/Function (xenobiotic clearance); Cardiovascular Health; Mood/Behavior Altering; Alertness/Drowsiness; Extreme Heat/Cold; Injury/Bleeding

High Concern

Safety Review

B. Review of Original Research Pertaining to Specific Military Concerns1

Adverse Effects, not severe

A. Review of Safety Using Reviews or Original Research if Reviews are Nonexistant

Severe AdverseEffects

Signal Detection-Adverse Effects

FRAMEWORK

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Prevalence of use A second criterion to commence a review relies on a proactive initiative by military leadership in response to the use of a new supplement similar to a drug or supplement that has previously caused safety concerns (e.g., bitter orange contains synephrine, closely related to ephedrine, the active component in ephedra); the high frequency of use of a supplement; or an increase in frequency of use in the general military population or specific subpopulations. To make such decisions, data from dietary supplement sales and survey data on dietary supplement use within the military would be required (see Chapter 2). For example, the military should review data on sales of dietary supplements from outlets located on base (e.g., Army and Air Force Exchange Service/Navy Exchange Service [AAFES/NEX ], fitness centers) annually to determine which supplements have become popular. Because of the low reporting rates for adverse events, the lack of data on adverse events does not necessarily show that a dietary supplement is safe. Also, because these products are bioactive, a review of the safety of widely used dietary supplements is warranted unless the dietary supplement has been declared to be of minimal concern. If no adverse effects are noted from the use of a specific supplement and its safety review reveals no concern, then the determination would be made that the dietary supplement is of minimal concern and no further evaluation would be needed. Many factors need to be taken into consideration in determining a level of concern from adverse events reported, including the strength of the evidence (e.g., how many adverse events were associated with the dietary supplements, the strength of the association, level of intake, intake of other medications/supplements, actual circumstances of use, characteristics of the individual user). The committee recommended that the evidence be reviewed and that the level of concern be determined by taking into consideration not only the the strength of the evidence but also the tasks of the specific military subpopulation and the environment in which it will be conducting them (e.g., extreme temperatures or altitudes). As described further in Chapter 6, the designated oversight committee should review adverse events reported by the general population and by the military (as recorded in summaries submitted by the Medical Treatment Facilities’ [MTF] Pharmacy and Therapeutic Committees [P&T]), as well as surveys of supplement use by military personnel, on an annual basis. As a result of these reviews, the designated oversight committee might recommend to the military leadership immediate action and/or conducting a review of published, science-based safety reviews by the review panel. The designated oversight committee may call a special meeting or conference call if adverse events are serious or frequent, as judged by the MTF P&T committees. Integrated Safety Evaluation 2005 IOM Framework: Integrated Safety Evaluation The third step of the 2005 IOM report framework is a fully integrated safety evaluation (conducted by a panel of experts) of those dietary supplement ingredients that warrant further investigation based on the concern level raised by initial signal review. There are four components to an integrative evaluation (see Jeffery, Figure 1, in Appendix B): in-depth search and review of literature, drafting of a safety monograph, integrating this information into an analysis to complete the monograph, and review of the draft monograph by an expert advisory

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5-11

committee. In accordance with the FDA’s designated function, the 2005 IOM report did not address any potential benefit of a dietary supplement. Safety reviews of dietary supplements can be performed at various levels, depending on factors such as urgency and the availability of human and economic resources to conduct the review. The 2005 IOM report recommends that four categories of safety data be collected for evaluation following the detection of a signal: human data, animal data, data on related substances, and in vitro data. In conducting the safety review, the panel of experts would also consider possible interactions between a dietary supplement and medications or other xenobiotics. (Examples of monographs and evidence models are available online at www.iom.edu/fnb). A focused evaluation reviewing only one key ingredient or single area of concern such as cardiac health or renal health might also be appropriate. Both the comprehensive and the focused evaluation might include consultation with an expert committee, FDA personnel, or both, depending on the quality and clarity of the available data. The integration of the available data using evidence-based principles is the final exercise in establishing a risk level for the dietary supplement, using a causal model diagram that integrates human, animal, in vitro, and even chemical information. Scientific principles for weighting and integrating data from these different categories were described in the 2005 IOM report (see also Jeffery, Box B-14 and Figures B-24 and B-25, in Appendix B). As Modified for the Military: Integrated Safety Evaluation Recommendation 5: The military should use the framework (Figure 5-1) to review the dietary supplements that raise safety concerns (per criteria above). The framework consists of the integrated evaluation of results from current, authoritative reviews (or, if no reviews are available, original research conducted over the previous 10 years) analyzing bioactivity and potential for drug interactions. Efforts to review and summarize information to determine the concern level about a dietary supplement should consider not only from individual adverse events reported about also integrate all other data pertinent to its safety. The scientific principles outlined for the FDA are expected to be used by the military to evaluate the data (see Jeffery, Box 3, in Appendix B). For the integrated evaluation, the committee recommends an approach less expensive and time consuming than the full evidence-based review in the 2005 IOM report: an initial review of safety reviews authored by other reputable scientists (see Box 5-2). Evidence of the effect of interaction of dietary supplements with medications, focusing on medications frequently used by service members, should be taken into consideration. A military review panel should write a monograph for a dietary supplement that raises concerns (see models in Chapters 3 and 4). This review panel will be provided oversight by the U.S. Army Research Institute of Environmental Medicine (USARIEM), an Army medical research laboratory that investigates military nutrition issues. They review panel would include nutritionists, epidemiologists, toxicologists, clinicians, and pharmacognosists. Although contracting performance of the reviews out to a nonmilitary group might be feasible, the safety and efficacy evaluation as it applies to military situations would be best conducted by a military review panel because they will be more cognizant of the demands and conditions unique to military operations and more experienced in identifying safety concerns relevant to military performance and survivability than a nonmilitary group.

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

In special cases, this activity could be followed by a more comprehensive safety review of original research, focused on performance and survivability as well as the particular health and environmental situations characteristic of military personnel. Some of these characteristics would be related to external situations (e.g., high-intensity physical activity, high altitude, temperature extremes) or health concerns (e.g., injury or bleeding; dehydration; function of the gastrointestinal, immune, renal, hepatic, or cardiovascular system; altered behavior, alertness or drowsiness). This focused approach would not only shorten the length of time necessary for the review, but might also reduce the types of expertise required and ultimately result in information that is more useful. Original research from the time of the last review or, where current reviews are not available, original research conducted over the preceding 10 years should also be surveyed. As a complement to database searches, a forum or coalition should be established to share data on adverse events and other information on dietary supplements (see Chapter 6). Once the reviews of the individual dietary supplement are concluded, the review panel should declare its level of concern. The committee developed criteria on which to base the level of concern that use the same principles as the 2005 IOM framework but with a focus on survivability and performance issues (see Box 5-1). The concerns are classified from minimal to high, reflecting the level of performance degradation and survivability and taking into account the special circumstances (environment, hazards, stresses, and performance requirements) of concern to military personnel. If the data are insufficient to establish a level of concern, then the review panel could leave the review incomplete, awaiting further research on safety (and efficacy) or, depending upon the level of military concern, could request that the additional research be performed. It may or may not be appropriate for the military commander to recommend that the substance not be used by military personnel until the determination of concern level has been made. The committee recognizes that owing to the potential for synergistic or antagonistic effects among ingredients, there are important challenges to applying this framework to products with multiple ingredients. However, because of safety concerns derived from these supplements and ingredient interactions, the committee’s approach should also be applied to them. Two approaches to determining level of concern are offered below. In addition, the committee recommends focusing attention on signals from adverse event reporting and data on military usage of these products. The committee did not provide a framework to evaluate efficacy; however, information on efficacy should also be collected and included in the monograph since the potential for benefits of a dietary supplement will be factored in the final level of concern.

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BOX 5-2 Approach to Data Collection The committee developed the following process to characterize the concern level (and efficacy) of a dietary supplement used by military personnel: (1) identify the dietary supplement that warrants review, (2) conduct literature searches, and (3) summarize conclusions about safety (and efficacy). A proposed search process that is both cost-effective and valuable is summarized in Figure 5-2 as a stepwise decision-making tree. The committee believes that although an evidencebased review of original journal articles might provide a more comprehensive evaluation of safety, an evaluation from well-conducted, authoritative reviews could serve the purpose of alerting the military to potential problems (or benefits) and the need for active management. In evaluating the safety of dietary supplements, data are needed on two basic attributes: bioactivity (negative or positive) of the ingredient and effects derived from synergistic or antagonistic interactions with other active substances (i.e., in foods, medications, or other active substances). 1. Bioactivity: Literature searches for systematic reviews of safety and efficacy of the dietary supplement of interest should be carried out in the appropriate databases (primarily PubMed, but also other databases [Napralert, Toxline, SciFinder, or other]). The focus should be on health concerns and unique environmental circumstances of military life. Some areas of particular interest to the military for safety (or efficacy) include specific conditions such as high level of physical activity; restriciton of caloric intake; high altitude; extreme heat or cold; health issues such as dehydration, function of gastrointestinal tract, immune, cardiovascular, biliary, or renal systems; and neurobehavioural health. Medical Subject Headings (MeSH) terms for the area of interest could help identify key search terms. Original research articles for safety (and efficacy) should be reviewed from the publication date of the last well-conducted review or for the previous 10 years if no systematic reviews exist. 2. Interactions with food, medications, or other bioactive substances: Data on interaction with other bioactive compounds are scarce. For identifying interaction with medications, two online databases are particularly recommended: PubMed Plus and Clinical Pharmacology. If the dietary supplement of interest is not included, it may be necessary to search the complete listing of reviews for medication interactions. To enable this, a list should be created of the 100 medications most frequently prescribed for active duty personnel, including mechanism of action and indications for use. This listing should be updated by the military on a regular basis but initially at least annually. Some of the potential warnings against the use of dietary supplements in combination with medications would be apparent from this list (e.g., the committee cautions against the use of melatonin in combination with other sedative substances). Because of the severe lack of data in the area of interactions, the committee suggests that hypothetical effects from interactions should be based on mechanistic rationale. Likewise, in the absence of clinical data, animal or in vitro data or chemical similarity to ingredients with known interactions can provide suggestive information about potential interactions. Conclusions from these latter approaches are uncertain though, as clinical research data have on occasion refuted initial speculations about synergistic effects. Once information is acquired on a potential interaction, further searches should be done specifically for possible interactive effects of the medication/dietary supplement combination, whether in review articles or original research and using the same databases as above.

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Review Process

A. Review of Safety

B. Specific Military Issues

C. Review of Drug Interactions

Search for reviews in Pubmed/other databases

Construct seach terms such as those footnoted on Figure 5-1

Consult MedLine Plus or Clinical Pharmacology online

Information Systematic review identified

available

Use these terms to search the systematic reviews

No information

No Yes Searching 10 years

Use drugs identified to search the systematic reviews

Construct a list of 100 most prescribed medications

Searching articles since review date

Integrate into a monograph

Construct using drug names where interactions are updated

FIGURE 5-2 Stepwise algorithm depicting search strategy to review the safety of dietary supplements.

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Decision to Take Action 2005 IOM Framework: A Safety Model for Decision Making The 2005 IOM report recommends that the results of the safety evaluation should play a pivotal role in the FDA’s determination of whether a supplement ingredient is unsafe. Furthermore, because an important component of the DSHEA is public education about dietary supplements, it was anticipated that any monograph developed might be made publicly available on the FDA website. Evidence that results in a high level of concern indicates the need for further investigation to determine whether a “significant or unreasonable risk of disease or injury” (the FDA basis for action) exists. Conversely, the 2005 IOM report suggested that when review of information (either at the initial review stage or as a result of an integrated safety evaluation) indicates a lower level of concern, the FDA should continue to monitor information about the dietary supplement ingredient. Monitoring could consist of passively receiving new signals of concern and/or maintaining routine searches of the scientific literature to gather data about specific existing or new concerns. As Modified for the Military: Integrating Safety and Efficacy Recommendation 6: The military’s decisions on dietary supplement policy (e.g., rules, education, monitoring of use) should be based on conclusions about both safety and efficacy derived from the available published, authoritative scientific literature and considering conditions associated with a specific type of mission, location, and environment. Although the development of a detailed process to establish a dietary supplement’s level of efficacy was not within the scope of the current task and this committee was not constituted to address the question of efficacy, the committee concluded that considerations of safety and efficacy should be integrated to make decisions about policy on the use of dietary supplements in a military context. A more general description of benefit levels (Table 5-1) was developed by the committee to classify present and future dietary supplements by potential benefit. The determination of level of benefit is dependent on the number and quality of studies that demonstrates the benefit (or lack thereof) of interest to the military. It is advised that a “road map” to assess benefits be developed, similar to the framework for safety evaluation. Because the determination of benefit and concern for a subpopulation is often specific to the mission, location, and environment, decisions on managing the use of dietary supplements should be made by the Office of the Assistant Secretary of Defense (Health Affairs) and by military commanders who will consider these factors along with the scientific evaluation recommended in this chapter. Considerations of the level of concern, potential benefit, and specific military population, tasks, and environments should be integrated in order to decide on appropriate action. The committee has developed the attached matrix (Table 5-2) as a guide to assist the military in making decisions on the use of dietary supplements. The potential actions suggested by the committee can be grouped into three different categories: policy, education, and monitoring. Any decisions for action should be made in consultation with the review panel of

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experts and the designated oversight committee, who will have a deep understanding of the scientific data.

TABLE 5-1 Guide to Determine Level of Concern and Benefit to Formulate Decisions on Managing Dietary Supplement Use Among Military Personnel, Based on Science and Physiological Effects Level of Concern or Benefit High Moderate

Low/Minimal/Uncertain

Level of Science Documenting an Effect (concern or benefit) High level of science (large number of consistent high-quality studies) High level of science (large number of high-quality studies) Moderate level of science Any level of science

Concern or Benefit Specific to Military Mission for Subpopulation of Interest High concern (or benefit) Moderate concern (or benefit) Moderate or high concern (or benefit) Low, minimal, or no concern (or benefit)

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TABLE 5-2 A Guide to Formulating Decisions on Managing Dietary Supplements for Military Personnel, Based on Safety Concerns and Modified by Potential for Benefit Suggested Actions Based on Level of Concern/Benefit*

Type of Action Concern Benefit High Benefit

Moderate Benefit

Low Benefit

High Concern

Moderate Concern

Low Concern

Minimal Concern

Policy

2

3

5

6

Monitoring

7

7

7

7

Education

8

8

8, 9

8, 9

Policy

2

3

-

-

Monitoring

7

-

-

-

Education

8, 9

9

9

9

Policy

1

4

-

-

Monitoring

7

-

-

-

Education

8, 9

9

9

9

* The determination of benefit and concern level for a military subpopulation is often specific to the task, environment, and location. Decisions on managing the use of dietary supplements should be made by Office of the Secretary of Defense (Health Affairs) and military commanders who will consider these factors along with the scientific evaluation recommended in this chapter. Policy: 1. DoD, service, and surgeon general implement policy to prohibit use of product. 2. DoD, service, and surgeon general specify parameters of use. 3. Unit & MTF commanders make decision on policy based on mission and subpopulation. 4. Posting of warning/educational labels (e.g., at military installation outlets and exercise facilities) 5. Commanders, health care personnel, and fitness center and unit trainers recommend that its use be considered for specific relevant personnel and circumstances. 6. Commanders, health care personnel, and fitness center and unit trainers recommend its use for specific relevant personnel and circumstances. Monitoring: 7. Monitor for adverse events and frequency of use. Education: 8. Educate commanders, health care personnel, and fitness center and unit trainers on risks and benefits of specific dietary supplements to enable them to make management decisions. 9. Educate all service members on risks and benefits of dietary supplements in general.

The framework developed should help the military make decisions regarding the risks/benefits of dietary supplement use by carefully examining the science-based evidence, and should point to research gaps. Making decisions to recommend or restrict the use of a dietary supplement based on the limited data available is difficult. Also, recommendations to use a dietary supplement should be made carefully and only after clear evaluation of risks and benefits,

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since these recommendations will raise questions related to the personal choce of service members as well as financial and logistical implementation of the recommendation or other. The committee recognizes the limitations of making decisions based on balancing risks and benefits; these limitations are related to the availability of data and the evaluation of risks and benefits. For example, for many products, lack of data on safety might preclude the military from determining the concern level. In these cases, the military might decide to support research and restrict the use of the supplement until a concern level can be determined. Furthermore, balancing considerations of benefits and concerns will present difficulties that derive from differences in strength of the evidence for safety and efficacy, lack of suitable indicators to compare the potential benefits and concerns, and the need to weigh the benefits and risks for different subpopulations. Other considerations will also need to enter into the decisions such as the availability of other methods/supplements to achieve a similar beneficial effect without the risks. Policy This committee believes that whereas the conclusions about the level of concern and benefit (parallel to the “risk assessment” concept in a risk analysis model) should be determined by scientists (i.e., nutritionists, epidemiologists, and/or toxicologists), the decisions about implementing military policy (paralleling the “risk management” concept in a risk analysis model) should be pursued by commanders at the appropriate level in the military organizational structure. The specific actions taken in response to a dietary supplement review should be the prerogative of military commanders who are knowledgeable about the demands of a particular military subpopulation and its tasks. This model can be successful only when the scientists in the review panel and the designated oversight committee (see Chapter 6) consult and communicate with military leadership and decision makers. Education Because members of the military obtain information about dietary supplements from many sources, often with no scientific authority, education based on objective analysis of the efficacy and safety data should be provided on which to make a decision to take supplements not restricted by military policy. Furthermore, educating the commanders, health care providers, and physical trainers about the safety and benefits of certain dietary supplements will permit these individuals to appropriately exercise leadership and provide guidance to military members. This educational component should be initiated as part of these leaders’ formal training and should continue throughout their military careers (see also Chapter 6). Communication between those responsible for the education of military service members and the designated oversight committee is critical. One way of providing information on dietary supplement safety and efficacy would be to develop a summary table showing both benefits and safety, together with an integrated concern level for the general military population and specific subpopulations (e.g., Table 5-3). Such a table could be used as a basis to develop educational materials for commanders, fitness or military unit trainers, and health care providers to inform service members. The committee cautions that such a summary table could be misinterpreted and therefore is not to be used as a sole source of information; it is meant to be used by those with sufficient scientific expertise as a tool to develop educational materials. Communication with service members should not establish a presumption that using dietary supplements is the norm or the expected behavior.

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Copyright © National Academy of Sciences. All rights reserved.

Elevation of circulating catecholamines at high dosages

Elevation of core body temperature by restriction of peripheral heat loss

Mild to moderate locomotor agitation, tachycardia, diuresis, and anxiety. Sleep disturbance can occur if ingestion is within a few hours of sleep time.

Moderate caffeine intake of 400 mg/day has not been associated with adverse effects in most people.

Military Survivabilityf

No data foundh

Other Health Risksa

An increasing number of dietary supplements, performance-enhancing foods, and sports drinks contain caffeine, even if it is not listed on the label. This can further increase the amount of caffeine being ingested and add to detrimental effects, tolerance, and adverse events.

Sympathomimetic stimulant that may have synergy with other psychostimulants

Interactions with Medicationsb or Other Bioactive Substances

Limited data indicating headache and caffeine craving

Withdrawal Effects

High potential for benefit (substantial evidence of beneficial effects for performance during sleep deprivation)

Substantial evidence that 100–600 mg caffeine can improve many aspects of cognitive and psychomotor performance during periods of sleep deprivation, and 200–600 mg can enhance physical endurance.

Putative Benefitsc

Moderate

Concern Leveld

b

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Causing risks to health, excluding those in note 2 above. Refers to 100 medications most prescribed for military personnel. c Improvements of performance during military tasks (e.g., physical endurance, muscle strength, alertness, memory, stress relief, sleep patterns) based on level of desirability of the benefit to the military and level of science documenting a benefit (see details in Table 5-2). d High, moderate, low, or minimal as described in Box 5-1 and modified based on putative benefits NOTE: Searches conducted were not comprehensive in some cases but focused on uses of the military (e.g., Ginkgo biloba for cognitive effects). INR=international normalized ratio; AUC=area under the curve; NSAID=nonsteroidal anti-inflammatory drug; ACTH=adrenocorticotropic hormone. e Causing detriments to performance during military tasks (e.g., physical endurance, muscle strength, alertness, memory, stress, sleep patterns) f Causing detriments to military survivability such as bleeding or injury, dehydration, malfunction of gastrointestinal tract, stress, or altered behavior g Composition of dietary supplements varies widely; these are general categories and many include other ingredients or a combination of ingredients. h “No data found” means that there were no data found in the subject area, either because the studies reviewed did not investigate this subject area or because, when investigated, there was no effect (e.g., health risk or otherwise).

a

Dietary Supplementsg Performance enhancers Caffeine

Military Performancee

Potential Detrimental Effects to

TABLE 5-3 Summary of Risks and Putative Benefits for Selected Dietary Supplements Used by Military Personnel

FRAMEWORK

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Gingko biloba

Garlic

No data found

Military Performance No data found

Copyright © National Academy of Sciences. All rights reserved.

No data found

Epidural hematoma, Increased INR

Other Health Risks

Thiazide diuretics: Reduced efficacy of diuretic

Omeprazole: Reduced plasma concentrations of dietary supplement

Warfarin, NSAID, alcohol: Theoretical interactions but studies do not support interactions

Acetaminophen: Altered metabolism but not clinically substantial

Chlorpropamide: Increased hypoglycemic effect

Warfarin: Increased clotting time and INR, additive effect

Ritonavir: No effect on AUC but increased incidence of gastrointestinal side effects

Protease inhibitors Saquinavir: Clinically substantial reduction of AUC

Interactions with Medications or Other Bioactive Substances

No data found

No data found

Withdrawal Effects

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

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Transient headaches, gastrointestinal disturbances, sleep disturbances, bleeding with warfarin and aspirin

Military Survivability Meniere disease Asthma bleeding, gastrointestinal disorders

Potential Detrimental Effects to

TABLE 5-3 continued

5-20

Low potential for benefit (substantial evidence of minimal beneficial effects)

Little evidence of cognitive benefits in healthy, young individuals

Low potential for benefit (substantial evidence of minimal beneficial effects)

Evidence of antimicrobial effects

No clinical studies for mental or physical performance

Putative Benefits

High due to potential impact of chronic use on blood clotting

High due to potential impact of chronic use on blood clotting

Concern Level

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

No data found

No data found

Tyrosine

Quercetin

Ginseng

Military Performance No data found

No data found

No data found

Copyright © National Academy of Sciences. All rights reserved.

No data found

No data found

No data found

Other Health Risks

No data found

Theoretical with monoamine oxidase inhibitors

Alcohol: Reduced blood alcohol concentration

Influenza vaccine: Increased the efficacy of vaccine when given in combination

Warfarin: Three case reports reporting reduction in the INR Phenelzine: Induced mania

Interactions with Medications or Other Bioactive Substances

No data found

No data found

No data found

Withdrawal Effects

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Military Survivability Gastrointestinal effects

Potential Detrimental Effects to

TABLE 5-3 continued

FRAMEWORK

Moderate potential for benefit (some level of science but high desirability)

Some evidence of immune system improvement and antiviral properties.

Moderate potential for benefit (moderate level of science but high desirability)

Evidence of improvement of cognitive function, mood states, and psychomotor functions especially under stressful situations

Low potential for benefit (substantial evidence of minimal beneficial effects)

Some evidence of memory improvement and reduction in mental fatigue

No benefits to physical performance in healthy, young individuals

Putative Benefits

Minimal

Minimal

Low

Concern Level

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Beta-hydroxy-betamethylbutyrate (HMB)

Nonsteroids

Dehydroepiandroster one (DHEA)

Steroids

Anabolic supplements (reported as “bodybuilding supplements” in surveys)

No data found

No data found

Military Performance

No data found

Military Survivability

Potential Detrimental Effects to

TABLE 5-3 continued

5-22

Copyright © National Academy of Sciences. All rights reserved.

No data found

Some drugs decrease DHEA blood levels (ACTH inhibitors and P450 inducers); caution when use concurrent with hormonal therapies

Interactions with Medications or Other Bioactive Substances

No data found

No data found

Withdrawal Effects

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No data found

Neoplasia in rat studies, correlation to breast cancer in epidemiological studies, androgenizing effects in women

Other Health Risks

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Moderate potential for benefit for untrained individuals or those in catabolic states such as negative energy balance (moderate level of science but high desirability)

Some evidence of increase in lean tissue and muscle strength of untrained individuals

Low potential for benefit (some evidence of minimal beneficial effects)

Some evidence for improvement in bone health and mood in older women

No effect on body composition, muscle, or cognitive function

Putative Benefits

Minimal

High

Concern Level

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Creatine

Beta-hydroxy-betamethylbutyrate (HMB)

Nonsteroids

Consider possibility of dehydration or renal effects

No data found

Military Performance

Copyright © National Academy of Sciences. All rights reserved.

No data found

No data found

Other Health Risks

NSAID and some vitamins: Theoretical interactions

Caffeine: Synergistic effect and opposing effects reported

No data found

Interactions with Medications or Other Bioactive Substances

No data found

No data found

Withdraw al Effects

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No dehydration or gastrointestinal problems

Case reports of renal failure

No data found

Military Survivability

Potential Detrimental Effects to

TABLE 5-3 continued

FRAMEWORK

Moderate potential for benefit (moderate evidence of benefits and high desirability

Potential for protection against traumatic brain injury

Some evidence of improvement in cognitive and psychomotor performance

Substantial evidence of increase in muscle mass

Substantial evidence of improvement in physical performance.

Moderate potential for benefit for untrained individuals or those in catabolic states such as negative energy balance (moderate level of science but high desirability)

Some evidence of increase in lean tissue and muscle strength of untrained individuals

Putative Benefits

Low

Minimal

Concern Level

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Chromium picolinate

Weight loss Ephedra (Ma huang)

No data found

No data found

Military Performance

Copyright © National Academy of Sciences. All rights reserved.

Absorption reduced with phytates and medications that alter acidity of stomach

Interactions with other sympathomimetic drugs such as caffeine

Interactions with Medications or Other Bioactive Substances

No data found

Palpitations

Withdrawal Effects

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2–4 fold increase in adverse effects: increased blood pressure, palpitations, heart rate. Case reports of cardiovascula r adverse effects, stroke, psychosis, heart failure, seizure, vision impairment, transient ischemic attacks, muscle failure, and death. Only isolated adverse effects reported

Other Health Risks

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Only isolated adverse effects reported (changes in cognitive behavior, allergic skin disorders, renal failure, and liver dysfunction)

Case reports of psychosis, vision impairment, muscle failure

Military Survivability

Potential Detrimental Effects to

TABLE 5-3 continued

5-24

Low potential for benefit (substantial evidence of minimal beneficial effects)

Some evidence of small effects on weight loss and body composition

Moderate potential for benefit (for weigh loss) (moderate level of science but high desirability)

Clinical studies show no evidence for performance enhancement

Few studies show a small but substantial effect for weight loss

Putative Benefits

Low

High

Concern Level

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No data found

Gastrointestinal effects

Drowsiness/ sedation effects

Gastrointestinal effects

Drowsiness/ sedation effects

Core body heat loss

Military Survivability

Could contribute to superfluous calories for inactive personnel

No data found

No data found

Other Health Risks

Unknown but unlikely, depending on individual ingredients.

Sedative hypnotics and anesthetics: Theoretical synergy

Sedative hypnotics and anesthetics: Theoretical synergy

Interactions with Medications or Other Bioactive Substances

No data found

No data found

No data found

Withdrawal Effects

5-25

High potential for benefit (substantial evidence of benefits and high desirability)

Evidence of improved exercise performance Supplement essential nutrients

Low potential for benefit (evidence of minimal beneficial effects)

Moderate potential for benefit (evidence of circadian benefits and some sleep benefits) Inconclusive evidence that valerian improves sleep

Substantial evidence of circadian reentrainment under controlled conditions

Some evidence of improvement of sleep

Putative Benefits

11

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Immune enhancers, antioxidants, energy supplements, enhance recovery or performance Refers to supplements containing macronutrients for energy or essential nutrients below the UL to meet physiological needs level or electrolytes to replenish those lost during exercise. If energy supplements contain other ingredients (e.g., creatine), then an evaluation of each individual ingredient and interaction is warranted.

10

Energy supplements11 Sports bars

No data found

Drowsiness / sedation effects

Valerian

General health10

Drowsiness / sedation effects

Melatonin

Sleep aids

Military Performance

Potential Detrimental Effects to

TABLE 5-3 continued

FRAMEWORK

Minimal

Moderate

Moderate

Concern Level

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No data found

No data found

Hyponatremia (with excessive use)

No data found

Military Survivability

Could contribute unnecessary calories for inactive personnel

Could contribute to superfluous calories for inactive personnel

Other Health Risks

Unknown but unlikely, depending on individual ingredients.

Unknown but unlikely, depending on individual ingredients.

Interactions with Medications or Other Bioactive Substances

No data found

No data found

Withdrawal Effects

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Plasma level better maintained during sweating when electrolytes are provided High potential for benefit (substantial evidence of benefits and high desirability)

Some evidence of increased muscle protein synthesis, superior hydration, and reduction in muscle damage after strenuous exercise when drinks contain protein; requires further substantiation

High potential for benefit (substantial evidence of benefits and high desirability) Evidence of improved exercise performance

Evidence of improved exercise performance Supplement essential nutrients

Putative Benefits

Minimal

Minimal

Concern Level

13

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Immune enhancers, antioxidants, energy supplements, enhance recovery or performance Refers to supplements containing macronutrients for energy or essential nutrients below the UL to meet physiological needs level or electrolytes to replenish those lost during exercise. If energy supplements contain other ingredients (e.g., creatine), then an evaluation of each individual ingredient and interaction is warranted.

12

Sports drinks

Energy supplements13 Sports bars

General health12

Military Performance

Potential Detrimental Effects to

TABLE 5-3 continued

5-26

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No data found

No data found

Selenium

No data found

Iron

Vitamins and Minerals Mineral Calcium

Military Performance

Copyright © National Academy of Sciences. All rights reserved.

Minimal when below UL

Minimal when below UL

Minimal when below UL

Military Survivability

Potential Detrimental Effects to

TABLE 5-3 continued

FRAMEWORK

May reduce absorption and/or efficacy of some medications

Interactions with Medications or Other Bioactive Substances

No data found

No data found

No data found

Withdrawal Effects

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Minimal when below UL

Minimal when below UL

Minimal when below UL

Other Health Risks

5-27

High potential for benefits (substantial evidence of benefits and high desirability)

Maintain immune function; potential for further benefits with supplemental amounts

High potential for benefits (substantial evidence of benefits and high desirability) To reach adequate levels by supplementing the diet

Sustain physical and cognitive performance

High potential for benefit (substantial evidence of benefits and high desirability) To reach adequate levels by supplementing the diet

Sustain bone health and mood states; potential for further benefits with supplemental amounts

To reach adequate levels by supplementing the diet

Putative Benefits

Minimal when below UL

Minimal when below UL

Minimal when below UL

Concern Level

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

No data found

No data found

No data found

No data found

Multivitamins/mult iminerals

Vitamin C

Vitamin D

Vitamin E

Vitamins

Zinc

Military Performance No data found

Copyright © National Academy of Sciences. All rights reserved.

Minimal when below UL

Minimal when below UL

Minimal when below UL

Minimal when below UL

Military Survivability Minimal when below UL

Potential Detrimental Effects to

TABLE 5-3 continued

5-28

Warfarin

Aspirin: Antithrombotic effects

Interactions with Medications or Other Bioactive Substances

Unknown but unlikely

No data found

No data found

No data found

No data found

Withdrawal Effects

High potential for benefit (substantial evidence of benefits and high desirability)

Maintain immune function

High potential for benefits (substantial evidence of benefits and high desirability) To reach adequate levels by supplementing the diet

Maintain bone health

High potential for benefit (substantial evidence of benefits and high desirability) To reach adequate levels by supplementing the diet

Minimal when below UL

Minimal when below UL

Minimal when below UL

High potential for benefit (substantial evidence of benefits and high desirability) To reach adequate levels by supplementing the diet Maintain immune function

Minimal when below UL

Minimal when below UL

Concern Level

To reach adequate levels by supplementing the diet

High potential for benefit (substantial evidence of benefits and high desirability)

To reach adequate levels by supplementing the diet

Putative Benefits

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Minimal when below UL

Minimal when below UL

Minimal when below UL

Minimal when below UL

Minimal when below UL

Other Health Risks

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

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FRAMEWORK

5-29

Monitoring Surveillance (generally passive, but also active where there is a high level of concern or high potential benefits coupled with low concerns) is a potential management action to assess trends in supplement use, particularly the use of dietary supplements of high concern, multi-ingredient products, or products with high potential for benefit and low concern. Surveys can include questions about the use of any specific dietary supplement of high concern, particularly multi-ingredient products (see Chapter 2). An additional source of information on the use of dietary supplements is on-base (e.g., from AAFES/NEX and fitness centers) sales data. Such data could be gathered on an annual basis for all supplements but is especially advisable for those of high concern level, those containing multiple ingredients, or those with high potential for benefit and low concerns. In addition to providing use trends, data from surveillance are vital to assess the strength of the adverse event signals and serve to complement data from adverse event reports (see Chapter 6). CHALLENGES OF THE PROPOSED FRAMEWORK FOR MILITARY PERSONNEL There are three types of challenges in evaluating the safety or efficacy of dietary supplements with the framework proposed by this committee and they are outlined in this section. Insufficient Scientific Data The practical value of the proposed framework depends on publicly available data. One critical challenge is acquisition of sufficient scientific data from literature searches to support an informed decision about the safety and efficacy of a dietary supplement within the military. Although there is an abundance of data for a few supplements, such as ephedra, the dearth of data for others hinders the determination of any definitive conclusion and further decision making. In Chapter 7, the committee provides its recommendations on the military undertaking research to address data gaps in areas of significant concern. The committee emphasizes that absence of evidence of risk, a frequent reality, does not necessarily indicate that there is no risk. Even if a study reported a lack of adverse effects, if the study is not adequately designed to identify risk (e.g., it is insufficiently powered, incompletely reported, does not include positive controls, or otherwise has inadequate mechanisms for detecting adverse events), its scientific validity is reduced or even null. Multi-Ingredient Dietary Supplements Dietary supplements commonly contain multiple ingredients, and their compositions are frequently altered (e.g., they are reformulated with different proportions, amounts, and even ingredients) without any product name change. Finding data on the safety (or efficacy) of the myriad multi-ingredient products in the market is yet a bigger challenge than finding data on single-ingredient products. The committee concluded that these products merit special attention by frequent monitoring of their use, sales, and adverse event reports. The following are two potential approaches to determining the safety (or efficacy) of these products. Recognizing that both of these approaches (i.e. determining the safety of a total product or determining the safety of individual ingredients) have advantages and disadvantages, the application of either approach to evaluate the safety (and efficacy) of multi-ingredient products should be the prerogative of the military. Among other factors, the military should consider the strength of detected signals,

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

prioritization of research gaps, and availability of resources. For either approach, there will be additional staff support required to maintain continuous surveillance of multi-ingredient products, including all the possible interactions. Determining Total Product Safety Given the virtual absence of data on multi-ingredient products, the military could decide to conduct research with study designs addressing military subpopulations and environments of interest, an approach that would be both expensive and time-consuming. In addition, the rapid turnover of products in the market may make it difficult or impractical to keep such research current. Determining Ingredient Safety The level of concern (or efficacy) associated with the consumption of a multi-ingredient product could be determined by examination of each individual ingredient and of each potential interaction with the approach recommended in this chapter. The challenges in this case relate not only to the ingredients themselves but to the potential interactions among ingredients in the product. Furthermore, safety data on ingredient interactions are typically unavailable. Presence of Contaminants The linking of an adverse event to the use of a dietary supplement ingredient might be confounded if the product contains adulterants or contaminants. Attribution of the source of the adverse event becomes a formidable task. If enforced, the newly adopted cGMP rule should minimize the potential for inclusion of adulterants or contaminants. Because this rule was adopted and will not be implemented until June 2008, its effectiveness remains to be evaluated. OVERALL RECOMMENDATIONS The committee recommends that the military use the proposed framework, modified from the 2005 IOM report framework, to determine whether a dietary supplement requires that military leadership take specific management actions to ensure optimal readiness and health protection of military personnel. This framework provides a methodology with a preestablished search strategy for generating a safety monograph for a dietary supplement, and a consistent format that provides key information that can be used to assist military policy makers, as well as criteria to initiate safety reviews based on signals generated from an adverse event, or proactively, based on significant changes in dietary supplement consumption by military personnel. The following are overall recommendations related to the application of the framework: x

x

Detemination of the level of concern of a dietary supplement should be based on published reviews of general safety concerns and on adverse effects and/or benefits specific to the military; the final integrated concern level should be predicated on safety concerns, modified by potential benefits, and based on special mission requirements and environments. The final, integrated concern level and the need for dietary supplement management should be determined in the context of specific subpopulations of the military and based on their special mission requirements, environments, and locations. This analysis should pay

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FRAMEWORK

x x

x

5-31

particular attention to military subgroups of interest for whom benefits and safety are of operational concern. Dietary supplement management should be predicated on safety concerns, modified by any proven benefits. A future task force or committee should more fully describe the process and framework to characterize the efficacy of dietary supplements of interest to the military and describe a detailed process to monitor the emergence of dietary supplements that could provide benefits to the military. To determine whether the level of concern for a dietary supplement should be reclassified as future research unfolds, research should be monitored on an annual basis, especially for those for which a concern level could not be established due to lack of data. Based on recommendations of the designated oversight committee, the military might also decide to support or conduct research on a specific dietary supplement depending on its relevance to the military. For example, dietary supplements of military interest that are classified as being of high concern based on equivocal animal data could be referred to the research community to more fully characterize the level of concern in humans. It may or may not be appropriate for the military commander to recommend that the dietary supplement not be used by military personnel until that determination has been made.

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REFERENCES IOM (Institute of Medicine). 2005. Dietary supplements: A framework for evaluating safety. Washington, DC: The National Academies Press.

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6 Monitoring Adverse Health Effects Associated with Dietary Supplement Use by Military Personnel

BACKGROUND Making definitive declarations about the safety of drugs, foods, or dietary supplements is a challenging task, even with the most robust premarket studies. Among the multiple strategies (preand postmarketing) available, postmarket monitoring of adverse effects associated with these products becomes a very important tool to assess their safety. Often, a postmarket monitoring system serves as a complement to a risk or safety assessment to identify adverse effects that are not recognized in a laboratory or a small clinical study. In the case of food ingredients (i.e., additives and generally recognized as safe [GRAS] substances), the standard of safety is a “reasonable certainty of no harm” as indicated by either the food additive petition approval, GRAS notification, or GRAS self-affirmation process. For example, prior to marketing food additives, a petition that includes a safety assessment (i.e., available data on safety of the product) is sent to the U.S. Food and Drug Administration (FDA). Upon review of the petition, the FDA may issue a safety declaration. Once on the market, there is no established monitoring system for adverse events from foods; however, if a new ingredient is introduced to a previously available food product, the FDA might informally ask the manufacturer to conduct postmarket monitoring of adverse events. Receipt of a sufficient number of complaints from consumers or consumer organizations might also prompt the FDA to investigate the safety of an ingredient. In contrast, for drugs, a premarket risk-benefit analysis is conducted, followed by a postmarket safety evaluation that includes a passive, voluntary surveillance system. The premarket risk-benefit analysis is composed of three types of studies: animal toxicology and pharmacological studies, proof-of-principle studies for the disease or condition under study, and confirmatory studies of safety and efficacy (FDA, 2007). As a result of this required risk-benefit review, by the time a medication is on the market there are multiple well-conducted studies available that can later be used in support of an alleged association with an adverse event. Under the Federal Food, Drug, and Cosmetic (FFD&C) Act, as amended by the Dietary Supplement Health and Education Act (DSHEA) of 1994, the law that regulates dietary supplement safety, the FDA does not have the authority to require a premarket safety assessment, yet bears the burden of proof to determine that a dietary supplement is unsafe before or after introduction in the marketplace. Because there are no premarket assessments required for dietary supplements, there is a paucity of laboratory safety studies; hence, postmarket monitoring of adverse events becomes even more significant for ensuring public health. The DSHEA provided the FDA with the authority to develop monitoring systems and to take necessary actions when it has sufficient evidence that a product is unsafe (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress, October 25, 1994). The FDA has established a program called MedWatch to provide and elicit information on safety issues; reports PREPUBLICATION COPY: UNCORRECTED PROOFS 6-1

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

from either health care professionals or consumers can be submitted voluntarily to the FDA or manufacturers via a standard form, form FDA 3500 (see Appendix E). The Dietary Supplement and Nonprescription Drug Consumer Protection Act made the reporting of life-threatening events to the FDA by manufacturers mandatory after December 2007 (MedWatch form 3500A is used for this purpose)(Dietary Supplement and Nonprescription Drug Consumer Protection Act, Public Law 109462, 109th Congress, December 22, 2006). Reports from both consumers and manufacturers are submitted through a passive monitoring system, that is, the FDA does not actively seek the adverse event reports. There are four steps to follow in such a system: (1) detect adverse events, (2) generate signals of public health concerns, (3) assess signals, and (4) take appropriate action. As with medications and food ingredients, health risks from dietary supplement use are derived mainly from a consumer’s individual susceptibility, or from the dietary supplement’s inherent biological activity or interactions with medications. For the majority of dietary supplements, inherent toxicity might be expected to be less than that of medications because of the lower concentrations and potency per unit. Nevertheless, there are factors (i.e., the lack of composition standardization or a product compendium; multi-ingredient products; biased consumer attitudes; and a potential of overuse by some consumers) that increase the risks to health from the use of dietary supplements. Because dietary supplements are regulated as foods and many have a history of traditional use, there is a perception that they are safe and do not need a premarket approval process. However, it should be noted that products with a history of safe use may now be used in a different manner (e.g., different solvents used for extraction, alternative plant parts used, duration of use) from traditional uses. Many consumers are also unaware that there is no requirement for federal approval of dietary supplements or advertisements promoting them, mistakenly assuming that dietary supplements must conform to the same regulations as drugs (Ashar et al., 2008). The differences in perception of risk between dietary supplements and drugs should be considered when attempting to model a surveillance system for dietary supplements. Many activities are critical to the evaluation of risk-benefit profiles such as adverse event surveillance, confirmatory laboratory safety studies, and data on use. Data from adverse events monitoring are complementary to data on use from dietary supplement surveys: survey data typically focus on the use of a specific dietary supplement within the population, whereas monitoring collects the numbers and types of adverse events resulting from its use. Both estimates are critical when making decisions about the safety of a product because their ratio (i.e., reporting proportion) may provide a rough estimate of the magnitude of a problem; in the case of dietary supplements, low reporting of adverse events and scarce information on dietary supplement use limit the utility of these data. Also, an association of use with an adverse event does not imply the demonstration of causality; rather, it intends to alert decision makers of potential concerns possibly requiring corrective actions. Determining causation requires rigorous clinical trials or research designs performed with animal models, not just analysis of adverse event report data (IOM and NRC, 2005). Associations identified from adverse event monitoring must be viewed as hypotheses regarding possible causal relationships between the substance and event, recognizing that there may be many possible reasons other than a direct causal relationship for the observed association (Almenoff et al., 2005). Based on the heightened risks and the absence of a process to report adverse events, this chapter discusses the need for the military to add dietary supplements to its current adverse event monitoring system for medications so that it responds to the unique risks and demands of military service. The chapter reviews the adverse event monitoring efforts for the general population and for the military population, highlights challenges, and recommends improvements that build upon the current

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MONITORING OF ADVERSE HEALTH EFFECTS

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military system. Challenges might be categorized as related to the process of adverse event monitoring itself or related to the analysis of the data. Since those relating to data analysis (e.g., data mining statistical methods, identification of trends) are not unique to the military system, the committee discussed them briefly and refers to the published literature for further reading. The committee focused its deliberations on process-related challenges (e.g., low reporting rate; quality of data; use of integrated, electronic data). Taking the current system and policies as its foundation, this chapter makes recommendations for a collaborative approach in which appropriate institutions share data and lessons learned from their respective monitoring systems. The proposed approach will alert the military of potential concerns derived from using specific dietary supplements, particularly when performance might be compromised, and will serve as a signal to initiate appropriate actions by military leadership, as described in Chapter 5. THE FDA’S PROCESS TO MONITOR ADVERSE EVENTS FROM DIETARY SUPPLEMENTS To make recommendations about approaches to monitoring military personnel for adverse health events that might indicate a concern associated with consumption of dietary supplements, the committee reviewed the FDA’s systems for both medications and dietary supplements. A more detailed description of the monitoring system for products regulated by the FDA is included in Appendix B (see sections by Dal Pan and Frankos and Mozersky). As mentioned above, to gauge the safety of dietary supplements, the FDA relies in part on evaluation of reports of adverse events possibly associated with their use. The FDA uses these evaluations to analyze trends and to detect a signal (i.e., a strong relationship between a dietary supplement and adverse events). However, a determination that a dietary supplement or dietary ingredient is unsafe would be based on a thorough assessment of not only reports of adverse events, but of the scientific peer-reviewed literature on the safety of the dietary supplement or dietary ingredient. Adverse events are most often reported via the submission of the MedWatch form FDA 3500 (see Appendix E), which is used to provide data originating from clinical trials, health care personnel, and consumer reports. To summarize the process, an individual (health care provider or consumer) communicates the information describing the event and the patient to the FDA’s Center for Drug Evaluation and Research, where the source of the event is categorized by origin (i.e., drug, dietary supplement, devices, biologics). The initial submission might be electronic or via phone, standard mail, or fax; all reports are transcribed regardless of the reporting mechanism. Reports are often submitted over the phone by a health care provider and received and transcribed literally by an FDA officer who typically does not probe for more information or details about the adverse event. By contrast, some manufacturers hire interviewers/facilitators trained to ask relevant questions of those submitting information on adverse events for entry in the MedWatch form to be sent to the FDA. When potentially associated with a dietary supplement, reports are redirected to the FDA’s Center for Food Safety and Applied Nutrition for evaluation. Processing of MedWatch 3500 forms requires only an identifiable reporter, a patient (anonymized), the suspect product, and a description of the adverse event. The information is reported regardless of the quality of the data, which is not validated. Apart from the patient’s personal data and medical conditions, the form includes fields for entry of important information about the product (type, brand name, lot number, expiration date) and use (dose, frequency, date of initiation of use, consistent or inconsistent use, reason for use, last time of use before adverse event). Critical in identifying a signal is the section of the form referring to the event itself: event description, actions taken in response to event (e.g., sought medical attention), and documented PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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diagnosis. The FDA officials consider it advantageous to format this section as open-ended questions, offering the possibility of acquiring valuable information about the event circumstances (Personal communication, Vasilios Frankos, Center for Food Safety and Applied Nutrition, May 30, 2007). The concomitant use of a drug and a dietary supplement or of a combination of dietary supplements might cause synergistic or antagonistic effects; the section in the form addressing the use of other medications and supplements is also therefore critical in evaluating the signal. Once information is collected and distributed to the FDA’s safety officers, analysis and signal detection follow. If an event is serious or uncommon, further steps are expeditiously taken: (1) a follow-up is requested, (2) other federal agencies are consulted, (3) a review of the literature is initiated, and (4) prior FDA reports on adverse events on similar products are consulted to identify trends. There is, however, no automatic signalling mechanism, and the weight of evidence is considered case by case; the experience and consensus of safety officers usually dictates the decisions taken. Until recently, these voluntary submissions and resultant MedWatch 3500 forms provided the only system to obtain information on postmarket adverse events associated with dietary supplements. To strengthen this system, the Dietary Supplement and Nonprescription Drug Consumer Protection Act mandates that after December 2007 serious adverse events1 reported voluntarily to dietary supplement manufacturers by consumers and others must be submitted by the manufacturer to the FDA via the MedWatch 3500A form (see Appendix D). The form is slightly different from Medwatch 3500 in that it also solicits composition information from the product label as well as the manufacturer’s contact information. Although this is a clear enhancement of the dietary supplement regulatory system and there is an expectation that the amount of data collected on adverse events will improve in both quality and quantity, the actual benefits from the act are still to be realized, as it was only implemented in December 2007. The potential misinterpretation of reports has resulted in some reluctance to make adverse event monitoring data available to others (see Kingston in Appendix B). Given the low report rate for dietary supplement-related adverse events, and the absence of a well-established system to monitor adverse events, it seems essential for organizations and manufacturers to collaborate to understand the limitations and uses of the current systems to report adverse events associated with dietary supplements. For example, the 2007 Institute of Medicine (IOM) report The Future of Drug Safety emphasized the importance of partnerships and the need for a concerted effort to utilize both public and private resources effectively to address drug safety (IOM, 2007). Efforts to incorporate information from other sources, such as poison control centers (PCCs), have, for various reasons, not always been successful. The PCCs are private organizations whose purpose is to provide medical advice on how to treat an adverse outcome, not to assess the safety of substances. Calls received by PCCs include those due to nontoxic or unintended exposures to dietary supplements, medications, or other substances by children. Direct comparison of data from PCCs and MedWatch forms is not appropriate since the same adverse event data elements are not collected. The FDA therefore reviews PCCs reports only when follow-up is necessary. The FDA has also been working with the University of California at San Francisco monitoring the PCCs reports received by the San Francisco Center for Drugs and Dietary Supplements. Through this collaboration, it was determined that most adverse events in the PCCs reports that were linked to dietary supplement use were associated with the use of stimulants (caffeine, ephedra-like products) and multi-ingredient dietary supplements, especially 1 A serious adverse event is defined as an event that results in death, a life-threatening experience, inpatient hospitalization; persistent or significant disability or incapacity, or a congenital anomaly or birth defect, or an event that requires, based on a reasonable medical judgment, a medical or surgical intervention to prevent an outcome from a serious adverse event (Federal Food, Drug, and Cosmetic Act, U.S. Food and Drug Administration, 2004).

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weight-loss products, and that these events were often associated with cardiac symptoms (Personal communication, V. Frankos, Center for Food Safety and Applied Nutrition, May 30, 2007; Haller et al., in press). Challenges in Adverse Event Data Collection Process and Analysis Many experts and organizations have discussed challenges related to various aspects of monitoring adverse events from dietary supplements (see Kingston in Appendix B; LSRO, 2004; OIG, 2001; Woolf, 2006). For example, a 2001 report from the U.S. Health and Human Services (HHS) Office of the Inspector General (OIG) provides a detailed analysis of the effectiveness of the FDA’s adverse event reporting system for dietary supplements in protecting the consumer (OIG, 2001). Although underreporting and suboptimal data quality are both attributes of a passive and voluntary system of surveillance, there are well-known advantages to a voluntary system, such as its nationwide character and the ability to distinguish at-risk groups and to generate safety signals. This section highlights some of the challenges of the FDA’s current system, many of which also apply to military reporting efforts (see below). Data Collection Process Low reporting rate Adverse events, when reported by the patient, are frequently described not directly to the FDA but to a health care provider. Receiving such information via the health care provider has obvious advantages in providing quality data, including the use of standardized medical terminology (e.g., symptoms, medications) and the opportunity to acquire information on other aspects of the patient’s medical records. Unfortunately, under the current voluntary system, the report rate is low—the OIG estimated in 2001 that less than 1 percent of all adverse events are reported to FDA—for any of the following possible reasons. First, there is generally little consumer awareness of the importance of reporting adverse events from dietary supplements or even about the availability of a reporting system; if an individual is aware of the system, lack of familiarity with the form or lack of clarity in questions might deter submission. Second, patients are often reluctant to report the use of alternative treatment to their health care providers (IOM and NRC, 2005). Third, for some consumers, dietary supplements might be regarded as inherently safe since they are “natural,” and consumers therefore fail to make a connection between the adverse effect and the use of the dietary supplement, and do not report it (IOM and NRC, 2005; Ashar, 2008). Fouth, there is no clear common knowledge of what constitutes an adverse event (e.g., for some only death or permanent disability would qualify, while for others it would include discomfort leading to absence from work or admission to an emergency room for treatment of a symptom such as dehydration). Finally, recording the dietary history or asking about dietary supplement use is not a routine part of the medical history in either emergency room or follow-up ambulatory visits (except for ambulatory visits with some registered dietitians). While health care providers should, in theory, be sensitive to the importance of adverse event reporting, surveys have shown that even in the case of medications, physicians’ beliefs and attitudes about the value of reporting adverse events contribute to low reporting rates (Figueiras et al., 1999). Other factors that might indirectly affect the report rate are the recency of introduction of the dietary supplement, media attention, and the level of educational or regulatory activity recently presented. Quality of data collected The quality of information reported by phone or MedWatch form 3500 depends on the reporter’s bias or beliefs as well as familiarity with medical reporting, signs, and symptoms. Forms filled by consumers often include incomplete or inaccurate information regarding

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an adverse event. For example, few consumers will be aware of how to code adverse events using standard codes for data entry (i.e.as found in Medical Dictionary for Regulatory Activities [MedDRA], which provides the coding of standard medical terminology [signs, symptoms, diagnosis, syndromes, laboratory and physiological data related to medical conditions] used by the FDA and others). To add to this difficulty, FDA safety officers do not typically probe for additional relevant information (e.g., about brand name, dose, and other products or medications being taken concomitantly), nor is there much follow-up with the initial reporter to obtain more information (Personal communication, Vasilios Frankos, Center for Food Safety and Applied Nutrition, May 30, 2007). The analysis of data from adverse events related to dietary supplements is complicated by numerous unknowns about the product ingested, including the following: (1) potential product adulteration; (2) lack of identification of the part of the plant (e.g., root, seed) from which the product is derived; (3) broad variation in plant nomenclature and geographical origin of plant; (4) unknown product composition due to lack of manufacturing and labeling requirements and continual product reformulation; and (5) patients’ inability to accurately recall the types or number of dietary supplements being taken. The identification of an association of a dietary supplement with an adverse event then becomes a significant challenge. An additional obstruction to data analysis is uncertainty of the length of time between the exposure and the adverse effect or duration of use. The 2001 OIG report highlighted the difficulties presented by data quality. Adverse event report data were categorized as suboptimal, specifically providing limited medical information, limited information on products and manufacturers, limited information about the consumer, and limited ability to analyze trends. The report found that in 1999, the FDA recorded only 400 adverse events from dietary supplements via submission of MedWatch 3500 forms. Of those, medical records were unavailable in 58 percent of the cases, ingredients could not be determined in 32 percent, and there was no patient follow-up information available for 27 percent (OIG, 2001). The user guidance recently issued on how to fill in the MedWatch 3500 form may help those reporting adverse events to submit accurate, appropriate information. Data Analysis: Generating Signals Data mining is defined as the analysis of observational data sets to find unsuspected relationships and to summarize the data in novel ways that are both understandable and useful to the data user (Hand et al., 2001). Different forms of data mining can be used when the datasets are large, as in the case of adverse event reports for medications. The methods commonly used in pharmacovigilance to identify associations account for the variability typically found with small report counts. Quantitative evaluation can be derived from the relationships between the frequency of use of a substance and events reported, taking into consideration also all other substances’ concomitant use and events (Almenoff et al., 2005). When evaluating these data, a typical challenge derives from a lack of data for the “denominator” (i.e., number of users for each dietary supplement) and low “numerator” data (i.e., number of adverse events reported for a particular dietary supplement). Data on dietary supplement sales and use (e.g., from commercial vendors or surveys) are valuable when estimating the percentage of the population that uses a dietary supplement. Signals detected by measuring disproportionality of drug-event combinations compared to known ratios from premarket efficacy trials are only statistical indicators of possible safety issues. Rare events (e.g., birth defects) are easiest to detect, but events that are commonly experienced by the population (e.g., diarrhea) are difficult to associate with the consumption of a specific dietary supplement or dietary supplement ingredient. The topic of data PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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analysis and mining from adverse events reports is complex and has been extensively reviewed by others (Almenoff et al., 2005; Strom, 2005). Unfortunately, for the reasons described above, the quantity and quality of data reported from dietary supplement-related events is often less than desirable, resulting in weak signals for safety concerns. If higher reporting rates accompany the increase in use, awareness, and new legal requirements to report adverse events, then data mining tools might be more useful in the future. In the case of medications, suggested signals derived from adverse event reports are complemented by other available information on the safety of the substance, such as from adverse events described in clinical studies, case reports, or cohort studies (Strom, 2005). Because there is no premarket approval requirement to conduct a safety assessment for dietary supplements, manufacturers might not be compelled to perform these studies, and safety data on health effects from products or interactions with other supplements or with other bioactive substances are mostly lacking. Still, both the published literature and studies sponsored by the National Center for Complementary and Alternative Medicine of the National Institutes of Health (NIH) can be used to support the attribution of adverse events to a particular dietary supplement. It is also encouraging that an increasing number of reports describe events from drug–dietary supplement interactions, although many are from case studies and not clinical trials. With these serious limitations in the data quality and quantity and with reviews often conducted on a case-by-case basis, the extensive experience and appropriate expertise of the reviewers becomes critical when identifying signals. THE MILITARY’S SYSTEM TO MONITOR ADVERSE EVENTS The monitoring of adverse events related to dietary supplement use as a signal detection system within the military is integral to maintaining the health and optimal performance of military personnel. This monitoring system would be a key component of the framework recommended in Chapter 5 and would serve as a criterion to initiate reviews of research and provide important input to military commanders’ policy decisions, as described in Chapter 5. It is especially important that such a system be operational at installations where military personnel face extraordinary physical and mental challenges. The military has a system to monitor adverse events from medications but does not currently have a separate and distinct system to monitor adverse events from dietary supplements. Many of the elements needed to implement such a system are already in place. The U.S. Army Medical Command has the official responsibility to make decisions regarding nutrition for all military services and would most likely address dietary supplement use and surveillance as part of that responsibility. This committee commends the military for their initiative in seeking methods to manage the safe use of dietary supplements by the troops; that is, conducting specific surveys of dietary supplement use as well as implementing educational programs and policies. The committee also acknowledges the value of past cooperation between the military and the FDA in evaluating adverse event reports from military installations at the time of high concern over ephedra use. This section describes and recommends improvements to the military adverse event monitoring system to include adverse events from dietary supplements. It also describes ongoing educational efforts in the military. Military Adverse Event Monitoring System for Medications Each military service has established a system to collect and evaluate data on adverse events related to medication usage. Reports of adverse events are received and evaluated at the local

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medical treatment facility (MTF). In addition, summary reports are aggregrated and reviewed by the medical headquarters of each service as well as by the Office of the Assistant Secretary of Defense (Health Affairs). In some cases, data are also evaluated at the major command level within each service (e.g., Air Mobility Command [AMC], U.S. Army Special Operations Command [USASOC], or Military Sealift Command). All adverse events potentially associated with the use of medications by Army personnel are reported using MEDMARX,2 a subscription-based, adverse drug reaction database. Briefly, health care personnel (physician, nurse, pharmacist, or other) at an MTF report an event to the MTF pharmacy; it would then be entered into a MEDMARX Adverse Drug Reaction (ADR) Data Entry Form (see Appendix E) by the patient safety manager or other designated person at the pharmacy. The ADR form allows MEDMARX subscribers to collect and analyze reports of adverse drug reactions. The ADR module collects information that describes the adverse reaction, the body system involved, the seriousness of the event, and the result of the reaction on level of patient care; the form also includes the Naranjo Probability Assessment Scale to determine the likelihood that use of a specific substance resulted in the adverse reaction. Adverse event reports might also be submitted via the Vaccine Adverse Event Reporting System (VAERS) (of the Centers for Disease Control and Prevention [CDC] and the FDA) form or MedWatch form 3500 (Appendix E). The Pharmacy and Therapeutics (P&T) Committee at each MTF—composed of physicians, nurses, pharmacists, and logisticians—is an advisory group on all matters relating to the acquisition and use of medications in an MTF. These include review of policies, review of medication errors, evaluation of clinical data on new drugs and preparations requested for use in the MTF, maintenance of the formulary of authorized medications for the installation, and review of drug adverse event reports. The P&T committee also proposes policy decisions to the medical commander (see Hoerner, Appendix B), from medication selection to restricting availability or issuing warnings and framing educational activities. It would appear sensible for the P&T committee in each MTF to oversee the dietary supplement functions related to adverse event monitoring at the local level. Military Policies on Reporting of Advese Events and Use of Dietary Supplements Regulations A review of the military policies currently in place for dietary supplements revealed that they are limited. It has been the policy of the Army Surgeon General to follow the FDA’s guidance and regulations concerning such products. For example, in 2005, when the FDA announced a crackdown on products containing androstenedione (commonly known as “andro”), possession of andro without a prescription became a Class II felony. Possession of the substance by a service member was therefore subject to action under the Uniform Code of Military Justice. In its Nuclear Weapons Personnel Reliability Program (PRP) Regulation (DoD, 1995), the Department of Defense (DoD) establishes requirements and procedures for the implementation of the program to ensure that only the most reliable people perform duties associated with nuclear 2

A national, Internet-accessible database that hospitals and health care systems use to track and trend adverse drug reactions and medication errors. Hospitals and health care systems participate in MEDMARX voluntarily and subscribe to it on an annual basis. It facilitates productive and efficient documentation, reporting, analysis, tracking, trending, and prevention of adverse drug events. It allows subscribing facilities to learn valuable lessons from the experiences of other users. Subscribers can access data from a national database of more than 1.1 million adverse drug event records. The data within MEDMARX follows standardized definitions.

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weapons. Although there is mention of prohibition of the use of alcohol and certain drugs under this program for safety reasons, there is no mention of restricting the use of dietary supplements. Likewise, there is no reference to the use of dietary supplements or reporting of adverse events included in medical requirements for Army aviation personnel (DoA, 2007). In 2000, the Army’s Office of the Surgeon General implemented policy specific to dietary supplements with a memorandum directing health care providers to document adverse events believed to be associated with dietary supplements in the patient’s medical record. Health care providers should also notify the local MTF P&T committees of any such adverse event (DoA, 2000). The memorandum also stated that health care providers will report adverse events to the FDA using the MedWatch 3500 form. In addition, per the 2007 Heat Injury Prevention Policy Memorandum from the Army’s Office of the Surgeon General, all cases of stroke and heat exhaustion reported to the Army Medical Surveillance Activity through the Reportable Medical Events System should include any history of dietary supplement use within the previous 2 weeks (USARIEM, 2007). In contrast, while heat injuries are reportable events for all services, neither the Navy nor the Air Force requires dietary supplement use to be reported (Personal communication, Asha Riegodedios, Navy Environment Health Center, October 26, 2007). There are other bodies whose personnel undertake tasks with high risks and demands (e.g. Coast Guard personnel or aircraft pilots) and their policies to restrict the accessibility and use of dietary supplements are presented here. Recognizing the potential risks associated with dietary supplements, the Coast Guard, a branch of the Department of Homeland Security, has recently implemented regulations to manage the use of dietary supplements. They include not only specifications of the kind of dietary supplements that may be used by all active duty members and aviators (U.S. Department of Homeland Security, 2003), but also provisions for the submission of all reports of patient adverse reactions associated with dietary supplement use (Coast Guard, 2007). According to Coast Guard regulations, clinics shall submit all pertinent patient adverse reactions or product quality problems to the commandant and the maintenance and logistic command, using MedWatch form 3500. Coast Guard pharmacies are not allowed to dispense any product not approved by the FDA (i.e., any herbal supplement or other dietary supplement), with the exception of vitamins having an established recommended dietary allowance. The Federal Aviation Administration, responsible for the safety of civil aviation, does not have any regulations or policy guidance concerning the use of vitamins or dietary supplements per se, except for a restriction on the use of melatonin (i.e., its use is prohibited within 12 hours of flight duty). The Airline Pilots Association advises pilots to avoid dietary supplements that are banned by the FDA or purchased overseas (Personal communication, Bill Edmunds, Air Line Pilots Association, January 25, 2008). Education Efforts to educate service members on the safety of specific dietary supplements include brochures and websites (Evans U.S. Army Community Hospital, 2006; Hooah 4 Health, 2007; NEHC, 2004; USACHPPM, 2000, 2003). The Navy and Marine Corps Public Health Center website provides, as part of their ShipShape weight management program, information on dietary supplements and links to the NIH Office of Dietary Supplements (ODS) website (Navy and Marine Corps Public Health Center, 2007). The ODS website offers information on dietary supplements for both the general public and scientists. The Air Force provides online information through the Human Performance Training Team website on its Air Force Knowledge Now portal. The Army offers information on dietary supplements on the Army Knowledge Online portal as part of its Ultimate Warrior Hooah Bodies and Weigh to Stay sites. PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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However, there is currently no centralized educational program that is effectively and consistently applied across military services and that considers specific military needs. One promising educational tool currently under development is a joint, online community of health care providers and active duty military personnel (see Jaghab in Appendix B; USACHPPM, 2007). This interactive website provides information about general nutrition, weight maintenance, and behavior management, and could be used as a centralized educational system to provide information about dietary supplements. The importance of educating health care providers about dietary supplements was indicated by results from a 2002 survey of Army Medical Department health care providers conducted by the DoD Nutrition Committee in partnership with the U.S. Army Center for Health Promotion and Preventive Medicine, in which health care providers asked to be provided with professional development regarding dietary supplements (Corum, 2004). The Aerospace Medicine program for physicians training to become flight surgeons includes specific information on dietary supplements and active ingredients of safety concern in their online preparation materials for the Aerospace Medicine Primary (AMP) course. However, it does not mention how to report adverse events involving dietary supplements, nor does the curriculum include any additional formal training on dietary supplements during the residency phase (Air Force Medical Service, 2007). Physical trainers in military fitness centers or assigned to organizational units are also key sources of information on nutrition and health. Moreover, the more casual environment and camaraderie experienced at fitness centers may encourage openness about sharing and requesting information about nutrition needs for optimal performance, health concerns, and even adverse events experienced. Adverse Event Data Collection Process and Analysis: Challenges and Opportunities Unique to the Military In addition to the complications, highlighted above, that are commonly encountered in monitoring adverse events within the general population, the military faces unique challenges related to the activities of service members and the locations, culture, and settings in which they operate. Challenges and opportunities discussed below relate to the collection of data and analysis by using the electronic health records system. Data Collection Process Low reporting rate in the military Factors contributing to a low reporting rate in the general civilian population are also encountered by the military: inconsistent definitions of the term adverse event, a voluntary monitoring system, poor communication with health care providers (e.g., reluctance to report dietary supplement use and adverse events as well as lack of discussions about dietary supplement use during medical visits), little consumer awareness of their potential harmful effects, belief that the federal government regulates dietary supplements in the same manner as medications, and perception that dietary supplements are inherently safe. Other factors also affect the reporting level in the military. For example, there is no separate system to report adverse events associated with dietary supplements. The extent to which military health care providers are following the few existing military policies on dietary supplement use is also not known. Despite policies and educational efforts mentioned in the section above, recent surveys of military personnel presented to this committee indicate that a low percentage of respondents (33 percent of men and 53 percent of women among those confirming use of dietary

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supplements during the previous 12 months) discuss the use of dietary supplements with their health care providers (see Marriott et al. in Appendix B). Likewise, a 2002 survey conducted by the DoD Nutrition Committee in partnership with the U.S. Army Center for Health Promotion and Preventive Medicine found that only about 60 percent of primary health-care providers ask their patients about dietary supplement use (Corum, 2004). Data suggest that the military reporting rate may be lower than that in the civilian population, as shown in a survey about reporting smallpox vaccine adverse events, even when adjusting for differences in representation of age and gender of subjects (McMahon et al., 2007). These authors speculated that factors contributing to this finding could be related to differences in behavior (i.e., civilian population having a lower threshold for reporting adverse events), accessibility to forms, or differences in policy implementation. Contributing to the problem of low reporting rate is the fact that those responsible for providing education about healthy and safe behaviors, such as military medical personnel or commanders, are themselves inadequately informed about the benefits and risks of consuming dietary supplements (Corum, 2004). Physical trainers at fitness centers and assigned to organizational units might also lack such information. As a result, service members are not educated about dietary supplements at the fitness center or the treatment facility. The lack of knowledge in both patient and health care provider (or physical trainer) about dietary supplements of specific interest to the military would contribute to the infrequency of reporting adverse events associated with dietary supplement use. An already low rate of reporting within the U.S. civilian population might be further diminished within the military by the fact that commanders have access to service members’ protected health information. For example, medical officers are allowed to share patients' medical information with the commanding officer without requiring specific consent, provided that service members are adequately warned that medical record information is not confidential (DoD, 2003). This practice might restrain the willingness of service members to talk freely with military health care providers about their dietary supplement use. Other factors that may contribute to a low reporting rate might be related to unique political and cultural characteristics of military service, including mobility of the troops. Quality of data collected The causes for low data quality or gaps in data that were identified in the FDA monitoring system are also relevant to the military system: lack of familiarity with medical reporting procedures, absence of a formalized process to probe for additional information, and challenges in obtaining dose consumed and ingredient data for dietary supplement products as well as effects from simultaneous consumption of other dietary supplements or medications. In addition, adverse event data may be submitted through various methods (e.g., FDA MedWatch forms, MEDMARX form, or the Army Reportable Medical Events System); this lack of integration allows for both duplication and absence of event reports. Electronic Health Record Limitations and Opportunities The military has unique opportunities not only because health care for most service members is provided within a single DoD system, but also because the military is taking pioneering steps toward the development of an electronic health records system. Despite its potential to be a state-of-the-art system, the current electronic medical record-keeping system (Armed Forces Health Longitudinal Technology Application) does not allow the inclusion of dietary supplements as part of the patient’s medication profile. Their use can be missed if the health care provider is not trained to inquire about it. Only some dietary supplements (i.e., vitamins and minerals) are included in the medication formulary of an MTF; their use can then be entered into the patient’s record, which allows for the

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possibility of establishing relationships between reported adverse events and the use of these dietary supplements. The switch from a paper-based system to an electronic system of documenting health-related data is in progress and will result in a longitudinal, centralized health care records system that is accessible anywhere, from the battlefield to large hospitals. This system will serve as a central, integrated clinical data repository where each patient has a single record; it will allow for aggregate analysis of data, drug interaction alerts, and patient allergy notifications (Charles et al., 2004). Such a modern computerized system will improve the ability to detect and attribute adverse events. For instance, such a system might be used to create computer-generated signals as a tool for identifying (and possibly preventing) likely specific adverse events or high-risk interactions of dietary supplements with medications or other dietary supplements, as an additional strategy to detect adverse events (Gardner and Evans, 2004). For example, a physician entering a prescription medication might be alerted to the specific risks of product interaction if the patient is using a given dietary supplement. A number of vendors have developed programs that are capable of generating alerts for medication interactions, but for most dietary supplements, the knowledge base for a similar system is not yet available. Clearly, it would be advantageous, albeit time consuming, for the military to establish place-, unit-, or mission-specific alert rules in a manner that results exclusively in alerts that are pertinent (i.e., false alerts are minimized). In summary, if a module including dietary supplements were to be developed and incorporated in the patient’s medication profile, this improved electronic system would permit not only the analysis of an individual adverse event, but also the analysis of dietary supplement use and adverse event trends among users in military subpopulations. Strategies to automate alerting mechanisms to prompt evaluation and reporting of adverse effects might help compensate for the problem of low reporting rates. PROPOSED ADVERSE EVENT SURVEILLANCE SYSTEM FOR DIETARY SUPPLEMENTS FOR THE MILITARY The Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2007 mandates that dietary supplement manufacturing companies report life-threatening events to the FDA. Nonlife-threatening adverse events are to be recorded by the manufacturer, and records retained for 6 years in case the FDA needs to inspect the information. This act defines the term adverse event very broadly as any health-related event associated with the use of a dietary supplement that is adverse. The term adverse event might identify a different effect in the context of the military. That is, the success of a military operation depends on each member’s optimal performance, and thus effects that might not be perceived as a serious problem in the general population (e.g., dehydration) might constitute a significant problem in the military context, depending on the unit and task. It is therefore critical that specific adverse effects that might pose harm to military performance be reported so that leadership can take appropriate actions. With this in mind, this committee has chosen to use the FDA’s definitions of adverse events and serious adverse events. For the military, the distinction between them is based on the extent of decrement to either the performance or the survivability of service members, taking into consideration their tasks (both physical and mental), the environmental surroundings (e.g., high altitude, extreme temperatures), and risks (e.g., bleeding, dehydration, infection, stress). A list of conditions to help categorize adverse events into high, moderate, low and minimal is found in Box 5-1. The committee’s reviews of selected dietary supplements show that some that are used frequently might present health and performance problems if misused, particularly for those

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subpopulations facing demanding tasks. For example, ginkgo biloba and garlic have anticoagulant effects that in a combat situation might result in extended bleeding, jeopardizing health and mission success. Other supplements should not be taken while performing tasks that require alertness because of their potential for sedative effects (e.g. valerian or melatonin). The use of ephedrine-like substances are also of concern because of potential harmful cardiac effects. In addition, sales data provided to the committee indicate high use of some multi-ingredient dietary supplements; the effects of ingredient interactions are mostly unknown and present concerns. Based on the heightened risks, frequency of use among military service members, the lack of consistent policies, and the absence of a process to report adverse events, a separate system for use by the military to monitor and evaluate adverse effects from dietary supplements is warranted. This section describes the committee’s recommendations to establish such a system. Ideally, a successful surveillance system will be economical, simple to use, and easily accessible, and yield data that is accurately representative of the population (Woolf, 2006). The data should be collected efficiently and in a consistent, unbiased manner. Vital to the effectiveness of the system is a database that allows for integrated and expeditious data analysis so that dissemination of findings to key public health officials and commanders is timely. It is also critical that encouragement to report adverse events be provided by broadening educational programs and outreach activities addressing various aspects of dietary supplement use, particularly the importance of reporting adverse events. The lower cost of a voluntary rather than an active system would make it more appropriate for use within the military population, provided that rates of response are substantially increased by educational programs and outreach activities. Active surveillance should be conducted occasionally as a tool to detect or investigate signals of concern from dietary supplements at installations whose military personnel face highly demanding tasks (e.g., Rangers or Special Forces). An active system entails a regular, periodic collection of case reports from health care providers or other personnel at those military installations. To support the data, questions about adverse effects should be included in surveys of dietary supplement use administered at these sentinel installations (see Chapter 2). The committee also emphasizes that there is much to be gained from collaboration with other groups. The regulatory environment has not always been able to keep up with the market growth of dietary supplements. There is no single system in place for surveillance of adverse events associated with dietary supplements; nongovernmental organizations, government agencies, and manufacturers have implemented new systems or adapted systems that were already in operation for other products. Any military system of surveillance should complement its data with data from other governmental agencies and industry. Clearly, many limitations will impede comparisons with databases maintained by other organizations (e.g., Consumer Product Safety Commission, the FDA, the American Association of Poison Control Centers), manufacturers, and trade associations (e.g., the American Chemistry Council, Consumer Specialty Products Association) (see description of their limitations in Kingston in Appendix B). While it is not feasible to directly integrate or compare data from these various sources, it is advisable to make in-depth comparisons, taking into consideration differences and limitations of data collection. A key committee recommendation is the formation of a partnership in which various parties with common interests work together in building knowledge by sharing data collected. Appendix B includes a description of postmarket surveillance efforts by both the private and public sectors. Also described is the surveillance system for products regulated by the U.S. Environmental Protection Agency, a system that engages the manufacturer as the primary point of contact for reporting adverse events. This industry role entails a significant training component or outsourcing of the surveillance system and design of a database and collection system.

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This section describes the committee’s recommendations in three different areas: (1) the collection and analysis of adverse events data, (2) sharing of adverse event surveillance data, and (3) training and outreach. To increase the reporting rate of adverse events, various strategies have been recommended: 1) the education of commanders, service members, and military health-care personnel; 2) dual mechanisms for reporting adverse events that is, one directly from service members and one from health-care personnel; 3) a centralized reporting system; 4) the establishment with other groups of a forum or coalition to share data from the general population on adverse events. Recommendations provide actions to take and identify the military organization logically responsible for implementing them. The committee did not attempt to include all the military organizations that might be involved with educational, decision-making, research, or other activities, but rather provided a broad organizational picture of the responsibilities. Recommendations for the Collection and Analysis of Adverse Event Data The recommendations in this section are related to the following questions: What is the process by which the military should monitor adverse events resulting from the use of dietary supplements? How would commanders get information in a timely fashion? How can reporting rates and data quality be improved? A critical analysis of the 2002 survey by the U.S. Army Center for Health Promotion and Preventive Medicine recommends various educational tools, but also urges that reports of adverse events associated with dietary supplements be reported through the Army Reportable Medical Events System. Regardless of the form used to report adverse events (e.g., MedMarx, MedWatch form 3500, Army Reportable Medical Events System’s ADR or other), the analysis and decisionmaking activities would be realized more efficiently by using a centralized process in which data are reported through an integrated electronic health record system as described earlier in this chapter. The following are recommendations to expand the current system to include reporting of adverse events from dietary supplements. Since collaboration will be critical to the success of an adverse event monitoring system, other organizations may also play a contributory role in collecting or sharing information. Recommendation 7: The military should use a centralized monitoring system for reporting dietary supplement adverse events (and data on use), in which data are recorded through the integrated electronic health record system already being implemented in the military. Improvement of the Electronic Health records system The military should ensure that future electronic health records adequately capture dietary supplement use and adverse event data. (As the military continues to move toward a single electronic health record for each service member, provisions will be needed to ensure entry of data on dietary supplement use and adverse events when service members receive health care from providers not located in the MTFs.). Implementation of a centralized system will have to address difficulties such as the need for additional staff time and training efforts to collect, identify, and code dietary supplements being used. In particular, the electronic system should:

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x

x

x

x

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Prompt the health care provider to ask the patient about dietary supplement use, safety, and benefits and to submit adverse event reports. It would also be appropriate to add a standard assessment question(s) as part of the routine office check-in, including questions about reasons for taking any supplements the patient reports using. Create standardized reports that can be aggregated for analysis (e.g., at the MTF based on common mission requirements, deployment status, and branch of service). Reports would include data on frequency of use and adverse events. Generate automated alerts in response to significant change in usage or reports of adverse events attributed to a dietary supplement of particular interest, which will help with adverse event attribution and identification of trends. This feature could be customized for use at various levels (e.g., at the MTF, or based on common mission requirements, deployment status, or military service). Generate automated alerts for individual patients when there is a risk of dietary supplement interaction with a medication or other treatment.

Recommendation 8: The military should designate a committee or military entity to be responsible for the oversight and coordination of dietary supplement-related activities, such as overseeing the adverse event surveillance system and parallel educational components. Based on the heightened risks, frequency of use among military service members, the lack of consistent policies, the suspected associations between adverse events in the field and the use of dietary supplements, the absence of a system to report these adverse events, and potential consequences of the unguided use of dietary supplements for an individual’s health or mission success, a military entity or committee (e.g. a committee from here on refered to as designated oversight committee) should be designated to oversee, coordinate, and provide guidance related to the use of dietary supplements by military personnel. The alternative, continuing without a designated group, would perpetuate the suboptimization of the existing resources and data and continue to put military members at risk owing to lack of science-based guidance, education, and policy. The committee recognizes that designating a new entity might not be feasible, and the tasks of an existing military committee or entity could be expanded to include the responsibilities related to dietary supplements. In addition to a key role in designing an adverse event reporting system for dietary supplements, this oversight committee should have access to military and nonmilitary information and data, and provide advice on surveillance, educational programs, adverse event reporting, and research activities (see a description of these tasks below). The actual operational and data collection activities would rest with other existing military organizations, such as the USARIEM (research), Center for Health Promotion and Preventive Medicine (educational materials), or Health Affairs Office (surveillance). This designated oversight committee should include the expertise of nutritionists, dietitians, epidemiologists, toxicologists, pharmacists, experts on adverse event reporting, physiologists, health promotion staff, health educators, physicians and health care providers, and military leadership. One possibility that could be considerd would be to include oversight for these activities in the formal charter of the DoD Dietary Supplement and Other Self-Care Products Committee under the authority of the Office of the Assistant Secretary of Defense (Health Affairs) (see Box 6-1), which addresses nutrition issues including those relating to dietary supplements.

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BOX 6-1 Dietary Supplement and Other Self-Care Products Committee The Dietary Supplement and Other Self-Care Products Committee (DSOPC) has requested an official charter from DoD Health Affairs. According to their draft charter, the DSOPC shall use peer-reviewed and militarily relevant research, evidence-based data, and the consensus of subject-matter experts to develop recommendations that support DoD activities, policies, and instructions relating to dietary supplements and other self-care products used to enhance health and human performance. Specifically, the DSOPC shall: x Establish Memorandums of Understanding (MOU) with the Food and Drug Administration (FDA) 1) to identify, in collaboration with the FDA, adverse events and their association, when possible, with particular dietary supplements and other self-care products used by the U.S. population; 2) to monitor and evaluate records of adverse outcomes for military beneficiaries. x Recommend methodologies for assessing prevalence of use of dietary supplements and other performance-enhancing/self-care products across and within DoD active duty populations and their family members. x Review trends on the use of dietary supplements and other performance-enhancing/selfcare products. x Assemble and document servicewide activities relating to dietary supplement use, education, and research. x Review servicewide educational approaches for military health-care providers (physicians, nurses, dietitians, etc.) and for the active duty population regarding the benefits and hazards of dietary supplement and other self-care product use. x Provide recommendations for and prioritize an operationally relevant research agenda on dietary supplements for health and human performance as well as other self-care products. x Develop evidence-based recommendations, in collaboration with other agencies, for servicewide policies that provide guidance on the use of dietary supplements and other selfcare products for health and human performance for active duty personnel. x Make recommendations to the Office of the Assistant Secretary of Defense for Health Affairs regarding appropriate resourcing and resource sharing for DSOPC initiatives among the services. x Recommend methodology for development of a DoD system-wide communication process for reporting and dissemination of all adverse events, current research initiatives, educational programs and implementation instructions relating to dietary supplements and other self-care products. x Serve as a consultant on the role of dietary supplements and other self-care products on human performance and health and medical conditions for unified and specified commands upon request. SOURCE: Personal communication, Patricia Deuster, Uniformed Services University of the Health Sciences, June 22, 2007.

This committee should review on an annual basis reported adverse events as well as surveys of supplement use by military personnel and, as indicated, recommend to the military leadership

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immediate action and/or conducting a review of published science-based safety reviews by the review panel. The following are specific responsibilities of the designated oversight committee. Develop adverse event submissions systems The committee recommends the development of two reporting mechanisms, one for use by the health care provider and one for use directly by the service member. The health care provider would enter dietary supplement use information in the patient’s record and submit appropriate adverse event forms to the MTF P&T committee. In addition, service members should be able to report adverse events without having to arrange a medical appointment. Adverse event report data should be submitted through a toll-free telephone number or interactive website that allows for follow-up by medical personnel. These data should be provided to the MTF P&T committee in a timely manner to be evaluated along with other adverse events reported from health care providers. The designated oversight committee will clearly define the systems intended to submit the adverse event reports, including the forms to be used (e.g., MedWatch, MEDMARX ADR) by health care providers and directly by service members; the committee will also designate a system to categorize adverse events for level of severity. Participate in forum or coalition The designated oversight committee should participate in a forum or coalition of military (i.e., the DoD and the corresponding support structures within each military service) and nonmilitary groups for the exchange of data and information related to dietary supplements, including data on adverse event reports (see below). Develop and implement reporting mechanisms For an adverse event reporting system to be of value, it is critical to have an efficient system to provide timely information about adverse events to those who need it (e.g., MTF P&T committees, commanders, fitness centers and unit trainers, health care providers). After adverse event report summaries are written (see below), the flow of information to share adverse event data and summaries by the various military groups should be defined (e.g., frequency of reporting and recipients of information). The designated oversight committee should establish a system of information flow that is effective (i.e., information is delivered to decision makers and educators) and timely (see Figure 6-1).

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Collect relevant data The designated oversight committee should identify relevant databases and efforts related to surveillance of adverse events associated with the use of dietary supplements by military and nonmilitary groups. The following information should be collected: x Data on adverse events. This task is related to the designated oversight committee’s participation in a partnership with other military and nonmilitary groups (see below for a list of the type of data and information to be collected). x Information on dietary supplement product ingredients to create a database in collaboration with the FDA, Office of Dietary Supplements (ODS, NIH), the U.S. Department of Agriculture, and the U.S. Pharmacopeia. In the future, such a database would be useful to estimate dosage and ingredients consumed and, in turn, to analyze adverse event data. x Data on dietary supplement use and associated risks and benefits, including those from interactions with medications, other dietary supplements, or foods. Of particular interest are data on risks and benefits when subjects are in environments similar to those experienced by military personnel. These data should be obtained from the expert panel conducting reviews of dietary supplements under the oversight of the USARIEM (see Chapter 5). Recommend policy The designated oversight committee should provide guidance to the DoD on military policies and regulations on the safety (and efficacy) of dietary supplement usage, such as strategies, educational programs, and materials highlighting benefits and risks of dietary supplement use for military members, as well as for health care professionals (see below). Recommendation 9: The responsibility of the local Medical Treatment Facilities’ Pharmacy and Therapeutics Committees (MTF’s P&T) should be extended to reviewing and summarizing the adverse events reports as submitted by health care providers or service members, and preparing and providing summaries via a process recommended by the designated oversight committee. Extension of the responsibility of the MTF’s P&T committees The military should assign specific responsibility for the oversight and coordination of the monitoring system and parallel education components at the local level. Because the local MTF P&T committees already review adverse reactions to drugs, the committee concludes that it would be feasible to expand their responsibilitites to review adverse reactions to dietary supplements at the local level. Modifications of the pertinent regulations (e.g., AFI 44-102, Medical Care Management, Paragraph 10.9) to include review and analysis of dietary supplement adverse events at the local level will ensure that local actions are initiated when appropriate. It may also be appropriate to identify the need for organizational units (e.g., Aerospace Medicine and U.S. Army Center for Health Promotion and Preventive Medicine) at the installation level to address dietary supplement usage and safety, as these organizational units have the responsibility to “optimize and enhance human performance” (e.g., AFI 40-101, Health Promotion Program; AFPD 48-1, Aerospace Medicine Program; AFI 48101, Aerospace Medicine Program; AFI 40-104, Nutrition Education; AR 40-3, Medical, Dental, and Veterinary Care; and NAVMED P-117, Manual of the Medical Department). Review of adverse events associated with dietary supplement use The committee supports the 2000 memorandum from the Army’s Office of the Surgeon General (Department of the Army, 2000) stating that health care providers should document adverse events believed to be associated with

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dietary supplements in the patient’s medical record. The committee also supports the local MTF P&T committees’ notification of any such adverse event by health care providers. The MTF P&T committees should develop summaries of these adverse event reports highlighting dietary supplements of concern and associated adverse events, and particularly emphasizing those concerns related to military performance and environments of specific military groups (e.g., Special Forces, Rangers). Enhance the expertise of adverse event reviewers Adverse event reviewers should include experts on epidemiology and adverse event surveillance, data mining and statistical techniques, nutrition, toxicology, diagnosis of diseases or conditions, physiology, and botany and pharmacognosy. Reviewers should be familiar with the demands and conditions unique to military operations and experienced in identifying serious or unexpected adverse effects, especially when relevant to military performance. Submit reports on adverse events through the military system To ensure that data are available in a timely manner to military commanders and then released to the FDA as the military deems appropriate, summaries of the adverse event reports should be submitted by the MTF’s P&T committees through a designated system. The frequency and specific process to submit these summaries should be established by the designated oversight committee. Recommendation to Share Adverse Events Data and Other Information Related to Dietary Supplements Recommendation 10: The committee recommends that a coalition or forum be established for the exchange of data and information related to dietary supplements, such as data from surveillance of dietary supplement use and adverse events. The committee found that only by establishing a joint forum or coalition will there be assurance that key data about adverse events reported would be shared by the FDA, military institutions, poison control centers, and others. Although it is not appropriate to make direct comparisons of the data owing to differences in data collection approaches, it is advisable to make in-depth examinations that take into consideration these differences and other data limitations. Members of this forum will also share other valuable information regarding new products in the market, increases in popularity of products, and latest research updates (see a list of suggested data and information to share below). With effective communication, there is much to be gained from such collaboration. The members of this forum or coalition would update or add new data to a database established for this purpose. They could also meet periodically to present data and information updates. Members of the designated committee to oversee dietary supplements activities would participate in this coalition and have access to the database. Participants of the forum should include, among others, experts in toxicology and safety evaluation of natural products. Representatives from the following groups could be invited to become part of this partnership: x Designated oversight committee (recommended by this committee to be under the DoD) x Registered dietitians from from the U.S. Air Force, U.S. Army, and U.S. Navy (DoD Nutrition Committee) x USARIEM

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Pharmacists from the DoD Pharmacoeconomic Center, U.S. Air Force, U.S. Army, and U.S. Navy Medical representatives from the U.S. Air Force, U.S. Army, and U.S. Navy FDA’s Center for Food Safety and Applied Nutrition Federal Trade Commission (FTC) Office of Dietary Supplements (ODS, NIH) Army and Air Force Exchange Service/Navy Exchange Service (AAFEX/NEX ) Other sales outlets located on military installations Industry trade associations Health and Wellness and Health Promotion Centers from the U.S. Air Force, U.S. Army and U.S. Navy Fitness centers or units trainers from the U.S. Air Force, U.S. Army, and U.S. Navy Other representatives

To support the goal of the partnership, the collaboration might include sharing information and fostering discussions on the following topics: x

x x

x

x x x

x x

x x

Sales outlet reports from AAFES/ NEX, Defense Commissary Agency (DeCA), and/or other sources at military installations to compare sales of dietary supplements from year to year and identify new products introduced to the market Reports from industry trade associations on changes in products and sales trends Summary of adverse events from specific military installations to identify regional differences, active surveillance data on adverse events at sentinel installations, and overall trends Summary of FDA adverse event reports as available, including relevant data from the poison control centers; in addition, data on health claims of efficacy for dietary supplements would also be shared as appropriate. Summary of FTC evaluation of dietary supplement products Summary of clinical trials registered by the Center of Alternative Medicine (NIH) that are evaluating dietary supplements Reports about dietary supplement use from in-depth surveys on sentinel installations. Sentinel sites would be selected based on the mission of forces stationed at the installation (e.g., Rangers, Army Special Forces, Air Force Special Operations Command, B-1B longrange bomber crew, Navy Seals) as well as the capacity to conduct such a survey (i.e., provision of electronic health records, health care personnel to manage the additional data collection) (see Chapter 2). Reports from USARIEM on performance-enhancing supplements that were selected for review as well as a summary of research findings and protocols Summary of medication and dietary supplementation education and materials (e.g., on safety, efficacy, interaction with medications) provided by pharmacy, health-promotion, dietetics, nursing, and medical staff to meet the requirements of the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO, 2007) Review efforts by each service to provide education on dietary supplements to their personnel (e.g., usage of websites and attendance of meetings about dietary supplements). Results from DoD’s Survey of Health-Related Behaviors that summarize trends and the characteristics of dietary supplement users

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Recommendations to Expand Education: Training and Outreach Recommendation 11: Military service members and commanders should be educated to recognize both the potential adverse effects and benefits from using specific dietary supplements and the importance (and the process) of reporting an adverse event. Recommendation 12: Health care personnel should be trained in evaluating dietary supplement use, informing and obtaining information from their patients, and appropriately reporting adverse events. The committee recommends expansion of all educational programs and outreach activities to increase awareness about the use of dietary supplements. These educational elements are key to the support of an effective, centralized adverse event monitoring system. If the evaluation of these educational activities shows that they are ineffective at improving the quality or rate of adverse event reporting from dietary supplement use, the military could explore additional strategies. For instance, in addition to continuing educational efforts, the DoD could subcontract a dietary supplement information and safety hotline service where service members could communicate, anonymously, with a health care specialist. This hotline service would serve two purposes, education of the service member and data collection of adverse events. The following are recommendations for educational activities: Develop educational materials on dietary supplements and balanced nutrition, tailored to military members The proposed designated oversight committee should oversee the development of educational materials to be disseminated through a variety of methods (e.g., point-of-sale brochures, posters, or websites). Such educational materials on dietary supplements will describe potential benefits, mechanisms of action, and how to report adverse effects. These materials should focus on the military’s special performance requirements and the need to protect each individual’s body and health; messages should connect the need to protect health with the importance of reporting adverse events. These messages should also emphasize that while some symptoms (e.g., diarrhea) are not particularly problematic while in garrison, they may be of concern during deployment when mission readiness becomes critical. When available or displayed at point of sale, these materials will remind and encourage the service member to contact the user’s primary physician or emergency room in the event that adverse effects are experienced, even if they do not require medical intervention. Actively pursue outreach activities Service members and their commanders must be educated so that they recognize both the potential adverse effects and the benefits from the use of a given dietary supplement, and the importance of reporting any adverse events to health care providers. This may be achieved through the following approaches: x Include information about dietary supplements in routine commanders’ calls and communication regarding force protection/performance enhancement and health promotion, to reinforce the concept that some dietary supplements should be used with care and the importance of reporting adverse effects for force protection. Military commanders will be made aware of issues surrounding dietary supplement use as part of their formal education and routinely rely on their medical staff for input. There will also be direct communication with the designated oversight committee or via summary tables and monographs, produced by the review panel, or other educational materials that are provided both to medical staff and commanders.

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Consider modifying current contracts for sale of dietary supplements to include requirements to allow placement of outreach and educational materials on dietary supplements at point of sale on military installations (e.g., outlets at Army and Air Force Exchange Service [AAFES]/Navy Exchange Service [NEX] and fitness centers).

Provide appropriate training and continuing education for health care personnel Health care personnel (e.g., emergency room staff, flight surgeons, medics, dietitians, pharmacists, and health promotion personnel) should improve their abilities to evaluate dietary supplement use, to inform military members, and to appropriately report adverse events. Education should be included in existing programs (e.g., Uniformed Services University of Health Sciences, internships and residencies, aerospace medicine training, independent duty medical technician training, and mandatory continuing education at medical staff meetings). Education and training should emphasize the following objectives: x Enhance health care personnel’s awareness and ability to pose relevant questions and provide information to patients relating to the use of dietary supplements. Identify and direct their patients to credible sources of information (e.g., NIH’s Office of Dietary Supplement). x Provide guidelines on how to effectively report adverse events. Training should address the following topics: (1) identificaiton of adverse events of interest to the military (see Box 5-1); (2) the forms and process used to report adverse events; (3) effective collection of the data necessary to evaluate an adverse event (e.g., include listing of different names by which the dietary supplement is known; prompt patient on whether the product information was confirmed from product label or website, whether product was taken in accordance with instructions on the product label, and what other medications, dietary supplements, or foods were consumed; verify contact information for follow-up); and (4) actions likely to be considered based on adverse event monitoring reports.

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Evans U.S. Army Community Hospital. 2006. Safety awareness bulletin for dietary supplements. http://evans.amedd.army.mil/ncd/dietarysupplementalert.htm (accessed October 24, 2007). FDA (U.S. Food and Drug Administration). 2007. From test tube to patient: The FDA’s drug review process: Ensuring drugs are safe and effective. http://www.fda.gov/fdac/special/ testtubetopatient/drugreview.html (accessed September 4, 2007). Figueiras, A., F. Tato, J. Fontainas, and J. J. Gestal-Otero. 1999. Influence of physicians' attitudes on reporting adverse drug events: A case-control study. Med Care 37(8):809-814. Gardner, R. M, and R. S. Evans. 2004. Using computer technology to detect, measure, and prevent adverse drug events. J Am Med Inform Assoc 11(6):535-536. Haller, C. A., T. Kearney, S. Bent, R. Ko, N. L. Benowitz, and K. Olson. In Press. Dietary supplement adverse events: Report of a one-year poison control center surveillance project. J Med Toxicol. Hand, D. J., H. Manilla, and P. Smyth. 2001. Principles of data mining. Cambridge, Massachusetts: The MIT Press. Hooah 4 Health. 2007. Herbs for health. http://www.hooah4health.com/body/nutrition/herbs.htm (accessed March 20, 2007). IOM (Institute of Medicine). 2007. The future of drug safety: Promoting and protecting the health of the public. Washington, DC: The National Academies Press. IOM and NRC (National Research Council). 2005. Dietary supplements: A framework for evaluating safety. Washington, DC: The National Academies Press. JCAHO (Joint Commission on the Accreditation of Healthcare Organizations). 2007. Comprehensive accreditation manual for hospitals: The official handbook. Chicago: Joint Commission Resources. LSRO (Life Sciences Research Office). 2004. Recommendations for adverse event monitoring programs for dietary supplements. Bethesda, MD: Life Science Research.

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McMahon, A. W., C. Zinderman, R. Ball, G. Gupta, and M. M. Braun. 2007. Comparison of military and civilian reporting rates for smallpox vaccine adverse events. Pharmacoepidemiol Drug Saf 16(6):597604. NEHC (Navy Environmental Health Center). 2004. NEHC nutri-facts dietary supplements. http://wwwnehc.med.navy.mil/downloads/hp/NutrFact_Dietary%20Supplements.pdf (accessed October 24, 2007). Navy and Marine Corps Public Health Center. 2007. Weight management (SHIPSHAPE). http://wwwnehc.med.navy.mil/hp/shipshape/ShipShape_Nutrition/About_Nutrition.htm (accessed December 4, 2007). OIG (Office of Inspector General). 2001. Adverse event reporting for dietary supplements: An inadequate safety valve. Department of Health and Human Services OEI-01-00-00180. Strom, B. L. 2005. Pharmacoepidemiology,4th ed. Chichester, England: John Wiley & Sons. USARIEM (U.S. Army Research Institute of Environmental Medicine). 2007. Memorandum: Heat injury prevention policy. http://www.usariem.army.mil/DOWNLOAD/ HeatInjuryPrevention2007.pdf (accessed October 25, 2007). USACHPPM (U.S. Army Center for Health Promotion and Preventive Medicine). 2000. Module 5: Dietary supplements: A basic guide. http://chppm-www.apgea.army.mil/ dhpw/Wellness/PPNC/PM_MOD5.pdf (accessed October 24, 2007). USACHPPM. 2003. The warfighter's guide to dietary supplements: What you really need to know. http://chppm-www.apgea.army.mil/documents/TG/TECHGUID/TG295.pdf (accessed October 24, 2007). USACHPPM. 2007. U.S. Army Center for Health Promotion and Preventive Medicine. http://chppmwww.apgea.army.mil/ (accessed October 29, 2007). U.S. Department of Homeland Security. 2003. Coast Guard aviation medicine manual. http://www.uscg.mil/directives/cim/6000-6999/CIM_6410_3.pdf (accessed November 6, 2007). Woolf, A. D. 2006. Safety evaluation and adverse events monitoring by poison control centers: A framework for herbs and dietary supplements. Clin Toxicol (Phila) 44(5):617-622.

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7 Research Needs

The committee was requested to select a limited number of dietary supplements to review and then determine whether further examination and integrative evaluation or research on each is warranted. There are numerous research questions about the safety and efficacy of the selected dietary supplements. A first step in developing a research agenda, however, is to set priorities to deliver answers to the questions most critical to the military with the most efficient use of resources. In a complex institution like the military, whose subpopulations within the various services might have different tasks, the coordination of efforts to prioritize research needs is key to the success of this endeavor. Consequently, the committee did not attempt to provide an exhaustive listing of research needs for any dietary supplement; instead, the committee presents an approach for the military to use to prioritize research needs. For example, research might focus on supplements with anticoagulant effects as a potential critical concern, regardless of the potential benefit for which they are marketed. Box 7-1 lists examples of research needs for the supplements reviewed in this report.

BOX 7-1 Examples of Potential Research Questions on the Dietary Supplements Selected for Committee Evaluation Of the supplements selected for review, the committee found no compelling reason for the military to make research on the following dietary supplements a high priority at this time: chromium, dehydroepiandrosterone, garlic, ephedra, ginseng, melatonin, valerian, and ginkgo biloba. For the remaining dietary supplements reviewed by the committee, the following specific questions could warrant further investigation: x What is the range of consumption of caffeine in the military population? What are the sources and amounts of total intake? To what extent are patterns of consumption approaching the limits for operationally effective doses of caffeine? x What are the beneficial or adverse effects of long-term use of tyrosine? Of creatine? x Are there tolerance or withdrawal effects from using creatine, caffeine, or other dietary supplements? x Given that ȕ-Hydroxy-ȕ-methylbutyrate (HMB) appears to improve muscle function or mass in physically untrained subjects or those in a catabolic state, what are the effects of HMB in new recruits or those with hypocaloric intake? x What are the effects of varying the protein content (amount and composition of amino acids) in sports bars or drinks and the timing of their consumption on recovery from strenuous activity (e.g., on reduction of immune suppression after exercise, hydration, or reduction of muscle soreness). x Are there any dietary supplements (e.g., quercetin) that help reduce poststress health effects such as respiratory infections?

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Future studies on dietary supplement use in the military should be approached from an etiological or mechanistic perspective, focusing on areas of particular concern or potential benefit for health, performance, and survivability (e.g., fitness, level, hydration; GI tract, hepatic, and cardiovascular function; and cognitive and neurobehavior function). In agreement with the committee’s recommendation that both risks and benefits be considered in management decisions about dietary supplements, studies that focus on answering questions about potential safety concerns and putative benefits may need to be prioritized separately according to the special needs of military subpopulations. The military has unusual access to its members’ medical records, and its population is in better general health and includes fewer individuals at risk for certain diseases and drug interactions, all of which should facilitate the identification of potential concerns and possible benefits associated with use of dietary supplements by service members. KEY CONSIDERATIONS FOR CONDUCTING MILITARY NUTRITION RESEARCH Study Designs In conducting research of interest to the military, it is critical that the efficacy and safety of dietary supplements be tested with representative subjects engaged in training that is similar to those in combat and in specific military conditions (e.g., under situations of sleep deprivation, extreme environments, moderate physical activity of long duration). Human models that mimic some of the physical stresses and environments that accompany military missions and training programs should continue to be included in the study designs. For example, a human model could consist of individuals exercising a predefined, outdoor running- and obstacle course or a specific physical activity in an environmentally controlled laboratory setting. The selection of study subjects should take into consideration physiological differences (e.g., blood pressure, body mass index) that reflect demographic factors (i.e., gender, age, or ethnicities) of the military population that might result in differential effects of dietary supplements. Research populations should represent the current targeted population participating in garrison training, serving in combat, or both. Animal Models Although the military can conduct studies of the effects of dietary supplements on subjects undergoing the physical stresses of training or conditions simulating combat, using human models for the simulation of severe mental and emotional stresses present practical and ethical limitations. Likewise, some procedures (e.g., multiple liver biopsies) would be difficult to justify on humans. The military should therefore continue the development of animal model systems that mimic the stresses of garrison training and combat to allow screening for physiological effects of dietary supplements under extreme conditions. Screening with well-designed and ethical animal studies could be followed with more focused and better-designed human studies. These models would not only provide preliminary information about the effects of dietary supplements but could also be applied to obtaining preliminary information about the effects of other interventions in preventing and treating diseases and injuries under conditions of garrison training and combat. To maximize and coordinate efforts in this area, collaboration with civilian researchers is of vital importance. Key elements of an animal model research program are:

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RESEARCH NEEDS

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Animal—Human Transposition This committee recommends that the military support and conduct experiments to understand animal–human transpositions. It is increasingly apparent that it is not possible to directly extrapolate data obtained in animal studies to humans (IOM, 2006; NRC, 2005, 2007). Not only are there differences in biological regulation between species, but the premises for most safety studies might also be inappropriate. For example, feeding test animals with multiples of expected exposure levels to increase the sensitivity of a test may yield inaccurate results as substances may act quite differently metabolically at low levels than they do at high levels. The development of animal models allowing animal–human transposition will require better understanding of fundamental biology. For example, better understanding of the molecular and genetic regulatory basis of physiological responses to extreme environments will permit more credible qualitative and quantitative comparisons of animal and human outcomes and hence, more precise predictions of adverse effects in humans. Methods to Quantify Stress There are many stressors experienced by deployed service members and the corresponding stress response can be perceived in the short or long term. Stress frequently results from military situations that include thermoregulatory challenges, physical exertion, inadequate sleep and rest, and psychological stressors such as confronting unknown, high-risk situations and the threat of death. Because of the multidimensional nature of stress, its measurement will continue to be difficult. The military should support or conduct studies on improving the methods to quantify stress. APPROACHES TO IDENTIFYING AND SELECTING RESEARCH NEEDS Coordinating Efforts Among Military Services To identify dietary supplement research topics of interest to the military, a clear coordinating process needs to be implemented between all services. Ideally, this process will include input from all the services and will evaluate the potential topics as well as the feasibility and implementation of the research methods. The highest priority research should be performed or sponsored by the military and should occur in conjunction with monitoring the results of research conducted in the civilian population for potential military implications. As with other aspects of dietary supplement management, recommending research to be conducted or sponsored by the military should be a task for the proposed Dietary Supplement Oversight Committee (see Chapter 6) . Specific criteria for priorities or concerns might be set by the individual services and submitted to the Dietary Supplement Oversight Committee. Identification of Research Needs for Specific Dietary Supplements This committee recommends that gaps in data or information be identified based on the following elements of the recommended approach to manage dietary supplement use: (1) the results of the surveillance system evaluating use of dietary supplements within the military (Chapter 2); (2) gaps identified in the reviews conducted for specific dietary supplements,

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especially those issues relevant to military performance and survivability (Chapter 5); and (3) the occurrence of adverse events of military importance associated with the use of specific dietary supplements (Chapter 6). As the committee evaluated dietary supplements (Chapters 3 and 4) using the framework, it identified examples of potential research questions for the selected dietary supplements (Box 7-1). Safety Following the framework illustrated in Figure 5-1, the military should develop a list of adverse effects of particular concern for service members (e.g., interference with blood clotting). One potential response for the military would be to generate requests for proposals for methods to evaluate safety in these areas or to identify any particular classes of compounds that could be expected to cause such safety concerns. Benefit There is a long history of use of botanicals (e.g., Chinese traditional medicines) with putative beneficial effects that could be the subject of research by the military. The committee recommends that the military narrow their research questions to those traditional botanicals that are believed to affect physical and mental functions; one approach to focus their searches might be consultation with expert ethnobotanists and pharmacognocists. In addition, the military should consider conducting research to develop a framework approach to determine the efficacy of dietary supplements. Such an approach should consist of a mechanism to determine the level of benefit to service members under specific environmental conditions and for specific military tasks; it should include elements such as recommendations for appropriate research designs, for conducting literature reviews, and for identifying research gaps. Concomitantly, the military could take a similar approach as that suggested for safety, that is, to make Requests for Proposals that address both methods for evaluation of efficacy and/or any particular class of compound that might be expected to confer these benefits.

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RESEARCH NEEDS

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POTENTIAL RESEARCH AREAS OF INTEREST Research on Adverse Effects from Supplements Relevant to the Military As mentioned above, the military should determine the adverse effects of dietary supplements in the context of specific military environments and tasks. Broad research areas that will shed light on the safety of dietary supplements are described below. As with benefits, for all areas of research described, it is necessary to determine the dosage and duration of use of the dietary supplement leading to adverse effects and to consider the impact of unique military environments on these effects. Frequency and Severity of Adverse Events Before prioritizing research on adverse effects or taking management action, it is important to determine the frequency and severity of adverse events of interest to the military; one way to acquire this information is the use of well-designed surveys (Chapter 2). Another approach recommended by the committee is the implementation of an adverse event monitoring system for the military (Chapter 6). Identification of Ingredients Associated with Adverse Events The concomitant analytical evaluation of the identity and integrity of the supplement products associated with reported adverse events is a key element in managing the use of dietary supplements. One potential strategy to conduct these analyses would be to contract with appropriate research facilities that are equipped for and experienced in chemical analysis of natural products.  Interactions with Other Compounds When designing surveys and studies and interpreting their results, researchers should be mindful of the large number of dietary supplements available, which are often consumed in combination and whose composition is often changed or is unknown. Intake of multiple supplements could lead to interactions having either synergistic or antagonistic effects. Likewise, dietary supplements could interact with other food components or medications. Speculation on the impact of the interactions is possible based on mechanisms of action or other factors, but there is minimal research in this area. Tolerance and Withdrawal Effects Research should assess the development of tolerance and/or withdrawal effects following chronic use of those dietary supplements frequently consumed by the military (e.g., caffeine, creatine, tyrosine). Multi-ingredient dietary supplement products Multi-ingredient dietary supplements, which are frequently reformulated and for which safety data are limited, will continue to be available and used by military service members. It is

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critical to identify concerns (or potential benefits) associated with these products. Use of the framework developed by the committee is recommended to identify concerns associated with the use of multi-ingredient dietary supplements; the same criteria for initiating a review (i.e., frequency of use and adverse event reporting) should be followed. A high prevalence (or significant increase) of use indicated by the surveillance system, adverse event reports suggesting a potential for concern, or a known hazardous component in a multi-ingredient dietary supplement constitute signals calling for review and possibly management action. If literature reviews fail to reveal any safety data, then the military should consider conducting safety evaluation studies of the product or significant ingredients and potential effects of ingredient interactions (see above). The development of methodologies to evaluate multiingredient products, including potential interactions, is an area of reasearch that should be supported by the military. Research on Beneficial Effects from Supplements Relevant to the Military When prioritizing research on potentially beneficial dietary supplements, the military might consider the general topics described below. For all topics, determining the dosage and length of exposure necessary to observe benefits and the impact of the military’s tasks and extreme operational environments on those effects are crucial research questions. (The reader is referred to the WHO [World Health Organization] monographs, a series of four volumes published by the Traditional Medicines Programme in Geneva, Switzerland; the German E monographs; or the United States Pharmacopeia [USP] monographs.) In all cases, these putative benefits of dietary supplements need to be proven scientifically and compared to those provided by alternative compounds (drugs) currently used as the standard of care. Mitigation of the Adverse Effects of Stressors on Service Member Performance One important category of research is determining which dietary supplements would be useful in alleviating physiological fatigue resulting from sleep deprivation, shift work, and transmeridian travel. An existing example of military interest in these types of supplements is the addition of caffeinated chewing gum to some military rations. Aside from research assessing the effects of caffeine on fatigue, few studies have been conducted to evaluate the actions of other naturally occuring stimulants, despite their worldwide use. Another category of research that might be addressed is the use of dietary supplements to moderate physiological responses to extreme environments, such as hypoxia and altitude sickness. Many ethnic groups (Peruvian, Indian, and Nepalese or Tibetan Sherpas) tolerate high altitude and cold with a hardiness for which no genetic link has been scientifically proven (Wu and Kayser, 2006). These groups use various herbs and other nutrients to maintain their strength and prevent altitude sickness, and these may be of interest to the military. Other stressors regularly encountered by military personnel that might be mitigated by dietary supplements are dehydration, radiation from explosive sources, physiological and psychological stress, and exhaustion. Prevention or Treatment of Injuries In addition to promoting recovery from the previously mentioned stressors, dietary supplements might also facilitate wound healing, a process frequently encountered in a military setting. Many plants have been used worldwide for wound healing and related concerns (e.g.,

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RESEARCH NEEDS

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sunburn relief). Some in vitro and in vivo data suggest the beneficial effects of these plants; however, there are few experimental studies on their value in human populations. Surveys on Dietary Supplement Use Analysis of surveys to determine the pattern and extent of dietary supplement use is a critical element of a dietary supplement research agenda. This need has been amply discussed in Chapter 2. Briefly, the committee recommends continuing the collection of usage data by expanding the Department of Defense (DoD) Health Related Behaviors Survey; it also recommends that more comprehensive surveys be conducted at select military sites where service members are likely to face higher risks due to the intensity of their training or exposure to extreme environments. As described in Chapter 5, adequate surveillance systems will help alert the military to potential concerns. Validation of the Recommended Approach to Manage Dietary Supplements Validation of the approach laid out by this committee is strongly recommended, especially for these elements of the approach: the surveillance system; the adverse event report monitoring system; and the framework for safety, including the recommendation to integrate consideration of risks and benefits as the basis for taking actions. The efficacy of this overall approach will best be determined by an annual status report and a 5-year review of the results from the surveillance, the adverse event report monitoring system, and the effectiveness of command recommendations to allow or restrict the use of specific supplements . The proposed Dietary Supplement Oversight Committee should decide on a timeline and specific criteria to validate this approach as well as to review the results. Research on Education Methods Research should be conducted to identify the effectiveness of various methods of communication and outreach to educate service members, commanders, health care personnel, and physical training and gymnasium staff on the use of dietary supplements. Information should be obtained on the awareness of use and knowledge about supplements among military personnel, commanders, and military physicians.

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REFERENCES IOM (Institute of Medicine). 2006. Dietary reference intakes research synthesis: Workshop summary. Washington, DC: The National Academies Press. NRC (National Research Council). 2005. Application of toxicogenomics to cross-species extrapolation: A report of a workshop. Washington, DC: The National Academies Press. NRC. 2007. Toxicity testing in the 21st century: A vision and a strategy. Washington, DC: The National Academies Press. Wu, T., and B. Kayser. 2006. High altitude adaptation in Tibetans. High Alt Med Biol 7(3):193208.

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Appendix A Workshop Agenda

Dietary Supplement Use by Military Personnel Food and Nutrition Board, Institute of Medicine, The National Academies The National Academies, 2101 Constitution Avenue NW Washington DC Lecture Room February 12–13, 2007

February 12, 2007 1:00

Welcome and Introductory Remarks M.R.C. Greenwood, Committee Chair

SESSION 1: INTRODUCTION Moderator: John Erdman, Committee on Military Nutrition Research 1:15

Perspectives on Committee’s Task and Workshop Goals: Prospective Uses Andrew Young, U.S. Army Research Institute of Environmental Medicine

1:35

Physiological Demands and Nutritional Needs of Military Personnel Scott Montain, U.S. Army Research Institute of Environmental Medicine

1:50

Efficacy of Dietary Supplements: Physical and Cognitive Performance Harris Lieberman, U.S. Army Research Institute of Environmental Medicine

2:20

Discussion

3:00

Break

3:15

Health Policy Development and Implementation for Military Personnel Lynn Pahland, Office of the Assistant Secretary of Defense, (Health Affairs)

3:45

Health Care and Physicians Perspective—How Do Military Hospitals Address the Use of Dietary Supplements by Their Patients? Whose Responsibility Is It to Address Dietary Supplements? Paul Hoerner, Lt Col USAF, BSC, Department of Defense Patient Safety Center

4:15

Design of Surveys on Dietary Supplement Use: Factors to Consider PREPUBLICATION COPY: UNCORRECTED PROOFS A-1

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David Kaufman, Boston University 4:45

Discussion

5:30

Adjourn

February 13, 2007 SESSION 2: SURVEYS ON USE OF DIETARY SUPPLEMENTS Moderator: Wayne Askew, Committee on Military Nutrition Research 8:00

Dietary Supplement Use in the United States Adult Population: An Analysis of the National Databases Paula Gardiner, Harvard Medical School

8:30

Insights into Dietary Supplement Usage by U.S. Active Military Personnel Steve French, National Marketing Institute

9:00

Beyond the DFAC (Dinning Facilities Administration Center): What Supplements Soldiers Are Taking and Why Sonya Corum, Lt Col U.S. Army Training and Doctrine Command

9:30

2006 Air Force Dietary Supplement Use Survey Information About Usage Charity J. Thomasos J Lt Col MIL USAF Eglin Hospital, Eglin Air Force Base, FL

10:00 Break 10:30 Dietary Supplement Use in the Last 12 Months as Reported by Active Duty Military Personnel Bernadette Marriot, Abt Associates, Inc. 11:00 Army Health Care Providers Knowledge of Dietary Supplement Usage Danny Jaghab Lt Col, U.S. Army Center for Health Promotion and Preventive Medicine 11:30 Dietary Supplement Use in U.S. Army Personnel Harris Lieberman, US Army Research Institute of Environmental Medicine 12:00 Summary Cheryl Anderson, Johns Hopkins University 12:15 Open Discussion 12:45 Lunch

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APPENDIX A

A-3

SESSION 3: FRAMEWORK FOR EVALUATING SAFETY Moderator: Johanna Dwyer, Committee on Military Nutrition Research 1:45

What Do We Know About Safety and Adverse Effects of Dietary Supplements Commonly Used for Physical Performance and for Weight Loss? Mary Hardy, University of California, Los Angeles

2:15 2:45

Dietary Supplements: An IOM Framework for Evaluating Safety Elizabeth Jefferey, University of Illinois Approaches for Postmarketing Adverse Effect Surveillance of Drugs and Biologicals Gerald J Dal Pan, Office of Surveillance and Epidemiology, FDA

3:15

Break

3:30

Current Approaches for Post-Marketing Adverse Effect Surveillance of Foods and Dietary Supplements Bill Frankos, FDA

4:00

Corporate Approaches to Safety and Postmarketing Adverse Effect Surveillance of Dietary Supplements Rick Kingston, SafetyCall International

4:30

Summary Sanford Miller, University of Maryland

4:45

Discussion

5:30

Adjourn

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Appendix B Workshop Papers

PHYSIOLOGICAL DEMANDS AND NUTRITIONAL NEEDS OF MILITARY PERSONNEL Scott J. Montain1 INTRODUCTION The U.S. military constitutes a large diverse workforce. It is diverse not only in demographic makeup, but also in mission responsibilities. The physiological demands of military jobs vary considerably, thus the nutritional requirements of the personnel performing them vary, as well. This brief overview will summarize the demographic makeup of the military, the range of physiological demands of military tasks, as well as current dietary practices to illustrate the makeup and challenges imposed upon our military personnel during implementation of their military duties. Military Demographics The U.S. military, comprised of the Army, Air Force, Navy, and Marine Corps, is a large workforce. As of 2005, there were 1.4 million individuals on active duty with the four Service Components of the military, with an additional 0.4 million assigned to reserve duty (Global Security, 2008). As illustrated in Figure B-1, the Army is the largest Service, accounting for 36% of the active duty personnel and 50% of reserve component. The Navy and Air Force have roughly equivalent numbers of personnel, whereas the Marines account for only 13% and 10% of the personnel in the active duty and reserve components, respectively. The U.S. military is a diverse workforce with respect to rank, race, and gender. Within the Army, 84% of the personnel are enlisted Soldiers, with 39% of those serving as noncommissioned officers (Maxfield, 2007). The Army National Guard and Army Reserve workforces are similarly distributed, with exception that the Army Reserve component contains Soldiers with more years of active duty experience and therefore a greater percentage of noncommissioned officers than the Active Duty component. White, non-Hispanics account for 61% of the Army active duty personnel, whereas, Blacks and Hispanics make up 22% and 11% of the force strength, respectively. The National Guard and Reserve forces combined are composed of 69% White, non-Hispanics, 17% Blacks, and 9% Hispanics. Females make up 14% of the Army 1

Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine (USARIEM), Natick MA

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active duty and 14% of the Army National Guard and Army Reserve workforces. Whereas 54% of the active duty Soldiers are married, 48-49% of Army National Guard and Army Reserve forces are married. Energy Cost of Military Activities The energy demands of military activities can vary considerably. The combat foot soldier, for example, can achieve quite high daily energy expenditures. As illustrated in Figure B-2 total daily energy expenditures of combat units during training exercises has ranged from 15.5 to 29.8 MJ (3,700 to 7,120 kcal/day); with the highest values occurring during cold-weather operations (Tharion et al., 2005). However, this warfighter population represents only a portion of the force strength. In fact, within the Army, the combat occupational specialty is only 1 of 10 career specialty areas. Many of these other military occupations involve more sedentary activities and the energy demands placed on personnel assigned to these duties can be relatively low, encompassing ranges typical of most sedentary or moderately-active civilian occupations.

FIGURE B-1 Distribution of personnel between the active duty and selective reserve components of the United States military. Inclusion of the National Guard Component would increase Army and Air Force personnel an additional 350,000 and 106,800, respectively. SOURCE: Global Security, 2008.

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APPENDIX B

B-3

FIGURE B-2 Energy expenditures of combat units during training exercises

During combat operations, the foot Soldier typically performs repeated cycles of long, sustained periods of low to moderate intensity work (expected metabolic rates of 250 to 450 Watts), with short periods of relatively high-intensity work (expected metabolic rates in excess of 600 Watts). Rest breaks are situational and sleep may be restricted to 3-5 hours per night. Factors contributing to their high daily energy expenditures are relatively long periods of work (> 15 hours/day), traversing rough terrain or soft surfaces (e.g., snow, mud, or sand), and carrying heavy loads. The loads they carry can be very heavy depending on what phase of a mission they are performing. A recent study in which soldier loads were measured during actual operations in Afghanistan, revealed that soldiers in the traveling phase of a mission carried an average of 59.3 kg (131 lb) (Dean and Dupont, 2003). Their approach load averaged 45.7 kg (101 lb), and their fighting load averaged 28.5 kg (63 lb). When normalized to body weight, these loads were equivalent to carrying 77 percent, 57 percent, and 35 percent of body mass, respectively. Mission length varies from 12 hours to up to 24 days (Koenig, 2004). Leaders in Afghanistan and Iraq report being away from FOB approximately 20 out of 30 days a month (Koenig, 2004). This population and the consequences of their lifestyle has been the focus of several earlier IOM Panels (e.g., Not Eating Enough, 1995; Nutrient Composition of Rations for Short-Term, HighIntensity Combat Operations, 2006). However, not all military occupations are this energy demanding. As illustrated in Figure 3, male personnel performing ground defense, engineering/construction duties, or general support duties have energy requirements of approximately 13-15 MJ/day (3,200-3,700 kcal/day) (Tharion et al., 2005). Even lower total energy expenditures have been measured in military women, in part because of their small total body and lean mass. As illustrated in Figure B-3, daily energy expenditures for females engaged in select sedentary jobs were 10-11.7 MJ/day (2,200 to 2,800 kcal/day).

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FIGURE B-3 Energy expenditures during combat support activities for men and women

Dietary Practices of Military Personnel In garrison, military personnel eat from a variety of food sources. The 2005 Department of Defense Survey of Health Related Behaviors (Bray et al., 2006) revealed that military dining facilities are utilized for either breakfast, lunch, or dinner greater than twice per week by only 17%, 27%, and 16% of warfighters. Breakfast was prepared from home at least twice per week by 42%, but same percent reported they skip breakfast at least twice per week. Lunch came from a variety of sources with 43% reporting bringing it from home at least twice per week and 2728% reporting eating food prepared by military facility or restaurants at least twice per week. While 63% report eat dinner at least twice per week at home, 30% report eating dinner in restaurants or from restaurant take out at least 2 times per week. The source of food during deployment depends on where military personnel are assigned. Personnel operating primarily at established bases typically have access to three full meals per day. Food sources include not only military or contractor prepared meals, but many of the same fast food meals available to us. The availability and variety of food available make it unlikely that personnel operating in this environment have difficulty receiving adequate energy and/or nutrients. Populations operating away from established bases subsist on individual and/or group military operational rations. Space availability in vehicle and/or individual warfighter’s pack forces units to prioritize what is most mission essential, and consequently, these individuals may have a more difficult time achieving adequate energy and nutritional intake. Reports regarding the behaviors of warfighters engaged in foot patrols in Afghanistan reveal that their units typically take sufficient rations to provide only 2 meals, ready-to-eat (MRE) per man per day or ~2,600 Kcal/man/day (Dean and Dupont, 2003; Koenig, 2004). Regardless of how much food is carried by personnel operating away from established bases, the amount of food actually consumed is dictated by frequency and duration available for food consumption, and that will depend on the PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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APPENDIX B

B-5

mission and enemy activity. It is common for this military population to lose weight during mission execution. However, they typically have access to more nutritionally complete, hot meals upon return to their operating base. Whether they can eat sufficient amounts to offset the energy debt is, however, dependent on length of time available to recover. A survey of combat foot soldiers operating in Afghanistan revealed that many had non-intentionally lost ~15 pounds during their tour (Koenig, 2004). Nutrition knowledge appears to vary considerably between military personnel. A survey of 157 Army Special Forces Soldiers and Special Forces support personnel revealed not only that they as a group were only able to answer roughly 50% of questions on fluid and hydration, general nutrition and nutritional supplements correctly, their scores ranged from 0 to 100% in each category (Table B-1; Bovill et al., 2003). In that survey, 65% of the soldiers believed that it is protein that provides the energy for physical activity, and 58% responded that vitamins provide energy. Thus, these warfighters generally had limited appreciation of proper dietary practices and/or the value provided by the different food groups. Equally important, 55% reported that friends and teammates were their primary source of nutrition information. A similar survey involving 3,000 Navy Sailors revealed that they were only able to answer 40-65% of nutrition knowledge questions correctly (Conway et al., 1989; Trent, 1992). There appears to be motivation for using nutritional supplements. A survey of nutritional supplement use by 2,215 males entering U.S. Army Special Forces and Ranger training revealed that 64% used nutritional supplements at least occasionally and 35% reporting daily use (Arsenault and Kennedy, 1999). Their practices were driven by the desire to improve general TABLE B-1 General Nutrition Knowledge of Special Operations Soldiers. Data are percent correct responses.

Subtopics Minimum Maximum Fluid and Hydration (8) 0 100 General Nutrition Information (25) 8 84 Special Dietary Concerns (11) 0 91 Nutrient Supplementation (4) 0 100 Prior Event Meal (6) 0 83 N=57 (number of questions per topic) SOURCE: Bovill et al., 2003. Reprinted, with permission, from Military Medicine: International Journal of AMSUS.

Mean ± SD 61 ± 21 50 ±17 46 ±19 42 ±24 34 ±20

health and increase performance. Whether they are making wise choices or will make wise choices, is cause for consideration, given their generally poor nutrition knowledge, as it may make them more susceptible to experimenting with marginal dietary practices and/or supplements advertised to provide desired health and/or performance benefits. Do Military Personnel Need Nutritional Supplements? Certain military job responsibilities might create opportunity for certain nutritional supplements to impart beneficial effects. For example, aviators, radar operators, and sentry duty personnel must remain vigilant for sustained periods of time. Likewise, personnel engaged in sustained operations need to be able to react quickly and correctly to dynamic situations despite inadequate and/or disrupted sleep schedules. Therefore, it should not be surprising if dietary sup-

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

plementation with food containing caffeine and other stimulants are regular dietary practices for these people. Just like the civilian population, a number of military personnel struggle with managing their weight. It is currently estimated that 11-22% of Army personnel exceed height/weight standards (Bathalon et al., 2006; Freidl and Leu, 2002). Non-compliance with these standards can lead to separation from military service. Of the approximately 203,000 enlisted personnel entering active duty in 1993, approximately 1,800 were separated within 48 months for failure to meet weight goals and body fat standards (GAO, 1998). In fiscal year 2003, 3,017 Service personnel across the DoD were discharged for failure to meet weight/body fat standards (personal communication, Grissom, September 2004). Overweight military personnel do resort to dietary supplements and non-dietary supplements to help them lose weight. McNulty (2001) reported that of active duty women serving in the Army, Air Force, Marine Corps, and Navy (n=3,613), 14.7% routinely used diet pills and 18% reported the routine use of diet pills to lose weight for an upcoming official weigh-in. Moreover, 46% of female Soldiers and 29% of male Army personnel reported using liquid diets as a strategy for weight loss (McGraw et al., 2005). The availability of dietary products such as Slim.Fast, might be a viable option for these individuals to assist them in managing their weight. In fact, investigators at the U.S. Army Research Institute of Environmental Medicine are currently evaluating the efficacy of Slim.Fast for achieving weight loss in Soldiers assigned to the Army’s Weight Management Program. While products such as Orlistat aren’t considered nutritional supplements, food products purported to produce the same outcome (i.e., less digestive efficiency) would likely be of interest to a number of these individuals. The physical nature of military activities exposes military personnel to musculo-skeletal injury. As illustrated in figure B-4, the disability discharge rate due to musculoskeletal disability has been progressively increasing for both men and women and is the predominant reason for disability discharge (Knapik, CHPPM, unpublished). Important to this discussion is that NSAIDS are commonly used to treat these injuries. A recent survey of 532,000 active duty Army Soldiers revealed that ~348,000 use NSAIDS (Kelly, AMEDDCS, unpublished). More remarkably, is that these Soldiers accounted for 740,000 NSAID prescriptions. Given that NSAIDS use can produce adverse health consequences (e.g., stomach ulcers, increased bleeding time) there is interest within the DoD for discovery of bioactive food components that can reduce pain and aid healing without the side effects posed by NSAIDS. Summary The military consists of a diverse population engaged in diverse activities. Military professions range from predominantly sedentary to very physically active. Whereas making time to eat and having adequate food presented to balance energy expenditure is quite simple for some, it is quite a challenge for others. Recommendations regarding the acceptability of specific nutritional supplements for military personnel must consider the whole military population, as it is likely that while a given product might present advantages and/or disadvantages for one population, the opposite might be true for a separate subpopulation that exists within the larger military personnel population.

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APPENDIX B

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FIGURE B-4 Incidence of disability discharge over time sorted by type of injury for men and women

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REFERENCES Arsenault, J., and J. Kennedy. 1999. Dietary supplement use in U.S. Army Special Operations candidates. Mil Med 164(7):495-501. Bathalon, G. P., S. M. McGraw, M. A. Sharp, D. A. Williamson, A. J. Young, and K. E. Friedl. 2006. The effect of proposed improvements to the Army Weight Control Program on female soldiers. Mil Med 171(8):800-805. Bovill, M. E., W. J. Tharion, and H. R. Lieberman. 2003. Nutrition knowledge and supplement use among elite U.S. army soldiers. Mil Med 168(12):997-1000. Bray, R. M., L. L. Hourani, K. L. R. Rae Olmsted, M. Witt, J. M. Brown, M. R. Pemberton, M. E. Marsden, B. Marriott, S. Scheffler, and R. Vandermaas-Peeler. 2006. 2005 Department of Defense survey of health related behaviors among active duty military personnel. RTI International: Research Triangle Park, NC. Report RTI/7841/106-FR. Pp 157-158. Conway, T. L., L. K. Hervig, and R. R. J. Vickers. 1989. Nutrition knowledge among Navy recruits. J Am Diet Assoc 89(11):1624-1628. Dean, C. E., and F. Dupont. 2003. Modern warrior's combat load - dismounted operations in Afghanistan. Letter Report. Ft. Leavenworth, KS: U.S. Army Center for Army Lessons Learned. Friedl, K. E., and J. R. Leu. 2002. Body fat standards and individual physical readiness in a randomized Army sample: Screening weights, methods of fat assessment, and linkage to physical fitness. Mil Med 167(12):994-1000. GAO (U.S. General Accounting Office). 1998. Military attrition: Better data, coupled with policy changes, could help the services reduce early separations. Washington, DC: United States General Accounting Office. Global Security. 2008. Military. http://www.globalsecurity.org/military/agency/end-strength.htm (accessed February 5, 2008). Kelly, B. LTC. US Army Medical Department Center and School. Unpublished data. Knapik, J. Center of Health Promotion and Preventive Medicine. Unpublished data. Koenig, C. A. CPT. 2004. Nutritional and environmental factors facing American soldiers in Afghanistan. USARIEM Information Paper. 15 November. Maxfield, B. 2007. Situation report. Soldiers 62(January):18-21. McGraw, S. M., G. P. Bathalon, B. Ellision, J. D. Graff, L. M. Burrell, R. E. Carr, C. M. Ross, D. A. Williamson, and A. J. Young. 2005. Dieting practices of soldiers in the U.S. Army Weight Control Program. Med Sci Sports Exerc 37(5):S142. McNulty, P. A. 2001. Prevalence and contributing factors of eating disorder behaviors in active duty service women in the Army, Navy, Air Force, and Marines. Mil Med 166(1):53-58. Tharion, W. J., H. R. Lieberman, S. J. Montain, A. J. Young, C. J. Baker-Fulco, J. P. DeLany, and R. W. Hoyt. 2005. Energy requirements of military personnel. Appetite 44(1):47-65. Trent, L. K. 1992. Nutrition knowledge of active duty Navy personnel. J Am Diet Assoc 92(6):724-728.

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LIMITED EFFICACY OF DIETARY SUPPLEMENTS FOR PHYSICAL AND COGNITIVE PERFORMANCE ENHANCEMENT IN MILITARY OPERATIONS Harris R. Lieberman1 INTRODUCTION Extraordinary physical and mental demands are placed on warfighters in the routine conduct of their duties. Severe degradation in physical and cognitive performance occurs as a consequence of exposure to a wide range of operational stressors, including heat, cold, high altitude, psychological stress, and sleep deprivation. Any safe and effective intervention that could help maintain or enhance operational performance would be of great value to the Department of Defense (DoD). In addition, appropriate use of dietary supplements could, in theory, provide an advantage to military forces that employ supplements when they engage less technologically sophisticated adversaries who lack the scientific and medical expertise to do so. Conversely, failure to employ interventions utilized by adversaries would put allied forces at a disadvantage. Precedent for the use of dietary supplements to enhance performance exists, as many military organizations have periodically employed drugs to enhance operational performance, including several branches of the U.S. DoD (Emonson and Vanderbeek, 1993; Jones, 1985; Lieberman and Cail, in press; Rosenkranz, 2003; Senechal, 1988). The potential utility of dietary supplements to enhance warfighter physical and cognitive performance has been of great interest to U.S. military scientists, scientific policy makers, and operational units for many years. In 1992, the Committee on Military Nutrition Research (CMNR) sponsored an important conference in which potential benefits and risks of a wide variety of supplements that might enhance physical, cognitive, or other aspects of warfighter function were considered (IOM, 1994). In their report, the CMNR stated with regard to dietary supplements that it “recognizes the potential value for performance enhancement in combat settings and suggests a number of areas for future research within the military” (IOM, 1994, p. 60). Department of Defense Interest in the Operational Use of Dietary Supplements—Impact of the Dietary Supplements Health and Education Act (DSHEA) Department of Defense interest in the operational use of dietary supplements predates the key 1992 CMNR meeting, as well as passage of the seminal DSHEA in 1994 (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress) (Banderet and Lieberman, 1989; McKenzie and Elliott, 1965; Penetar et al., 1989; Spinweber, 1986). The DSHEA provided a statutory definition of dietary supplements and clarified their regulatory status. It greatly expanded the number and types of products that could be categorized as dietary supplements, and largely deregulated these products in the United States. Subsequently, use of dietary supplements in the United States rapidly increased. For example, from 1994–1998, herb sales doubled in the United States from $2 billion/year to $4 billion/year 1

Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine (USARIEM), Natick, MA

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(Blumenthal et al., 2006). Currently a wide variety of products intended to modify physical performance, cognitive function, and sleep, as well as many other functions, are available in most U.S. supermarkets and pharmacies, as well as thousands of specialty stores devoted to the sale of dietary supplements. At most large U.S. military bases, supplements can be found at the base exchange (PX) and at a specialty store located on base. Some of the products that were deregulated by DSHEA previously were considered to be drugs for regulatory purposes, such as ephedra, dehydroepiandrosterone (DHEA), and the hormone melatonin. Based on a scientific, as opposed to legal definition, ephedra, DHEA, and melatonin are, in fact, most appropriately classified as drugs. As would be expected, DSHEA, by clarifying and broadening the definition of supplements, as well as increasing their general availability, increased DoD interest in the operational use of these products. Military scientists awareness of, and willingness to study, supplements increased, and funding to support such studies was often available. Widespread consumer use of compounds of potential operational use, previously intensely regulated by the FDA, such as melatonin to enhance sleep and speed reentrainment following rapid deployment across multiple time zones, stimulated such research. Food and Drug Administration approval was no longer required when such supplements were tested in DoD research studies or used operationally (Comperatore et al., 1996; Headquarters, USAF, 2003; Wesensten et al., 2002). Furthermore, representatives of operational military units, especially elite units such as the Special Forces, Rangers, SEALS and U.S. Marines frequently requested guidance regarding specific supplements and occasionally permitted studies of supplements to be conducted with their units (for examples, see Deuster et al., 2003; Flakoll et al., 2004; Goforth et al., 2006; Lieberman et al., 2002a,b; Ross et al., 2003; Shurtleff et al., 1994). The DSHEA’s changing of the legal status of dietary supplements, by permitting sale of supplements without requiring demonstration of their efficacy by the manufacturer, was also a potential barrier to the use of supplements by the DoD. Unlike drugs, where the manufacturer must conclusively demonstrate for any indication claimed both safety and efficacy to the satisfaction of the U.S. FDA, supplements are marketed with no requirement that the manufacturer provide such information or have the product evaluated by an independent scientific regulatory entity. This puts the onus on the DoD, without approval of another government agency, to be certain about a supplement’s safety and efficacy prior to endorsing its use operationally, in garrison, or providing it in rations. Academic, and in some cases supplement manufacturer-sponsored research, can be of great value for determining potential efficacy and safety of particular supplements, but this information will typically not be of the quality required for FDA approval of a drug. The FDA process for approval of a drug generally requires multiple, carefully designed and monitored research studies. First, extensive studies must be conducted in several animal species for an initial safety determination. In addition, in most cases comprehensive, preclinical studies with animals are conducted by the company to determine the likely efficacy and mechanism of action of the compound of interest. Then three phases of human research of increasing complexity must be successfully completed before the FDA will consider approval of a drug. This testing process is usually sponsored by a company attempting to get FDA approval of their proprietary compound. The third and pivotal phase of human testing can require several studies involving thousands of volunteers each. Generally, prior to the initiation of the studies, the FDA must approve their design, statistical analyses proposed, and the outcome measures. Data submitted to the FDA must meet formal chain-of-custody standards and are subject to intensive

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APPENDIX B

B-11

audit prior to FDA approval of the compound (FDA/CDER, 2006). In addition, an independent advisory board of experts must review the data submitted to the FDA, publicly meet and vote on whether to recommend the FDA approve the drug in question. The process takes many years and has been estimated to cost over $800 million per drug (DiMasi et al., 2003). When compared to the requirements for publication in a peer-reviewed journal, these standards are extraordinary, but given the harm that has occurred when dangerous drugs are approved, they are understandable. Dietary supplements can also be harmful; for example, supplements containing the essential amino acid tryptophan, manufactured by a reputable Japanese manufacturer, were responsible for numerous deaths and severe illnesses in 1989. The final cause of the illness, eosinophilia-myalgia syndrome (EMS), was never definitively established, but it appeared to be related to a minor change in the fermentation process during manufacturing (Belongia et al., 1990). It should be noted that in instances where popular dietary supplements are tested in large, carefully designed and conducted studies, these products are often found to be inert (Gardner et al., 2007; Hypericum Depression Trial Study Group, 2002; Solomon et al., 2002) or in some cases, dangerous (Lonn et al., 2005). FINDINGS OF AN INTERNATIONAL DEFENSE PANEL ON DIETARY SUPPLEMENTS The issues pertaining to the use of dietary supplements and other performance-enhancing treatments has not been limited to the U.S. DoD. Several of our allies have conducted research on performance-enhancing interventions and, in several conflicts, used prescription drugs in combat (Lagarde and Batejat, 1995; Lieberman and Cail, in press; Nicholson, 1984). One international defense organization, The Technical Cooperation Program (TTCP), recognizing the importance of such issues, appointed a panel of scientists and clinicians with substantial expertise in the area to evaluate the available scientific information, and when justified, conduct appropriate research on performance-enhancing treatments of potential operational use. TTCP consists of military scientists from five nations; Australia, Canada, New Zealand, United Kingdom, and the United States, and was created to facilitate sharing of scientific information and collaborative research. A comprehensive description of the purpose and objectives of TTCP and the wide variety of military domains in which the organization operates can be found at a public website (TTCP, 2007). Unfortunately, publications of TTCP are restricted to defense use only, unless prior approval for their public release is obtained from all five participating nations (TTCP, 2006). In 1992, TTCP initially formed a provisional working group to consider any interventions that could potentially enhance physical performance. In 2 years, that working group evolved into a full panel with a 5-year term, which was subsequently extended for 5 more years. Interventions of interest included drugs, training procedures, and dietary supplements. Initially, the focus of the group was on addressing the needs of units from the special forces of the five member nations. Subsequently, the panel’s area of focus expanded to include cognitive, as well as physical, performance enhancement and conventional, in addition to special forces, personnel. Over the course of its 12 years of existence, the TTCP panel (HUM TP-8) produced a variety of reports, including multiple editions of what was initially A Compendium of Ergogenic Aids and subsequently evolved into A Compendium of Ergogenic and Cognitive Aids. Application papers providing guidance for medical officers and commanders who wished to employ selected interventions operationally were also written by the panel. The purpose of the compendia was to summarize and interpret the available scientific literature on any intervention that purportedly PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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enhanced either physical or cognitive performance in less than 4 weeks. Interventions requiring longer periods of pretreatment were not considered, as these were judged to be impractical to employ in military operations. A key element of all work conducted by the panel was the potential military operational utility of interventions reviewed or studied. The panel recognized that military use of performance-enhancing interventions was inherently different than civilian use. In particular, it was noted that unlike sporting events, the objective of military use of performance-enhancing treatments was to provide a measurable advantage to allied forces, not to “play fair.” The TTCP panel consisted of military scientists from a wide range of disciplines including: exercise and environmental physiology, pharmacology, cognitive psychology, nutrition, and medicine. Over the course of its life span, over 20 scientists served on the panel. The diversity of disciplines represented on the panel, and its long period of existence, provided a unique framework to objectively evaluate a wide range of dietary supplements and draw consensus conclusions regarding their potential operational use to enhance physical and/or cognitive performance. If sufficient information was available to conclude that a dietary supplement was safe and efficacious, an “application paper” was written to provide specific guidance including appropriate dose, benefits, risks, and the anticipated operational advantages of its use. If the available scientific information on a particular supplement suggested it might be of value operationally, but was not conclusive, research studies were usually conducted either by individual laboratories, independently by several laboratories, or as a consortium of interested nations. These studies were typically designed with input of the whole panel, even if only a single laboratory was conducting the study, and were intended to determine if the supplement in question was likely to be effective in an operationally relevant scenario. Box B-1 provides a list of the publications that resulted from these efforts, as well as selected relevant publications from the laboratories represented on the panel. In addition to these individual laboratory or collaborative research projects, the panel, as noted above, also produced four editions of the compendia of aids in 1994, 1997, 2001, and 2004. Initial editions were limited to treatments that would potentially modify physical performance, but later editions included cognitive performance entries (Baranski et al., 2001, 2004; Jacobs et al., 1997). The final 2004 edition had 86 individual entries of which 52 were dietary supplements, and these are listed in Table B-2. Each entry was no more than 2-pages long and included the following sections: claimed benefits, effectiveness, mode of action, duration of effect, dose/time course and method of administration, chronic treatment, hazards, other benefits, comments, summary judgment, and several selected citations. Although the panel continuously reviewed the scientific literature and other sources for information on promising dietary supplements, and tested any deemed to be of potential use for defense applications, only a very small number were judged to be reasonably safe and effective, thereby warranting writing an application paper (Box B-2).

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APPENDIX B

B-13

BOX B-1 Selected Publications from Members of the TCP Panel on “Physical and Cognitive Performance Enhancement for Conventional and Special Operations” (HUM TP-14) or Their Laboratories Amendola, C.A., J. D. E. Gabrieli, and H. R. Lieberman. 1998. Caffeine’s effects on performance and mood are independent of age and gender. Nutr Neurosci 1:269-280. Arnall, D. A., and H. W. Goforth. 1993. Failure to reduce body-water loss in cold water immersion by glycerol ingestion. Undersea Hyperb Med 20:309-320. Baker-Fulco, C. J., C. S. Fulco, M. D. Kellogg, E. Glickman, and A. J. Young. 2006. Voluntary muscle function after creatine supplementation in acute hypobaric hypoxia. Med Sci Sports Exerc 38:1418-1424. Banderet, L. E., and H. R. Lieberman. 1989. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in human. Brain Res Bull 22:756-762. Baranski, J., and R. A. Pigeau. 1997. Modafinil during 64 hours of sleep deprivation: Doserelated effects on fatigue, alertness, and cognitive performance. Mil Psychol 10:173-193. Baranski, J., and R. Pigeau. 1997. Self-monitoring cognitive performance during sleep deprivation: Effects of modafinil, d-amphetamine and placebo. J Sleep Res 6:84-91. Bell, D. G., and I. Jacobs. 1999. Combined caffeine and ephedrine ingestion improves run times of the Canadian Forces warrior test. Aviat Space Environ Med 70:325-329. Bell, D. G., and T. M. McLellan. 2002. Endurance performance 1, 3 and 6 hours after caffeine ingestion in caffeine users and non-users. J Appl Physiol 93(4):1227-1234. Bell, D. G., I. Jacobs, and J. Zamecnik. 1998. Effects of caffeine, ephedrine and their combination on time to exhaustion during high-intensity exercise. Eur J Appl Physiol 77:427433. Bell, D. G., I. Jacobs, T. M. McLellan, M. Miyazaki, and C. M. Sabiston. 1999. Thermal regulation in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med 70:583-588. Bell, D. G., I. Jacobs, T. M. McLellan, and J. Zamecnik. 2000. Reducing the dose of combined caffeine and ephedrine preserves the ergogenic effect. Aviat Space Environ Med 71(4):415-419. Bell, D. G., I. Jacobs, and K. Ellerington. 2001. Effect of caffeine and ephedrine ingestion on anaerobic performance. Med Sci Sports Exerc 33(8):1399-1403. Bell, D. G., T. M. McLellan, and C. M. Sabiston. 2002. Effect of ingesting caffeine and ephedrine on 10 km run performance. Med Sci Sports Exerc 34(2):344-349.

continued

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BOX B-1 Continued Bordeleau, R., D. G. Bell, I. Jacobs, and J. Zamecnik. 1999. Caffeine, ephedrine and their combination: Effects on blood pressure and heart rate. Report No. TR 1999-069. Toronto, ON, Canada: Defence and Civil Institute of Environmental Medicine. Bourdon, L., I. Jacobs, W. A. Bateman, and A. L. Vallerand. 1994. Effect of modafinil on heat production and regulation of body temperatures in cold-exposed humans. Aviat Space Environ Med 65(11):999-1004. Casey, A. 2001. Creatine supplementation and physical performance in military personnel. UK Journal of Defence Sciences 6(3):204-210. Casey, A., D. Constantin-Teodosiu, S. Howell, E. Hultman, and P. L. Greenhaff. 1996. Creatine ingestion favourably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol 271(1 Pt 1):E31-E37. Cole, K. J., D. L. Costill, R. D. Starling, B. H. Goodpaster, S. W. Trappe, and W. J. Fink. 1996. Effect of caffeine ingestion on perception of effort and subsequent work production. Int J Sport Nutr 6(1):14-23. Comperatore, C. A., H. R. Lieberman, A. W. Kirby, B. Adams, and J. S. Crowley. 1996. Melatonin efficacy in aviation missions requiring rapid deployment and night operations. Aviat Space Environ Med 67:520-524. Dawson, R. T., M. W. Harrison. 1997. Use of insulin as an anabolic agent. Brit J Sport 31(3):259. Doan, B., P. Hickey, J. Fischer, J. Miller, and H. Lieberman. 2004. The effect of caffeinated tube food on cognitive performance during fatigue/circadian desynchronosis. Technical Report No. AFRL-HE-BR-TR-2004-0189. Brooks City-Base, TX: Human Effectiveness Directorate. Doan, B. K., P. A. Hickey, H. R. Lieberman, and J. R. Fischer. 2006. Caffeinated tube food effect on pilot performance during a 9-hour, simulated nighttime U-2 mission. Aviat Space Environ Med 77:1034-1040. Fulco, C. S., P. B. Rock, L. A. Trad, M. S. Rose, V. A. Forte, Jr., P. M. Young, and A. Cymerman. 1994. Effect of caffeine on submaximal exercise performance on altitude. Aviat Space Environ Med 65:539-545. Fulco, C. S., K. W. Kambis, A. L. Friedlander, P. B. Rock, S. R. Muza, and A. Cymerman. 2005. Carbohydrate supplementation improves time-trial cycle performance during energy deficit at 4300 m altitude. J Appl Physiol 99:867-876. Fulco, C. S., M. Zupan, S. R. Muza, P. B. Rock, K. Kambis, T. Payn, M. Hannon, E. Glickman, and A. Cymerman. 2006. Carbohydrate supplementation and endurance performance of moderate altitude residents at 4300 m. Int J Sports Med Oct 6 (Epub ahead of print). continued

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APPENDIX B

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BOX B-1 Continued Goforth, H. 1981. Effect of induced erythrocythemia upon aerobic-anaerobic threshold and 3mile track run. Int J Sports Med 1(13):6. Goforth, H., N. L. Campbell, J. A. Hodgdon, and A. A. Sucec. 1982. Hematological parameters of trained distance runners following induced erythrocythemia. Med Sci Sports Exerc 14(2):174. Goforth, H., A. A. Sucec, C. A. Sadler, and J. A. Hodgdon. 1989. Blood donation and autologous reinfusion: Effects upon aerobic capacity of female and male distant runners. Int J Sports Med 10:302. Goforth, H. W., D. A. Arnall, B. L. Bennett, and P. G. Law. 1997. Persistence of supercompensated muscle glycogen in trained subjects after carbohydrate loading. J Appl Physiol 82(1):342-347. Goforth, H., C. Forbes-Ewan, M. Harrison, I. Jacobs, H. R. Lieberman, and R. Nicholson. 2006. The use of nutritional supplements by special operations personnel of TTCP nations. J Defence Sci 6:73-79. Ivy, J. L., H. W. Goforth, B. M. Damon, T. R. McCauley, E. C. Parsons, and T. B. Price. 2002. Early postexercise muscle glycogen recovery is enhanced with a carbohydrate-protein supplement. J Appl Physiol 93:1337-1344. Jacobs, I. 1981. Lactate, muscle glycogen and exercise performance in man. Acta Physiol Scan Suppl 495:1-35. Jacobs, I. 1999. Dietary creatine monohydrate supplementation. Can J Appl Physiol 24:503514. Jacobs, I., and D. G. Bell. 1997. Modafinil prolongs time to exhaustion during high-intensity submaximal exercise. Med Sci Sports Exerc 29(Suppl):S39. Jacobs, I., P. Kaiser, and P. Tesch. 1981. Muscle strength and fatigue after selective glycogen depletion in human skeletal muscle fibers. Eur J Appl Physiol Occup Physiol 46:47-53. Jacobs, I., S. Bleue, and J. Goodman. 1997. Creatine ingestion increases anaerobic capacity and maximum accumulated oxygen deficit. Can J Appl Physiol 22:231-243. Jacobs, I., H. S. Pasternak, and D. G. Bell. 2003. Effects of ephedrine, caffeine, and their combination on muscular endurance. Med Sci Sports Exerc 35:987-994. Johnson, R. F. 1991. Rifle firing simulation: Effects of MOPP, heat, and medications on marksmanship. In Proceedings of the 33rd Annual Conference of the Military Testing Association. San Antonio, Texas. Pp. 530-535. Johnson, R. F., and D. J. Merullo. 1996. Effects of caffeine and gender on vigilance and marksmanship. In Proceedings of the Human Factors and Ergonomic Society 40th Annual Meeting. Santa Monica, California. Pp. 1217-1221. continued

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BOX B-1 Continued Johnson, R. F., and D. J. Merullo. 2000. Caffeine, gender, and sentry duty: Effects of a mild stimulant on vigilance and marksmanship. In Countermeasures for battlefield stressors, Vol. 10, Pennington Center Nutrition Series, edited by K. E. Friedel, H. R. Lieberman, D. H. Ryan, and G. A. Bray GA. Baton Rouge: Louisiana State University Press. Pp. 272-289. Kamimori, G. 2000. Effect of three caffeine doses on plasma catecholamines and alertness during prolonged wakefulness. Eur J Clin Pharmacol 56:537-544. Kamimori, G. H., S. I. Lugo, D. M. Penetar, A. C. Chamberlain, G. E. Brunhart, A. E. Brunhart, and N. D. Eddington. 1995. Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans. Int J Clin Pharmacol Ther 33:182-186. Kamimori, G. H., C. S. Karyekar, R. Otterstetter, D. S. Cox, T. J. Balkin, G. L. Belenky, and N. D. Eddington. 2002. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Int J Pharmaceutics 234:159-167. Laurent, D., K. E. Schneider, W. K. Prusaczyk, C. Franklin, S. M. Vogel, M. Krssak, K. F. Petersen, H. W. Goforth, G. I. Shulman. 2000. Effects of caffeine on muscle glycogen utilization and the neuroendocrine axis during exercise. J Clin Endocrinol Metab 85:2170-2175. Lieberman, H. R. 1989. Cognitive effects of various food constituents. In Handbook of the Psychophysiology of Human Eating, edited by R. Shepherd. Chichester, UK: Wiley. Pp. 251270. Lieberman, H. R. 2001. The effects of ginseng, ephedrine and caffeine on cognitive performance, mood and energy. Nutr Rev 59(4):91-102. Lieberman, H. R., R. J. Wurtman, G. G. Emde, C. Roberts, and I. L. Coviella. 1987. The effects of low doses of caffeine on human performance and mood. Psychopharmacology 92(3):308312. Lieberman, H. R., G. P. Bathalon, C. M. Falco, F. M. Kramer, C. A. Morgan, III, and P. Niro. 2005. Severe decrements in cognition function and mood induced by sleep-loss, heat, dehydration and undernutrition during simulated combat. Biol Psychiatry 57(1):422-429. Lieberman, H. R., C. M. Falco, and S. S. Slade. 2002. Carbohydrate administration during a day of sustained aerobic activity improves vigilance, assessed with a novel ambulatory monitoring device, and mood. Am J Clin Nutr 76:120-127. Lieberman, H. R., W. J. Tharion, B. Shukitt-Hale, K. L. Speckman, and R. Tulley. 2002. Effects of caffeine, sleep loss, and stress on cognitive performance and mood during U.S. Navy SEAL training. Psychopharmacology 164:250-261. Lieberman, H. R. 2003. Nutrition, brain function, and cognitive performance. Appetite 40(3):245254. continued

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BOX B-1 Continued Magill, R.A., W. F. Waters, G. A. Bray, J. Volaufova, S. R. Smith, H. R. Lieberman, N. McNevin, and D. H. Ryan. 2003. Effects of tyrosine, phentermine, caffeine D-amphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation. Nutr Neurosci (4):237246. McLellan, T., I. Jacobs, and W. Lewis. 1988. Acute altitude exposure and altered acid-base states. II. Effects on exercise performance and muscle and blood lactate. Eur J Appl Physiol 57:445-451. McLellan, T. M., M. B. Ducharme, F. Canini, D. Moroz, D. G. Bell, J. V. Baranski, V. Gil, A. Buguet, and M. W. Radomski. 2002. Effect of Modafinil on core temperature during sustained wakefulness and exercise in a warm environment. Aviat Space Environ Med 73:1079-1088. McLellan, T. M., D. G. Bell, H. R. Lieberman, and G. H. Kamimori. 2003-2004. The impact of caffeine on cognitive and physical performance and marksmanship during sustained operations. Canad Mil J 4(4):47-54. McLellan, T. M., D. G. Bell, and G. H. Kamimori. 2004. Caffeine improves physical performance during 24 h of active wakefulness. Aviat Space Environ Med 75(8):666-672. Morris, A., I. Jacobs, T. M. McLellan, A. Klugerman, L. C. Wang, and J. Zamecnik. 1996. No ergogenic effect of ginseng ingestion. Int J Sport Nutr 6:263-271. Nicholson, A. N., and C. Turner. 1998. Intensive and sustained air operations: Potential use of the stimulant, pemoline. Aviat Space Environ Med 69(7):647-655. Pasternak, H. S., I. Jacobs, and D. G. Bell. 1999. Effects of ingesting caffeine and ephedrine on muscular endurance. Can J Appl Physiol 24:S471. Paul, M. A., G. Gray, G. Kenny, and R. A. Pigeau. 2003. Impact of melatonin, zaleplon, zopiclone, and temazepam on psychomotor performance. Aviat Space Environ Med 74(12):1263-1270. Paul, M. A., G. Gray, M. MacLellan, and R. A. Pigeau. 2004. Sleep-inducing pharmaceuticals: A comparison of melatonin, zaleplon, zopiclone and tamazepam. Aviat Space Environ Med 75:512-519. Paul, M. A., G. Gray, T. M. Sardana, and R. A. Pigeau. 2004. Melatonin and zopiclone as facilitators of early circadian sleep in operational air transport crews. Aviat Space Environ Med 75(5):439-443. Penetar, D., U. McCann, D. Thorne, G. Kamimori, C. Galinski, H. Sing, M. Thomas, and G. Belenky. 1993. Caffeine reversal of sleep deprivation effects on alertness and mood. Psychopharmacology 112:359-365.

continued

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BOX B-1 Continued Penetar, D. M., U. McCann, D. Thorne, A. Schelling, C. Galinski, H. Sing, M. Thomas, and G. Belenky. 1994. Effects of caffeine on cognitive performance, mood, and alertness in sleepdeprived humans. In Food components to enhance performance, edited by B. Marriott. Washington, DC: National Academy Press. Pp. 407-431. Robinson, T. M., D. A. Sewell, A. Casey, G. Steenge, and P. L. Greenhaff. 2000. Dietary creatine supplementation does not affect some haematological indices, or indices of muscle damage and hepatic and renal function. Brit J Sports Med 34:284-288. Shurtleff, D., J. R. Thomas, S. T. Ahlers, and J. Schrot. 1993. Tyrosine ameliorates a coldinduced delayed matching-to sample performance decrement in rats. Psychopharmacology 112:228-232. Shurtleff, D., J. R. Thomas, J. Schrot, K. Kowalski, and R. Harford. 1994. Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacol Biochem Behav 47(4):935-941. Stone, B. M., C. Turner, S. L. Mills, and A. N. Nicholson. 2000. Hypnotic activity of melatonin. Sleep. 23:663-669. Subudhi, A. W., K. A. Jacobs, T. A. Hagobian, J. A. Fattor, C. S. Fulco, S. R. Muza, P. B. Rock, A. R. Hoffman, A. Cymerman, and A. L. Friedlander. 2004. Antioxidant supplementation does not attenuate oxidative stress at high altitude. Aviat Space Environ Med 75:881-888. Tharion, W. J., B. Shukitt-Hale, and H. R. Lieberman. 2003. Caffeine effects on marksmanship during high-stress military training with 72-hour sleep deprivation. Aviat Space Environ Med 74(4):309-314. Vallerand, A. L., I. Jacobs, and M. F. Kavanagh. 1989. Mechanism of enhanced cold tolerance by an ephedrine-caffeine mixture in humans. J Appl Physiol 67:438-444. Wesensten, N. J., G. Belenky, M. A. Kautz, D. R. Thorne, R. M. Reichardt, and T. J. Balkin. 2002. Maintaining alertness and performance during sleep deprivation: Modafinil versus caffeine. Psychopharmacology (Berl) 159(3):238-247. Wesensten, N. J., G. Belenky, D. R. Thorne, M. A. Kautz, and T. J. Balkin. 2004. Modafinil vs. caffeine: Effects on fatigue during sleep deprivation. Aviat Space Environ Med 75(6):520-525. Wright, J. E., J. A. Vogel, J. B. Sampson, J. J. Knapik, J. F. Patton, and W. L. Daniels. 1983. Effects of travel across time zones (jet-lag) on exercise capacity and performance. Aviat Space Environ Med 54:132-137.

The following diets or dietary supplements resulted in application papers for physical performance: carbohydrate loading, carbohydrate supplementation, dietary creatine supplementation, and caffeine. For cognitive performance enhancement, only caffeine was judged to be effective and safe. The CMNR concurred with this recommendation regarding operational use of caffeine (IOM, 2001).

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TABLE B-2 Dietary Supplements in the 2004 “Assessment of Ergogenic and Cognitive Aids” Database (Baranski et al., 2004) Amino acids - Glycine - Ornithine Amino acid supplements

Colostrum Co-enzyme Q10 - Ubiquinone Creatine - Creatine monohydrate Dichloroacetate (DCA)

Androstenedione - Dehydroepiandrosterone Antioxidants Aspartate salts - Magnesium aspartate - Potassium aspartate Bee pollen Boron

Dihydroxyacetone (with Pyruvate) Echinacea Ephedrine - Ma-Huang Ginkgo biloba Ginseng

Brahmi Branched-chain amino acids - Leucine - Isoleucine - Valine Caffeine

Glucosamine sulfate - Chondroitin sulfate - N-acetly glucosamine - Glucosamine HCL Guarana ß-hydroxy ß-methylbutyrate (HMB)

Caffeine with Ephedra Calcium Carbohydrate loading Carbohydrate supplementation

Carnitine - L-carnitine - Beta-hydroxy trimethylamino butyrate Carnosine Choline - Lecithin Chromium

Hyperhydration - Glycerol Inosine - Nucleic acids - Purine ribonucleotide - Adenosine - Adenine Iron

Kava kava Magnesium

Niacin (formerly Vitamin B3) - Nicotinic acid - Nicotinamide Omega-3 fatty acids Pantothenic acid Phosphate—inorganic - Sodium phosphate - Calcium phosphate Phosphatidylserine Phosphorous Ribose Selenium Sodium bicarbonate - Sodium citrate St. John’s Wort - Hypericum perforatum Taurine Tryptophan - 5-hydroxytryptophan Tyrosine Vanadyl - Vanadyl sulfate - Vanadium Vitamins - Multivitamin supplements Zinc

NAD(H), NADPH

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BOX B-2 Application Papers from TTCP Panel on “Physical and Cognitive Performance Enhancement for Conventional and Special Operations” (HUM TP-14) Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Adaptation to hot environments. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Blood loading. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Caffeine for cognitive performance enhancement. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Caffeine for physical performance enhancement. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Carbohydrate loading. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Carbohydrate supplementation. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Dietary creatine supplementation. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Ensuring sleep with hypnotics for cognitive performance enhancement. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. continued

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BOX B-2 Continued Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003. Application papers: Napping for cognitive performance enhancement. In: Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss.2003. Application papers: Oral hydration for physical performance. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01.

A few other dietary supplements, such as ephedra, tryptophan, and tyrosine, were considered likely to be efficacious, but due to lack of definitive data were not identified as suitable for operational use. Application papers for ephedra and tryptophan were never authored due to safety concerns (Hertzman et al., 1990; Final rule, 2004). The amino acid tyrosine was of great interest, but definitive evidence for operational utility did not exist. Although an application paper for creatine was written, this supplement is controversial among military scientists, as doubts regarding its operational utility exist. From a purely scientific perspective, there is little doubt that creatine enhances certain aspects of anaerobic performance (Bemben and Lamont, 2005). The TTCP panel concluded it would be of use in special circumstances, but it is the position of the U.S. Army Research Institute of Environmental Medicine (USARIEM) that its benefits are too modest to justify its widespread use. Although the TTCP panel would certainly agree that widespread use would be inappropriate, such as by including creatine in rations, the panel was able to reach consensus that certain units, such as the Special Forces, would benefit by using creatine for certain missions in which a modest improvement in anaerobic performance could be critical. One of the few supplements that enhanced aerobic performance, ephedra, was banned by the U.S. FDA due to safety concerns (Final rule, 2004). This product was extremely popular in the United States, in both civilian and military populations, perhaps because its effects were clearly perceived by users, in particular cardiovascular and cognitive stimulation (Lieberman, 2001). Research conducted by one TTCP laboratory contributed to understanding the actions of ephedra (Bell et al., 1999, 2000, 2002). The TTCP panel never recommended this product for operational use. The work conducted by members of the TTCP panel and USARIEM had a significant impact on U.S. rations (Bell and McLellan, 2002; Fine et al., 1994; Johnson and Merullo, 2000; Kamimori, 2000; Lieberman et al., 2002a; McLellan et al., 2003/2004). Caffeine in pill form and a caffeine-containing gum, Stay Alert, was tested in a number of scenarios designed to provide convincing evidence of efficacy for both physical and cognitive performance enhancement (Bell and McLellan, 2002; Kamimori, 2000; McLellan et al., 2003/2004). These studies in aggregate demonstrated a caffeine dose of 200 mg significantly improved cognitive and physical performance (Doan et al., 2006; Kamimori, 2000; Kamimori et al., 1995; 2002; Lieberman et al., 2002a; McLellan et al., 2003/2004). Caffeine-containing gum is now available in the DoD supply system, and ration components containing caffeine are present in U.S. rations. A special PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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caffeine-containing food was developed by the Combat Feeding Directorate of the U.S. Army Natick Soldier Research, Development and Engineering Center for U-2 pilots, who can only consume tube foods in flight. This product was tested in a simulated U-2 mission scenario and demonstrated to enhance multiple aspects of cognitive performance compared to placebo (Doan et al., 2006). Research conducted by USARIEM, as well as other TTCP member laboratories, also contributed to the recognition of the importance of carbohydrates to enhance physical and also, under certain circumstances, cognitive performance (Baranski et al., 2003a,b; Goforth et al., 1997; Lieberman et al., 2002b; Montain et al., 1997). The carbohydrate content of U.S. rations has been adjusted accordingly, and special carbohydrate-containing products are now available in the U.S. ration system (DoD, 2006). Perhaps what is most surprising about the work of the TTCP panel is that, in spite of substantial, sustained effort over 12 years, only a very small number of dietary supplements were found to clearly enhance either physical or cognitive performance. Many members of the panel had hoped to be able to demonstrate that various dietary supplements could be effectively employed to enhance either physical or cognitive performance. The panel recognized the military need for interventions that could provide allied forces with an advantage over their adversaries or reduce the extraordinary physical and psychological stress on warfighters. The panel was committed and resources were available to study supplements for which adequate scientific justification for further research existed. Unfortunately, the seeming promise of dietary supplements to enhance performance, as is the common belief in many members of our society including warfighters, athletes, and the general population, has not, in most cases, been documented by definitive scientific research. Why Have So Few Dietary Supplements Been Found to Be Effective? Given the widespread commercial, military, and public interest in the use of dietary supplements, it is somewhat puzzling that so few have been found to enhance either physical or cognitive performance. The general public and members of the uniformed services are clearly willing to spend large amounts of money on such products, thereby providing substantial impetus for their commercial development (Blumenthal et al., 2006; Bovill et al., 2003). Although it is true that DSHEA removed any requirement that manufacturers formally demonstrate efficacy, products that work in the intended manner certainly are more likely to be successful than those that do not. Caffeine is the most widely consumed psychoactive compound in the world (IOM, 2001), and its positive effects on cognitive state are readily perceived by users and welldocumented scientifically (Johnson and Merullo, 2000; Lieberman, 2001, 2003; Lieberman et al., 2002a; Smith et al., 1999, 2005). The public is often aware of scientific findings regarding dietary supplements due to extensive press coverage and appear to change their buying habits accordingly, increasing consumption of products reported to have beneficial effects, even if only in animal models, and reducing use of supplements reported to be ineffective (for example, see Baur et al., 2006). Examination of the scientific process for the development of new drugs provides some insight into why so few dietary supplements have been found to be efficacious. Although the regulatory requirements for demonstrating safety and efficacy of drugs are specified by statue, the scientific process for finding new drugs that will meet scientific and regulatory requirements are less clear. The typical process for the development of a drug begins when libraries containing

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thousands of compounds are screened by drug companies using in vitro assays, and then a few of the most promising compounds are selected for extensive animal studies. Frequently, based on the findings of either of these steps, new compounds are synthesized in an attempt to optimize the desirable properties of the compound and minimize the undesirable characteristics. In addition to efficacy and safety, other issues that must be addressed are mode of administration, duration of action, interaction with other drugs, and ease of commercial synthesis. Few screened compounds reach human phase 1 testing, and even fewer are eventually approved. In many instances, the process of drug development starts with a natural product, but many years of work are required to modify it so that a drug that is safe and effective is developed. For a dietary supplement, no such iterative process exists—either it works or not. Natural products such as ephedra, willow bark, and melatonin have been successfully modified in the laboratory to yield a number of drugs, but the natural products themselves are often of limited utility (Lieberman, 2001; Roth et al., 2005). Given the absence of an iterative development process, and the many difficulties associated with identifying and developing effective drugs, it is not surprising that naturally occurring substances rarely effectively enhance either physical or cognitive performance. Acknowledgements The opinions or assertations contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. Human subjects participated after giving their free and informed voluntary consent. The investigators adhered to the policies for protection of human subjects as prescribed in Army Regulation 70-25, and the research was conducted in adherence with the provisions of 32 CFR Part 219. Citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.

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REFERENCES Banderet, L. E., and H. R. Lieberman. 1989. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull 22(4):759-762. Baranski, J., D. Bell, A. Casey, R. Edwards, C. Forbes-Ewan, H. Goforth, G. Kamimori, H. R. Lieberman, T. McLellan, J. Ross, C. Turner, and D. Voss. 2001. Assessment of potential physical and cognitive aids for performance enhancement of conventional and special operations, 3rd rd. Report of Technical Panel 8—Physical and Cognitive Performance Enhancement for Conventional and Special Operations, Technical Report No. TTCP HUM/01/11. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003a. Application papers: Carbohydrate loading. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. Lieberman, T. Mclellan, J. Ross, C. Turner, and D. Voss. 2003b. Application papers: Carbohydrate supplementation. In Physical and cognitive aids for enhancement of conventional and special operations performance. Report of TTCP HUM, Technical Report No. TTCP/HUM 03/01. Baranski, J., D. Bell, A. Casey, K. Cole, R. Edwards, C. Forbes-Ewan, G. Kamimori, H. R. Lieberman, T. McLellan, M. Paul, C. Turner, and D. Voss. 2004. Assessment of potential physical and cognitive aids for performance enhancement of conventional and special operations, 4th ed. TR-HUM-4-2004. Baur, J. A., K. J. Pearson, N. L. Price, H. A. Jamieson, C. Lerin, A. Kalra, V. V. Prabhu, J. S. Allard, G. Lopez-Lluch, K. Lewis, P. J. Pistell, S. Poosala, K. G. Becker, O. Boss, D. Gwinn, M. Wang, S. Ramaswamy, K. W. Fishbein, R. G. Spencer, E. G. Lakatta, D. Le Couteur, R. J. Shaw, P. Navas, P. Puigserver, D. K. Ingram, R. de Cabo, and D. A. Sinclair. 2006. Resveratrol improves health and survival of mice on a high calorie diet. Nature 444(7117):337-342. Bell, D. G., and T. M. McLellan. 2002. Endurance performance 1, 3 and 6 hours after caffeine ingestion in caffeine users and non-users. J Appl Physio 93(4):1227-1234. Bell, D. G., I. Jacobs, T. M. McLellan, M. Miyazaki, and C. M. Sabiston. 1999. Thermal regulation in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med 70(6):583-588. Bell, D. G., I. Jacobs, T. M. McLellan, and J. Zamecnik. 2000. Reducing the dose of combined caffeine and ephedrine preserves the ergogenic effect. Aviat Space Environ Med 71(4):415419. Bell, D. G., T. M. McLellan, and C. M. Sabiston. 2002. Effect of ingesting caffeine and ephedrine on 10 km run performance. Med Sci Sports Exerc 34(2):344-349. Belongia, E. A., C. W. Hedberg, G. J. Gleich, K. E. White, A. N. Mayeno, D. A. Loegering, S. L. Dunnette, P. L. Pirie, K. L. MacDonald, and M. T. Osterholm. 1990. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. New Eng J Med 323(6):357-365. Bemben, M. G., and H. S. Lamont. 2005. Creatine supplementation and exercise performance: Recent findings. Sports Med 35(2):107-125. PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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Blumenthal, M., G. K. L. Ferrier, and C. Cavaliere. 2006. Total sales of herbal supplements in United States show steady growth. Herbal Gram 71:64-66. Bovill, M. E., W. J. Tharion, and H. R. Lieberman. 2003. Nutrition knowledge and supplement use among elite U.S. Army Soldiers. Mil Med 168(12):997-1000. Comperatore, C. A., H. R. Lieberman, A. W. Kirby, B. Adams, and J. S. Crowley. 1996. Melatonin efficacy in aviation missions requiring rapid deployment and night operations. Aviat Space Environ Med 67(6):520-524 Deuster, P. A., A. Sridhar, W. J. Becker, R. Coll, K. K. O’Brien, and G. Bathalon. 2003. Health assessment of U.S. Army Rangers. Mil Med 168(1):57-62. DiMasi, J., R. Hansen, and H. Grabowski. 2003. The price of innovation: New estimates of drug development costs. J Health Econ 22(2):151-185. Doan, B. K., P. A. Hickey, H. R. Lieberman, and J. R. Fischer. 2006. Caffeinated tube food effect on pilot performance during a 9-hour, simulated nighttime U-2 mission. Aviat Space Environ Med 77(10):1034-1040. DoD (Department of Defense). 2006. Operational rations of the Department of Defense, 7th ed., NATICK PAM 30-25. Washington, DC: DoD. Emonson, D. L., and R. D. Vanderbeek. 1993. The use of dextroamphetamine in support of tactical air operations during Operation Desert Shield/Storm. Aviat Space Environ Med 64:421. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk, final rule. U.S. Federal Register 69, 6787-6854 (February 11, 2004) 21 CFR Part 119. Fine, B. J., J. L. Kobrick, H. R. Lieberman, R. H. Riley, B. Marlowe, and W. J. Tharion. 1994. Effects of caffeine or diphenhydramine on visual vigilance. Psychopharmacology 114(2):233-238. Flakoll, P. J., T. Judy, K. Flinn, C. Carr, and S. Flinn. 2004. Postexercise protein supplementation improves health and muscle soreness during basic military training in marine recruits. J Appl Physiol 96(3):951-956. FDA/CDER (U.S. Food and Drug Administration/Center for Drug Evaluation and Research). 2006. Drug approval application process. http://www.fda.gov/cder/regulatory/applications/ (accessed March 12, 2007). Gardner, C. D., L. D. Lawson, E. Block, L. M. Chatterjee, A. Kiazand, R. R. Balise, and H. C. Kraemer. 2007. Effect of raw garlic vs. commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: A randomized clinical trial. Arch Int Med 167(4):346-353. Goforth, H. W., D. A. Arnall, B. L. Bennett, and P. G. Law. 1997. Persistence of supercompensated muscle glycogen in trained subjects after carbohydrate loading. J Appl Physiol 82(1):342-347. Goforth, H., C. Forbes-Ewan, M. Harrison, I. Jacobs, H. R. Lieberman, and R. Nicholson. 2006. The use of nutritional supplements by special operations personnel of TTCP nations. J Defence Sci 6:73-79. Headquarters, USAF (U.S. Air Force). 2003, December 2. Modafinil and management of aircrew fatigue. Washington, DC: USAF. Hertzman, P. A., W. L. Blevins, J. Mayer, B. Greenfield, M. Ting, and G. J. Gleich. 1990. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. New Eng J Med 322(13):869-873.

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Hypericum Depression Trial Study Group. 2002. Effect of Hypericum perforatum (St. John’s Wort) in major depressive disorder: A randomized controlled study. J Am Med Assoc 287(14):1807-1814. IOM (Institute of Medicine). 1994. Food components to enhance performance. Washington, DC: National Academy Press. IOM. 2001. Caffeine for the sustainment of mental task performance. Washington, DC: National Academy Press. Jacobs, I., A. Allsopp, C. Forbes-Ewen, H. Goforth, M. Harrison, H. Lieberman, and R. Nicholson. 1997. Assessment of potential ergogenic aids for Special Operations, 2nd ed. Physical Performance Enhancement for Special Operations. Report of Technical Panel HUM-G8. Johnson, R. F., and D. J. Merullo. 2000. Caffeine, gender, and sentry duty: Effects of a mild stimulant on vigilance and marksmanship. In Pennington Center Nutrition Series, Volume 10: Countermeasures for battlefield stressor, edited by K. Friedl, H. L. Lieberman, D. H. Ryan, and G. A. Bray. Baton Rouge: Louisiana State University Press. Pp. 272-289. Jones, F. D. 1985. Sanctioned use of drugs in combat. In Psychiatry: The state of the art 2. Vol. 6, edited by P. Picht, P. Berner, R. Wolf, and K. Thau. New York: Plenum Press. Pp. 489494. Kamimori, G. 2000. Effect of three caffeine doses on plasma catecholamines and alertness during prolonged wakefulness. Eur J Clin Pharmacol 56(8):537-544. Kamimori, G. H., S. I. Lugo, D. M. Penetar, A. C. Chamberlain, G. E. Brunhart, A. E. Brunhart, and N. D. Eddington. 1995. Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans. Int J Clin Pharmacol Ther 33(3):182-186. Kamimori, G., C. S. Karyekar, R. Otterstetter, D. S. Cox, T. J. Balkin, G. L. Belenky, and N. D. Eddington. 2002. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Int J Pharmaceutics 234(1):159-167. Lagarde, D., and D. Batejat. 1995. Disrupted sleep-wake rhythm and performance: Advantages of modafinil. Mil Psychol 7(3):165-191. Lieberman, H. R. 2001. The effects of ginseng, ephedrine, and caffeine on cognitive performance, mood and energy. Nutr Rev 59(4):91-102. Lieberman, H. R. 2003. Nutrition, brain function, and cognitive performance. Appetite 40(3):245-254. Lieberman, H. R., and J. Cail. In press. Performance maintaining/enhancing drugs and food components. In Medical aspects of deployment to harsh environments. Textbook of Military Medicine. Vol. 3, edited by K. B. Pandolf and R. E. Burr. Washington, DC: Borden Institute Press. Lieberman, H. R., W. J. Tharion, B. Shukitt-Hale, K. L. Speckman, and R. Tulley. 2002a. Effects of caffeine, sleep loss, and stress on cognitive performance and mood during U.S. Navy SEAL training. Psychopharmacology 164(3):250-261. Lieberman, H. R., C. M. Falco, and S. S. Slade. 2002b. Carbohydrate administration during a day of sustained aerobic activity improves vigilance, assessed with a novel ambulatory monitoring device, and mood. Am J Clin Nut 76(1):120-127. Lonn, E., J. Bosch, S. Yusuf, P. Sheridan, J. Pogue, J. M. Arnold, C. Ross, A. Arnold, P. Sleight, J. Probstfield, G. R. Dagenais, HOPE and HOPE-TOO Trial Investigators. 2005. Effects of

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long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. J Am Med Assoc 293(11):1338-1347. McKenzie, R., and L. Elliott. 1965. Effects of secobarbital and d-amphetamine on performance during a simulated air mission. Aerosp Med 36:774-779. McLellan, T. M., D. G. Bell, H. R. Lieberman, and G. H. Kamimori. 2003/2004. The impact of caffeine on cognitive and physical performance and marksmanship during sustained operations. Canadian Mil J 4:47-54. Montain, S. J., R. L. Shippee, and W. J. Tharion. 1997. Carbohydrate-electrolyte solution effects on physical performance of military tasks. Aviat Space Environ Med 68:384-391. Nicholson, A. N. 1984. Long-range air capability and the South Atlantic Campaign. Aviat Space Environ Med 55(4):269-270. Penetar, D. M., G. Belenky, J. J. Garrigan, and D. P. Redmond. 1989.Triazolam impairs learning and fails to improve sleep in a long-range aerial deployment. Aviat Space Environ Med 60(6):594-598. Rosenkranz, K. 2003. High Fliers. New York Times, January 23. Ross, T. A., J. A. Alemany, J. H. Georgelis, L. J. Marchetelli, S. J. Montain, B. C. Nindl, and A. J. Young. 2003. Dietary protein supplementation during military operational stress and underfeeding: Effects on lean body mass. Med Sci Sports Exer 35:S101. Roth, T., C. Stubbs, and J. K. Walsh. 2005. Ramelteon (TAK-375), a selective MT1/MT2receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep 28(3):303-307. Senechal, P. K. 1988. Flight surgeon support of combat operations at RAF Upper Heyford. Aviat Space Environ Med 59(8):776-777. Shurtleff, D., J. R. Thomas, J. Schrot, K. Kowalski, and R. Harford. 1994. Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacol Biochem Behav 47(4):935-941. Smith, A., W. Sturgess, and J. Gallagher. 1999. Effects of a low dose of caffeine given in different drinks on mood and performance. Hum Psychopharmacol 14(7):473-482. Smith, A., D. Sutherland, and G. Christopher. 2005. Effects of repeated doses of caffeine on mood and performance of alert and fatigued volunteers. J Psychopharmacol 19(6):620-626. Solomon, P. R., F. Adams, A. Silver, J. Zimmer, and R. DeVeaux. 2002. Ginkgo for memory enhancement: A randomized controlled study. J Am Med Assoc 288(7):835-840. Spinweber, C. L. 1986. Sedating and nonsedating sleeping aids in air operations. In Biochemical enhancement performance, advisory group for aerospace research and development (AGARD) Conference Proceedings (NATO). London, England. Pp. 11-12. TTCP (The Technical Cooperation Program). 2006. Policies, organisation, and procedures in non-atomic military research and development (POPNAMRAD). TTCP Document DOCSEC-1-2006. TTCP. 2007. Home page. http://www.dtic.mil/ttcp/ (accessed March 12, 2007). Wesensten, N. J., G. Belenky, M. A. Kautz, D. R. Thorne, R. M. Reichardt, and T. J. Balkin. 2002. Maintaining alertness and performance during sleep deprivation: Modafinil versus caffeine. Psychopharmacology 159(3):238-247.

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MONITORING DIETARY SUPPLEMENTS AT MILITARY MEDICAL TREATMENT FACILITIES Paul Hoerner1 INTRODUCTION Members of the military are often placed in positions or jobs where they are challenged to improve their physical performance. As do civilians, military members who seek to improve their physical performance sometimes turn to dietary supplements to aid them. Military medical staffs use various methods to document usage and side effects of these substances in their military members. This paper will describe the basic details of how that information flows, is incorporated into medical decisions, how providers and patients are educated about dietary supplements, and finally what are some possible first steps to improving those processes. REVIEW OF LITERATURE A review of Department of Defense (DoD), Army, Navy, and Air Force regulations was performed to identify what policies were in place regarding the use of dietary supplements. Additionally, an Internet search of military medicine websites was performed to gain additional insight into educational offerings, local policies and procedures, and clinical guidance (Arsenault and Kennedy, 1999; Corum, 2004; USACHPPM, 2006). This information was used to further expand the author’s first-hand knowledge of dietary supplement use in the military. DISCUSSION AND CONCLUSIONS Clearly dietary supplements are being utilized by military members for various reasons including improving physical performance. Unfortunately some of these military members are experiencing adverse effects from these dietary supplements (Arsenault and Kennedy, 1999). Dietary supplement adverse event reporting in the DoD mirrors the process for medication adverse event reporting. Normally a physician, pharmacist, or nurse initiates the report after witnessing an event or after a patient-reported event. That person initially documents this information using a variety of methods (paper or electronic forms, website, telephone hotline recorder, or a copy of the description in the medical record). The information is then entered online into the MEDMARX Adverse Drug Reaction (ADR) reporting module. MEDMARX is a national, Internet-accessible database that civilian and military hospitals use to track and trend adverse drug reactions(See Appendix E). The pharmacy or the patient safety manager enters the information directly into the MEDMARX module; sometimes they will contact the initial reporter for clarification or additional information. ADR reports are then printed out and sent to the Food and Drug Administration (FDA) at the discretion of the medical provider involved or by direction of the pharmacy and therapeutics committee (P&T). Individual hospitals and clinics can track and follow trends of either their reported events or all of the events in the database. Unfortunately, DoD, Army, Navy, or Air Force specific reports cannot be aggregated at this time. Individual hospitals and clinics can only compare their ADR reports to MEDMARX’s aggregated national data. 1

Deputy Director of the Department of Defense (DoD) Patient Safety Center, Silver Spring, MD

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The P&T committee reviews all of the ADR reports for trends and makes operational and clinical policy decisions based on their findings. The P&T committee is a group of physicians, nurses, pharmacists, and logisticians and is led by a physician. Although P&T committees are composed of senior members of a hospital’s or clinic’s staff, their expertise with dietary supplements varies between individual facilities. Generally, the P&T committee is responsible for oversight of the safe and effective use of all medication processes at a facility. Most P&T committee definitions of a medication include dietary supplements if they are being used for other than caloric purposes. Additionally, the P&T committee’s chain of command or authority falls under the chief medical officer (top physician). The P&T committee regulates all aspects of the medication use process including broad-ranging policies related to drug evaluation selection, procurement, storage, distribution, administration, and use. This regulation includes dietary supplements that are being used for other than caloric purposes, but is limited to use within each respective hospital or clinic. The P&T committee cannot restrict use beyond the walls of a particular hospital or clinic. Some potential P&T committee responses to an unexpected incidence of serious adverse events associated with a particular substance could be to limit the conditions under which the substance can be used, limit availability of the substance to certain departments or specialists, issue a warning or educate the medical staff and/or patients about those events, or ultimately delete that substance from the facility’s inventory. An example is that some P&T committees have issued cautionary statements asking physicians to evaluate the potential role of the dietary supplement glucosamine in unexpected elevated blood glucose levels of diabetics.) Military medical providers need more knowledge on dietary supplements (Corum, 2004). They do not routinely receive special training on dietary supplements. Normally medical providers must have a special interest this type of training and facilitate receiving the training. Additionally, the Composite Health Cares System (CHCS) and the Armed Forces Health Longitudinal Technology Application (AHLTA) (DoD’s medical computer systems for ordering and documenting medical care) allow for the documentation of dietary supplement usage but normally not as a part of the medication profile. Usually, it is documented in a free text comments section of the electronic medical record, thus it is not as easily indexed or retrievable as the medication profile. When dietary supplements are a part of the medication formulary and also dispensed by the pharmacy they are entered into the patient’s medication profile. This situation allows for full screening of potential drug interactions, dosing errors, and allergies just as when prescription medications are dispensed. Unfortunately this screening doesn’t occur when dietary supplements are not dispensed by the pharmacy. Few military regulations exist on dietary supplements, and most of them are limited to special groups such as flying crews or those working near nuclear weapons. The regulations require a physician to review what dietary supplements these special groups are taking and determine if the dietary supplements may affect their ability to do their jobs. There have been many educational bulletins and newsletters circulated in the military discouraging the use of some dietary supplements considered unsafe. Generally, their verbiage stops short of banning those substances. Many military installations have vendors such as General Nutrition Centers that offer a host of dietary supplements for purchase on the installation. The prevalence of these vendors speaks well to the popularity of dietary supplements within the military community. SUGGESTIONS FOR FUTURE IMPROVEMENTS Below are some suggested first step improvements. First, approach the United States Pharmacopeia (owner of MEDMARX) about developing a multifacility module for their Adverse PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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Drug Reaction module similar to the multifacility module they developed for medication errors. This would allow for aggregation and thus visibility of dietary supplement adverse events reported into MEDMARX at the DoD level and the Army, Navy, and Air Force branch levels. Currently those MEDMARX reports can only be aggregated at the individual hospital or clinic level, although the entire (DoD and civilian) group of facilities that report to MEDMARX can be aggregated via a report with the individual reporting facilities deidentified. Second, modify CHCS and/or AHLTA to allow documentation within the patient’s electronic medication profile of all over-the-counter dietary supplements that patients purchase and consume without a physician’s prescription. Third, explore the legal processes that local military post/base commanders have available for banning or restricting the sale of dietary substances on military installations when a substance has been considered dangerous by a panel of medical experts (FDA, DoD, American Medical Association, etc). Fourth, develop an educational awareness campaign, possibly incorporating existing military publications, with a focus on the positives and negatives of dietary supplement use by military members.

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REFERENCES Arsenault, J., and J. Kennedy. 1999. Dietary supplement use in U.S. Army Special Operations candidates. Mil Med 164(7):495-501. Corum, S. 2004. Dietary supplement use in the military. U.S. Army Medical Department Journal Jan-Mar:36-38. USACHPPM (U.S. Army Center for Health Promotion and Preventive Medicine). 2006. Warfighter’s guide to dietary supplements. Technical Guide 295. Aberdeen Proving Ground, MD: USACHPPM. Additional Resources Air Force Instruction 44-102, Medical Care Management, http://www.e-publishing.af.mil/shared/media/epubs/AFI44-102.pdf Army Regulation 40-3, Medical, Dental, and Veterinary Care, http://www.apd.army.mil/pdffiles/r40_3.pdf Navy Medicine Directives. http://navymedicine.med.navy.mil/ General Dietary Supplement Advices, https://www.cnet.navy.mil/nascweb/sas/misc_files/dietary_supplement_policy.pdf

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DESIGN AND CONDUCT OF SURVEYS ON DIETARY SUPPLEMENT USE: FACTORS TO CONSIDER David W. Kaufman1 INTRODUCTION This discussion will focus on issues that need to be considered in the design and conduct of surveys, with a particular emphasis on surveys of dietary supplement use. It is organized into four basic areas: how the specific survey goals affect the design; technical aspects of survey conduct; issues of validity that must be taken into account in evaluating the results of surveys; and the Slone survey as an illustrative example of the concepts that have been covered. The latter is a U.S. population-based telephone survey that obtained comprehensive information on the use of medications, including dietary supplements. HOW SURVEY GOALS AFFECT DESIGN It is perhaps an obvious point that the goals must be clearly understood as the first step in implementing a survey, because the goals affect how the survey should be designed and conducted. Some design aspects that are determined by the goals include the population to be surveyed, what information should be obtained on exposures of interest and additional factors, and the number of subjects to be included in the survey. Survey Population Survey populations can be defined in a variety of ways, depending on the objectives. One choice is by geography, for example, the U.S. population or residents of a particular state. Another choice is by membership in an organization, for example, the U.S. military or a subgroup such as Special Forces. Still another approach is to define the population according to some other characteristic, such as use of a medication (e.g., antihypertensives) or having a disease (e.g., breast cancer). Usually it is necessary to enroll a representative sample of the base population for the survey to provide valid data. Once the population is defined, the next step is to determine an enrollment approach that can achieve the required representativeness. As described below, this can sometimes present a formidable technical challenge. Survey Information In defining the information that will be obtained, it is most important to specify the data items for primary exposures of interest, in this case, supplements. The first determination to make is the exposure period to be enquired about. Depending on the survey goals, the period of enquiry could be 1 week, 1 month, 1 year, 5 years, and so on, all the way up to lifetime exposure. Because surveys generally rely on self-reported information, the level of detail that can be obtained is greatest for exposures in the recent past and declines with an increasing exposure interval, as does the accuracy of information about sporadic use. With supplements, the information should start with the complete product name so that the ingredients can be determined. Details of

1

Slone Epidemiology Center at Boston University, MA

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use might include frequency, duration, and for longer exposure intervals, timing. Some measure of dosage may also be desirable, but difficult to obtain for past use. Additional information would usually include demographic data and may be extended to aspects of medical history; other exposures such as drugs, alcohol, tobacco; and other factors such as occupation. Job details may be particularly relevant for surveys of military personnel. Number of Subjects A survey needs to include enough subjects so that the data are informative. The targeted number will depend partly on the expected prevalence of exposure to the main items of interest. Uncommonly used supplements will require large numbers of surveyed individuals to produce sufficient users for meaningful analysis. On the other hand, the size of a survey may be limited by available funds and other practical considerations such as an externally imposed timetable or difficulty in contacting prospective subjects. It is incumbent upon investigators to determine in advance the number that can feasibly be enrolled and determine whether this will be sufficient to answer the questions posed about specific exposures. Technical Aspects of Survey Conduct There are two “domains” in the conduct of surveys that require very different skills from the study team: (1) enrolling the subjects, and (2) obtaining the information from subjects after enrollment. This dichotomy will be apparent throughout the remaining discussion. Methods of Subject Enrollment There are a number of ways to enroll a representative sample of the base population. Here we will focus on two approaches, random digit dialing (RDD), and the targeted sample. RDD is a frequently used method of conducting telephone surveys. Most typically, a sample is generated that is representative of telephone number “blocks” (area code, exchange, and first two digits) in the geographic region being covered, with the last two digits selected randomly. A refinement, known as “list-assisted” RDD, is to confine the sample to blocks known to contain at least one residential number—this increases the proportion of eligible numbers from less than 15 percent to about 45 percent. The numbers are called until eligible households are identified, and then a subject is selected for interview and the survey is conducted. Drawbacks to RDD include limitation of the sample to subjects with telephones, inefficiencies due to time spent calling ineligible numbers or repeated calls that are not answered, and a high refusal rate because of “cold calls.” Refusals in such surveys are known to be more likely among men, people of low socioeconomic status, and minorities. There is also a growing problem with cellular telephone numbers. Generally calls are not placed to known cellular numbers, and individuals are likely to resist participating in surveys on their cell phones because they are charged for the time. Until recently, this was not an issue because the overwhelming majority of the cell phone users also had landline telephone service, but there is now a growing number, particularly younger people, who use cell phones for their only service and are thus excluded from the sample. Despite these drawbacks, RDD is often the only feasible approach that is rigorous enough to achieve a reasonably representative sample of a geographically defined population. A targeted sample can be generated if there are records that cover the base population (e.g., military service records), and this approach avoids many of the drawbacks of RDD. In a telephone survey, use of a targeted sample allows initial contact by letter or e-mail (if addresses are PREPUBLICATION COPY: UNCORRECTED PROOFS 33

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available) before the telephone call, which can increase the participation rate. This approach can also be used for in-person interviews or self-administered questionnaires, which in certain circumstances are preferable to telephone interviews (see below). It is probably the best approach to conducting a survey of military personnel. Other approaches to enrolling survey populations are sometimes used, including convenience samples (e.g., passersby on a street), voluntary panels, and voluntary Internet surveys. These methods are frequently used in market research. They all have the problem of not enrolling representative samples. Even if, as with many panels, the subjects are selected to have a similar demographic distribution as a known base population, the initial decision to participate, such as in response to an advertisement, could be related to one or more factors of interest, thus producing inaccurate prevalence estimates. In most instances these approaches should be avoided. Methods of Data Collection The two main approaches to survey data collection are personal interview and selfadministered questionnaire. Each approach has advantages and drawbacks, and these need to be considered and balanced in devising the best strategy for a particular project. Carefully conducted interviews provide the best assurance of consistency and quality of information, because the process is controlled by study personnel. Interviews can be conducted in person or by telephone. The latter method allows the coverage of a large geographic area from a central location, but is limited by the lack of face-to-face contact (although this can be an advantage for sensitive topics due to the relative anonymity). Extremely long and complicated interviews are better conducted in person. Computerized interviews (either by telephone or in person) are efficient in that data entry is accomplished at the same time as the interview is being conducted, and software can readily allow for complicated skip patterns in questions. Self-administered questionnaires can be filled out at the convenience of the subject and over several sessions if necessary, and are thus appropriate for very long or complicated topics. Another advantage is that the anonymity may be best for very sensitive topics. An Internet-based self-administered questionnaire can also automatically enter the data into a computer database, bypassing a step, although modern scanning technology greatly facilitates data entry with paper questionnaires. The main drawback to this approach is the relative lack of control over the quality and consistency of the information, because the subject is answering written questions on his or her own. A related point is that the responses are limited to what is elicited by the written questions, whereas an experienced interviewer can assist the subject if he or she has difficulty answering particular questions. Finally, it may be easier for subjects to avoid filling out the questionnaire than to refuse to speak with an interviewer; thus, the participation rate may be lower. Whether by interview or questionnaire, what are the best strategies for obtaining information about supplement use? Open-ended questions (what supplements did you take?) are generally not optimal because they do not sufficiently stimulate memory, and therefore lead to underreporting of use. An approach that has been used successfully in many studies is to ask systematically about a list of reasons for use. A further level of questioning is to ask about specific products of interest by name. We have shown in the context of drugs that the list of reasons obtains considerably more information than an open-ended question and the large majority of the information that can be gathered by a specific question (Mitchell et al., 1986). This is important as it is not possible to ask about all products of interest by name. Finally, the subject can be asked to gather the containers of supplements taken and the product names can be directly recorded from the containers. Although this last approach yields the most accurate information, it is limited to PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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products for which the containers are available, which will almost always be a subset of the total, so at best it is an adjunct to other questioning. It is most practical if the period of enquiry is relatively short and recent, which would not be feasible in many surveys. Once product names are obtained, it is very important to have a procedure for determining the ingredients. This is a particular issue with supplements, which can have many individual ingredients that are often not well characterized. A final practical note regarding data collection concerns the timeliness of the information. There should be sufficient resources and infrastructure to enable the data to be made available as soon after collection as possible, so that conclusions are current. This aspect of planning surveys is sometimes overlooked or subject to funding cuts, with the result that the data are of less than optimal utility. Issues of Validity To be valid, survey results should reflect the base population’s experience with regard to dietary supplement use. This requires appropriate selection and enrollment of survey subjects and accurate collection of information from them about their supplement use. The degree to which this has been accomplished must be considered when interpreting the results, because once the data are collected, there is very little that can be done to mitigate selection or information problems. Selection bias occurs when enrollment into the survey is related to the factor(s) of interest, in this case, supplement use. With a low participation rate, there is substantial potential for selection bias to influence the results, even when the survey population appears to be “representative” of the base population, for example, according to demographic factors. If the nonparticipants are materially different than the participants with respect to supplement use and there are many nonparticipants, then those who do participate are unlikely to reflect the experience of the base population. If, on the other hand, there are relatively few nonparticipants, then such differences cannot have much impact on the estimates derived from the participants. Thus, the key to minimizing selection bias is to have an appropriate sampling strategy that is consistently carried out, with as high a participation rate as possible. Survey information can be inaccurate due to memory loss on the part of the subject or deliberate misreporting. The best defense against dishonest answers is careful design of questionnaires to be nonthreatening to subjects and settings that put them at ease. Anonymity, as with self-administered questionnaires, can encourage truthful answers; when data are collected by interview, the rapport that skilled interviewers can establish with subjects is also helpful. Memory loss can be minimized by good questionnaire design and interviewing techniques, as discussed earlier. Since there is usually no “gold standard” against which survey information can be validated, its accuracy is ultimately a matter of judgment, based on an understanding of the design and conduct of the survey. The Slone Survey: An Example of Survey Design and Conduct The Slone survey had the general objective of providing comprehensive, ongoing data on the current use of all medications—prescription, nonprescription, and dietary supplements—in the U.S. population. It was an RDD population-based telephone survey of medication use in the United States that was conducted continuously by the Slone Epidemiology Center at Boston University from 1998 to 2007 (Kaufman et al., 2002). All residents of households with landline telephones in the 48 contiguous states and District of Columbia were eligible; the institutionalPREPUBLICATION COPY: UNCORRECTED PROOFS 35

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ized population was not included. At each contacted number, one individual in the household was selected for interview by a computer-generated random number procedure. Parents were interviewed for children under age 14; those aged 14–17 could be interviewed directly with parental permission. Interviews were conducted in English or Spanish. For subjects who did not speak English or Spanish, the interview was conducted if someone in the household could act as an interpreter. More than 25,000 subjects were surveyed. Strategies to maximize participation by eligible subjects included extensive interviewer training and monitoring of their work; making up to 20 calls over a 2-month period (sometimes this is extended) before a number was retired; recontacting subjects who initially refused to offer another opportunity to participate—about a third of these eventually completed the survey; and regular assessment of the participation rate, with adjustments to the approach as indicated by the ongoing experience. These efforts yielded a 60 percent participation rate, a figure that is at the high end of what could be expected (O’Rourke et al., 1999). The interviewing approach was flexible rather than rigidly scripted, which allowed interviewers more scope in establishing rapport with subjects. There was considerable emphasis on consistency during the interviewer training, and certain key elements were required to be conveyed verbatim. Information was recorded on use of prescription and nonprescription drugs, vitamins and minerals, and herbal and natural supplements during the prior 7 days. The interviewer explained that information was being sought on use of all medications taken during this time period, including supplements, and asked the subject to gather the relevant bottles or packages. A list of reasons for use (e.g., pain/headache/backache, depression/tension/emotional disorders) was then read to elicit recall of additional medications. After the names of all reported medications were recorded, the following information was obtained for each: reason for use, route of administration, number of days taken in the week before the interview, and total duration of the present episode of use (defined as continuous use at least once a week). Other information obtained included age, sex, race, Hispanic origin, years of education, annual household income (in ranges), and since August 2005, a brief medical history. Medication names were coded for analysis using a dictionary developed and maintained by the Slone Epidemiology Center (Kelley et al., 2003). The dictionary is a computerized linkage system composed of individual agents and multicomponent products, including herbals/supplements, each assigned specific code numbers. All combination products are linked to their individual components. Thus, groupings of supplements that contain a particular entity (e.g., ginseng-containing products) can be automatically generated. Research pharmacists identify the components of newly reported products that are not in the dictionary and assign code numbers. In this way the dictionary is continually kept up to date. An overview of supplement use in the U.S. adult population in 2005 is given as an example of Slone survey data. Demographic information from the subjects interviewed in 2005 was compared to data from the 2000 U.S. Census (race, ethnicity, education, region) (U.S. Census, 2000) and to U.S. Census projections for 2005 (age, sex) (U.S. Census, 2005). The distribution of survey subjects according to race and geographic region was similar to that of the U.S. population. Survey participants were somewhat older (median age 40 years in survey, 37 years in the United States) and more likely to be female (57 percent in the survey, 51 percent in the United States). The survey included somewhat fewer individuals of Hispanic origin (9 percent vs. 12 percent). Survey subjects had more education (37 percent college graduate vs. 25 percent) and higher annual household incomes (66 percent with at least $35,000 vs. 58 percent) than the U.S. popula-

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tion. An overrepresentation of women and persons with higher levels of education are consistent with other telephone surveys (Thornberry, 1987). In 2005, there were 2,684 subjects interviewed who were at least 18 years of age. One-week prevalence of use of supplements is reported, meaning any use during the 1-week period preceding the interview. All percentages are weighted according to household size, a factor that is inversely related to the probability of selection within each household. Overall prevalence estimates are adjusted to the age and sex distribution of the U.S. Census projections for 2005 (U.S. Census, 2005). As shown in Figure B-5, 40 percent of adults overall had taken one or more vitamins or minerals in the previous week, and 23 percent had taken herbals or other natural supplements. The prevalences increased with increasing age and were higher among women than among men in each age group. Among women aged 65 years or more, the prevalence of vitamin use was 63 percent, and of herbals, 33 percent. Table B-3 shows the most common specific supplements. Most vitamins were taken in the form of multivitamin products, used by 26 percent of adults. The most commonly used herbals, lutein and lycopene, were almost entirely used as ingredients in mainstream multivitamins (e.g., Centrum Silver). A finding of potential importance because of the possibility of unintended interactions, is that 30 percent of prescription drug users had taken one or more herbal or natural supplements.

FIGURE B-5 Overall use of dietary supplements during the preceding week by U.S. adults, 2005.

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TABLE B-3 Most Commonly Used Vitamins and Herbal/natural Supplements by U.S. Adults in 2005 Supplement

Prevalence (%)*

(95% CI)

40

(+/-1.9)

26

(+/-1.7)

23

(+/-1.6)

Lutein

9.4

(+/-1.1)

Lycopene

7.8

(+/-1.0)

Glucosamine

4.0

(+/-0.7)

Garlic

2.6

(+/-0.6)

Chondroitin

2.5

(+/-0.6)

Ginkgo biloba

1.6

(+/-0.5)

Vitamins Multivitamins Herbal/natural supplements

*Weighted according to household size and adjusted to the age and sex distribution of the 2005 U.S. population. NOTE: CI = confidence interval

How is the interpretation of the Slone survey results informed by the key validity issues related to selection and information? With regard to selection, the survey population is relatively similar to the U.S. population, with some underrepresentation of men, younger ages, individuals of low socioeconomic status, and Hispanics. We were able to adjust the overall prevalences to the age and sex distribution of the 2005 U.S. population. The participation rate was high for an RDD survey but not so high that bias can be ruled out. With regard to information, the survey enquired about a recent period that should have been well remembered; the interview was carefully designed to maximize recall; and product names were confirmed from the containers wherever possible. There is no reason to believe that subjects deliberately misreported their supplement use. With the above caveats, we conclude that the results provide a reasonable reflection of supplement use in the noninstitutionalized U.S. adult population. In conclusion, the Slone survey results have documented the widespread use of dietary supplements in the U.S. adult population. Among the key findings, vitamins are taken by 40 percent of adults in any given week, with the majority of use being multivitamins; herbal or natural supplements are taken by 23 percent. Thirty percent of prescription drug users are also taking herbal products. Among the key methodological points, considerable efforts were made to enroll a representative sample of the U.S. population, with a focus on maximizing participation. The interview obtained a comprehensive history of recent medication use, with numerous design features to maximize the completeness and accuracy of the information. In these and other respects, the survey provides an example of many of the concepts discussed here.

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Acknowledgement I wish to thank my colleague, Judith P. Kelly, for her helpful comments on the manuscript and the presentation on which it is based. REFERENCES Kaufman, D. W., J. P. Kelly, L. Rosenberg, T. E. Anderson, and A. A. Mitchell. 2002. Recent patterns of medication use in the ambulatory adult population of the United States: The Slone survey. J Am Med Assoc 287(3):337-344. Kelley, K. E., T. P. Kelley, D. W. Kaufman, and A. A. Mitchell. 2003. The Slone Drug Dictionary: A research driven pharmacoepidemiology tool. Pharmacoepidemiol Drug Safety 12(S1):S168-S169. Mitchell, A. A., L. B. Cottler, and S. Shapiro. 1986. Effect of questionnaire design on recall of drug exposure in pregnancy. Am J Epidemiol 123(4):670-676. O’Rourke, D., and T. Johnson. 1999. An inquiry into declining RDD response rates. Part III: A multivariate review. Survey Res 2-3:1-3. Thornberry, O. T., Jr. 1987. An experimental comparison of telephone and personal health interview surveys. Vital Health Stat 2(106):1-4. U.S. Census Bureau. 2000. 2000 Census of population and housing. Summary social, economic, and housing characteristics. Washington, DC: Bureau of the Census. U.S. Census Bureau. 2005. Projections of the total resident population by 5-year age groups, and sex with special age categories: Middle series, 2001 to 2005. http://www.census.gov/population/projections/nation/summary/np-t3-b.txt. (accessed February 11, 2005).

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DIETARY SUPPLEMENT USE BY YOUNG ADULTS IN THE UNITED STATES Paula Gardiner, MD, MPH1 Catherine Buettner MD, MPH2 Russell S. Phillips, MD2 INTRODUCTION Little is known about the prevalence of dietary supplement use by young adults in the United States. The National Health and Nutrition Examination Survey (NHANES) and the National Health Interview Survey (NHIS), two nationally representative interview surveys, have collected information on dietary supplement use. The purpose of the current report is to provide comparative information on the use of dietary supplements among young adults from these two large databases. Focusing on any dietary supplement (vitamins, minerals, herbs, and other dietary supplements) (NHANES) and the use of “natural herbs” (NHIS), we describe prevalence of dietary supplement use among U.S. young adults, along with demographic factors associated with use. REVIEW OF LITERATURE Many American adults use vitamins, minerals, herbs, and other dietary supplements on a regular basis (Barnes et al., 2004; Fennell, 2004; Gardiner et al., 2006; 2007a; Graham et al., 2005; Kelly et al., 2005; Kennedy, 2005; Ni et al., 2002; Radimer et al., 2004; Tindle et al., 2005). Although dietary supplement use varies by age, gender, race, and ethnicity, little is known about dietary supplement use among young adults. Previous studies have reported 26 percent to 79 percent of young adults use dietary supplements, yet much of this data has focused on college students and athletes (Ambrose and Samuels, 2004; Calfee and Fadale, 2006; Herbold et al., 2004; Greenwood et al., 2003; Green et al., 2001; Johnson and Blanchard, 2006; Martens et al., 2006; Newberry et al., 2001; Perkin et al., 2002; Rockafellow and Saules, 2006; Scofield and Unruh, 2006). Using data from the 2002 NHIS and the 1999–2002 NHANES, we examined the overall prevalence and demographic factors associated with dietary supplement use among young adults. Methods Data for this study were from two nationally representative surveys: the 1999–2002 NHANES and the 2002 NHIS. These surveys were administered by the Center for Disease Control’s National Center for Health Statistics (NCHS). Both surveys involved in-home interviews to collect data and are representative of the civilian, noninstitutionalized population of the United States (NHIS, 2002; Ervin et al., 2004; NHANES, 2006). The interview response rates for the NHANES in 1999–2000 and 2001–2002 were 82 percent and 84 percent, respectively, for the entire population (N = 21,044) (NHANES, 2006). The NHIS interview response rate in 2002 was 73.4 percent (N = 31,044). 1 Boston University Medical School, Department of Family Medicine, Boston. Dr. Gardiner is supported by an NIH Institutional National Research Service Award, Grant No. T32-AT0051-03 from the National Center for Complementary and Alternative Medicine (NCCAM). 2 Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, MA. Dr. Phillips is supported by a NIH MidCareer Investigator Award K24-AT000589 from the NCCAM, National Institutes of Health.

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APPENDIX B

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Assessment of Variables NHANES Survey Dietary supplement use was assessed from responses to questions asked during the household interview: “Have you used or taken any vitamins, minerals, or other dietary supplements in the past month?” Participants who affirmed supplement use were asked to show the supplement containers to the interviewer so that supplement details could be recorded. If the container was not available, participants were asked to recall the name of the product and that was documented. Demographic data was based on self-report and included information on age, sex, education, average total family income and race/ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, all others) (NHANES, 2006). NHIS Survey Dietary supplement use was assessed from responses to the following: “Some people use natural herbs for a variety of health reasons. Some people drink an herbal tea to remedy a flu or cold. Others take a daily pill to help with a health condition or just stay healthy. Have you ever used natural herbs for your own health or treatment? (for example ginger, echinacea, or black cohosh including teas, tinctures, and pills)” (NHIS, 2002). Respondents who reported using natural herbs were then asked: “During the past 12 months, did you use natural herbs for your own health or treatment?” (NHIS, 2002). Those who said yes, were asked a series of questions about use of 35 different dietary supplements (29 supplements were plant based; 6 supplements were not plant based including SAM-e, progesterone cream, melatonin, bee pollen, fish oil, and glucosamine with or with out chondroitin). Self-reported demographic data included information on age, sex, education, annual family income, and race/ethnicity (Hispanic, non-Hispanic white, non-Hispanic black, non-Hispanic other (Asian, American Indian/Alaskan native, Asian Indian, Chinese, and Filipino). Unlike NHANES, respondents were asked how important herbs or supplements were for maintaining their health, the reason for herb or supplement use, and whether they disclosed such use to their conventional health care providers. Statistical Analyses Using methodology from a previous analysis in NHANES, we grouped dietary supplements into two categories: any dietary supplement, including multivitamins, prenatal vitamins, single vitamins and mineral supplements and herbs, and other dietary supplements, which included botanical products and nonbotanical products (e.g., probiotics, melatonin, protein powders, and other sport supplements) (Gardiner et al., 2007b). The second category only included nonvitamin and nonmineral supplements. A supplement may have been counted in more than one category based on ingredients and labeling claims. Because questions used to determine dietary supplement use in the NHIS interview differed than NHANES, we assessed any affirmative response to “use of any natural herbs in the last 12 months” as the separate group that we will refer to as “natural herbs and supplements.” We carried out statistical analyses using SAS software (Version 9.1; SAS Institute, Inc, Cary, NC) and used SUDAAN (Release 9.0, Research Triangle Institute, Research Triangle Park, NC, or survey commands in STATA (Version 8; Stata Corp, College Station, TX) to account for the complex sampling design of the NHANES and NHIS. We also used sample weights to account

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

for the unequal probability of selection and nonresponse of participants to produce prevalence estimates that allow for national representation. Descriptive data are presented as weighted percentages. We performed multivariable logistic regression to assess the association of demographic factors with use of any dietary supplements (NHANES), nonvitamin/mineral supplements (NHANES), and natural herbs and supplements (NHIS). All variables were entered into the final model simultaneously. Results A total of 3,236 young adults (18–30 years) participated in the NHANES, and 6,666 young adults (18–30 years) participated in the NHIS. Both surveys had similar distributions of female to males and age distributions (Table B-4). The respondents’ race, ethnicity, and income reflected the diversity of the U.S. population (Table B-6). For education, however, NHIS respondents had a higher rate of high school graduates (60 percent for NHIS versus 48 percent NHANES). TABLE B-4 Characteristics of US Adults Age 18–30 in the 1999–2002 NHANES (N = 3236) and the 2002 NHIS data (N = 6666) Demographic Age 18–22 years old 23–30 years old Gender Female Male Race/Ethnicity Non-Hispanic White Non-Hispanic Black Hispanic* Mexican American* All others Family income < $15,000 $15,000–$34,999 $35,000–$64,999 > $65,000 Refused or don’t know Education < High school High school > High school

NHANES Weighted Percent

NHIS Weighted Percent

41 59

40 60

51 49

51 49

61 12 13 14

64 14 16 6

27 31 22 18 2

26 24 10 2 38

24 28 48

16 24 60

*Mexican American is defined in NHANES; Hispanic is defined in NHIS.

Prevalence of Supplement Use Among NHANES respondents, 37 percent reported using any dietary supplement in the last month (Table B-5). Twenty-three percent of respondents used multivitamins (6 percent prenatal vitamins), 7 percent vitamin C, and 7 percent nonvitamin/mineral supplements.

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TABLE B-5 NHANES Frequency of Individual Dietary Supplements Used by Young Adults 18–30 (Weighted Percents) N

Use a Dietary Supplement (%)

1,164 791 415 387

37 23 17 6

153 45 51 100 71

7 2 1 2 3

170 128

7 5

92

4

46

2

Type of Dietary Supplement Any dietary supplements Any multivitamin Nonprenatal Prenatal Single vitamins Vitamin C Vitamin E Vitamin B Iron Calcium Nonvitamin/mineral supplementsa Sport and weight loss supplementsb Herbal supplementsc d

Other nonherbal supplements a

All nonvitamin/mineral supplements include herbal, weight loss, sport, and other supplements. b Weight loss and sport examples include creatine, protein powders, and any advertised weight-loss supplement. c Herbal supplement examples include ginseng, gingko, echinacea, and other herbs. d Other nonherbal dietary supplements examples include fish oil, probiotics, and other nonherbal dietary supplements.

Among NHIS respondents, 17 percent reported using at least one herb or other dietary supplement in the last 12 months. The most commonly used supplements have already been published in a previous analysis and are shown in Figure B-6 (Gardiner et al., 2007c). Table B-6 shows that in NHANES, young adult respondents who reported any dietary supplement use were more likely to be older, female, non-Hispanic white, and had greater education. Those who used nonvitamin/mineral dietary supplements were similar, with the exception that males were more likely to use these types of supplements. Among NHIS respondents, those who used natural herbs and supplements were more likely to be older, female, non-Hispanic other or non-Hispanic white, have higher family income, and greater education.

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

FIGURE B-6 2002 NHIS top individual natural herbs reported by natural herb users

Multivariable Models Table B-7 shows that after adjustment for demographic factors, NHANES respondents who had used at least one dietary supplement over the last month were more likely to be non-Hispanic white and have higher incomes and more education, than those who had not used dietary supplements during the last month. Respondents of the NHIS who used natural herb and supplements over the last year were more likely to be non-Hispanic white and have greater education than those who reported no use. NHIS Specific Questions Among NHIS respondents who reported using herbs and other supplements, 19 percent reported they were very important in maintaining their health and well-being. Forty-three percent reported that supplements combined with conventional medical treatments would be helpful, while 53 percent thought they would be interesting to try. Only 24 percent of those who reported using natural herbs and supplements disclosed their herb use to a health professional (Gardiner et al., 2007c).

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APPENDIX B

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TABLE B-6 Frequency of Any Dietary Supplement, Nonvitamins/Mineral Supplement, and “Natural Herbs and Supplement” Use Among U.S. Young Adults Ages 18–30 (Weighted Percent) NHANES (1999–2002) Percent Who Use Percent Who Use Nonvitamin/Mineral Any Dietary SuppleSupplements ments

Demographic Age 18–22 years old 23–30 years old Gender Female Male Race/Ethnicity Non-Hispanic white Non-Hispanic black Hispanic (Mexican b American ) All others Family income < $15,000 $15,000–$34,999 $35,000–$64,999 > $65,000 Refused or don’t know Education Less than high school High school More than high school a

NHIS (2002) Percent Who Use “Natural Herbs and Supplements”a

30 42

5 8

15 19

43 31

6 8

18 16

44 26 24

9 4 5

19 13 12

29

5

20

29 36 39 51 31

5 8 7 8 9

18 21 23 30 12

19 33 49

3 7 9

7 15 21

Thirty-five different dietary supplements (29 supplements were plant based and 6 supplements were not plant based including SAM-e, progesterone cream, melatonin, bee pollen, fish oil, and glucosamine with or with out chondroitin). b Mexican American for NHANES.

Discussion For the general use of dietary supplements, young adults do not differ substantially from older adults (Barnes et al., 2004; Kelly et al., 2005; Radimer et al., 2004; Yu et al., 2004). Our analysis of NHANES demonstrates that 37 percent of young adults in the United States used at least one dietary supplement in the last month. Additionally, in both surveys the types of supplements used are similar to those used in the general adult population (Barnes et al., 2004; Kelly et al., 2005; Radimer et al., 2004; Yu et al., 2004). Our multivariate analysis in NHIS shows similar findings compared to other survey studies. For example, factors associated with greater herb use include having greater than a high school education (Bruno, 2005; Kelly et al., 2005). The comparison in prevalence between the NHANES and NHIS results is subject to several caveats. Although both studies used face-to-face interviews, NHANES recorded “any dietary supplement information in the last 30 days” and recorded information directly from supplement containers (available in 75 percent of the cases) or based on self-report (when containers unavailable). NHIS used only self-report data for the question of “natural herb use” in the last year. PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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TABLE B-7 Adjusted Odds Ratios and 95% Confidence Intervals for Use of Any Dietary Supplement, Nonvitamins/Mineral Supplement, and “Natural Herb and Supplement” Use Among U.S. Young Adults Ages 18–30 NHANES (1999–2002) Adjusted Model Adjusted Model Any Dietary Supplements Nonvitamin/Mineral Supplements

Characteristic Demographic Age 18–22 years old 23–30 years old Gender Female Male Race/Ethnicity Non-Hispanic white Non-Hispanic black Mexican Americanb All others Family income < $15,000 $15,000–$34,999 $35,000–$64,999 > $65,000 Refused or don’t know Education < High school High school > High school

NHIS (years) Adjusted Model “Natural Herbs and Supplements”a

1.0 1.03 [0.82–1.29]

1.0 1.64 [1.00–2.68]

1.0 1.06 [0.88–1.27]

1.0 .86 [0.73–1.02]

1.0 1.42 [1.00–2.02]

1.0 .87 [0.75–1.02]

1.0 .40 [0.32–.50] .53 [0.42–.67] .60 [0.44–.82]

1.0 .29 [0.16–0.53] .45 [0.27–0.75] .48 [0.18–1.27]

1.0 .71 [0.57–.88] .80 [0.63–1.02] 1.06 [0.75–1.50]

1.0 .80 [0.56–1.15] 1.09 [0.75–1.58] 1.46 [1.06–2.01] 1.87 [0.81–4.31]

1.0 .84 [0.19–3.69] 1.66 [0.44–6.20] 1.71 [0.48–6.15] 1.95 [0.32–11.64]

1.0 1.14 [.92–1.40] 1.12 [.85–1.49] 1.54 [.96–2.45] .65 [.53–.81]

1.0 1.20 [0.80–1.79] 1.55 [1.09–2.21]

1.0 .97 [0.49–1.93] 1.09 [0.55–2.16]

1.0 2.05 [1.51–2.78] 2.80 [2.10–3.73]

a

Thirty-five different dietary supplements (29 supplements were plant based, 6 supplements were not plant based including SAM-e, progesterone cream, melatonin, bee pollen, fish oil, and glucosamine with or with out chondroitin). b Mexican American for NHANES.

A limiting factor with many studies on dietary supplements is the differing definitions of a dietary supplement. In our analysis, NHANES focused on dietary supplements using a broad definition. NHIS, on the other hand, asked a focused question that limited subject responses to the use of commonly used herbs read from the examiners list. Furthermore, both studies used different time frames for supplement use, and this would have affected the prevalence rates. To create a similar statistical analysis for both surveys, we limited ourselves to variables found in both surveys. Therefore, results may be due to undermeasured confounders; however, other studies have found similar findings. Although the ascertainment of supplement information was more detailed in NHANES, both NHANES and NHIS may have missed use of some types of supplements such as teas, sport drinks, nutraceutical foods, raw herbs, home remedies, and folk remedies. These methodological differences likely explain the two surveys estimates of dietary supplement use in young adults.

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REFERENCE Ambrose, E. T., and S. Samuels. 2004. Perception and use of herbals among students and their practitioners in a university setting. J Am Acad Nurse Pract 16(4):166-173. Barnes, P. M., E. Powell-Griner, K. McFann, and R. L. Nahin. 2004. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 343:1-19. Bruno, J. 2005. Herbal use among US elderly: 2002 National Health Interview Survey. Ann Pharmacother 39(4):643-648. Calfee, R., and P. Fadale. 2006. Popular ergogenic drugs and supplements in young athletes. Pediatrics 117(3):e577-e589. Ervin, R. B., J. D. Wright, and D. Reed-Gillette. 2004. Prevalence of leading types of dietary supplements used in the third National Health and Nutrition Examination Survey, 1988-94. Adv Data (349):1-7. Fennell, D. 2004. Determinants of supplement usage. Prev Med 39(5):932-939. Gardiner, P., R. E. Graham, A. Legedza, D. M. Eisenberg, and R. S. Phillips. 2006. Factors associated with dietary supplement use among prescription medication users. Arch Intern Med 166(18):1968-1974. Gardiner, P., R. Graham, A. T. Legedza, A. C. Ahn, D. M. Eisenberg, and R. S. Phillips. 2007a. Factors associated with herb use among adults in the United States. Altern Ther Health Med 13(2):22-29. Gardiner, P., C. Buettner, R. Davis, R. Phillips, and K. Kemper. 2007b. Dietary supplement use among adolescents in the United States: An analysis of National Health and Nutrition Examination. BMC Complement Altern Med (In press). Gardiner, P., K. J. Kemper, A. Legedza, and R. S. Phillips. 2007c. Factors associated with herb and dietary supplement use by young adults in the United States. BMC Complement Altern Med 7:39. Graham, R. E., A. C. Ahn, R. B. Davis, B. B. O'Connor, D. M. Eisenberg, and R. S. Phillips. 2005. Use of complementary and alternative medical therapies among racial and ethnic minority adults: Results from the 2002 National Health Interview Survey. J Natl Med Assoc 97(4):535-545. Green, G. A., F. D. Uryasz, T. A. Petr, and C. D. Bray. 2001. NCAA study of substance use and abuse habits of college student-athletes. Clin J Sport Med 11(1):51-56. Greenwood, M., R. B. Kreider, C. Melton, C. Rasmussen, S. Lancaster, E. Cantler, P. Milnor, and A. Almada. 2003. Creatine supplementation during college football training does not increase the incidence of cramping or injury. Mol Cell Biochem 244(1-2):83-88. Herbold, N. H., B. K. Visconti, S. Frates, and L. Bandini. 2004. Traditional and nontraditional supplement use by collegiate female varsity athletes. Int J Sport Nutr Exerc Metab 14(5):586-593. Johnson, S. K., and A. Blanchard. 2006. Alternative medicine and herbal use among university students. J Am Coll Health 55(3):163-168. Kelly, J. P., D. W. Kaufman, K. Kelley, L. Rosenberg, T. E. Anderson, and A. A. Mitchell. 2005. Recent trends in use of herbal and other natural products. Arch Intern Med 165(3):281-286. Kennedy, J. 2005. Herb and supplement use in the US adult population. Clin Ther 27(11):18471858. Martens, M. P., K. Dams-O'Connor, N. C. Beck. 2006. A systematic review of college studentathlete drinking: Prevalence rates, sport-related factors, and interventions. J Subst Abuse Treat 31(3):305-316. PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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Newberry, H., K. Beerman, S. Duncan, M. McGuire, and V. Hillers. 2001. Use of nonvitamin, nonmineral dietary supplements among college students. J Am Coll Health 50(3):123-129. NCHS (National Center for Health Statistics). 2002. CAPI manual for NHIS field representatives. Atlanta, GA: NCHS. NHANES. 2006. 1999-2000, 2001-2002, National Health and Nutrition Examination Survey. http://www.cdc.gov/nchs/nhanes.htm (accessed July 24, 2007). Ni, H., C. Simile, and A. M. Hardy. 2002. Utilization of complementary and alternative medicine by United States adults: Results from the 1999 National Health Interview Survey. Med Care 40(4):353-358. Perkin, J. E., W. J. Wilson, K. Schuster, J. Rodriguez, and A. Allen-Chabot. 2002. Prevalence of nonvitamin, nonmineral supplement usage among university students. J Am Diet Assoc 102(3):412-414. Radimer, K., B. Bindewald, J. Hughes, B. Ervin, C. Swanson, and M. F. Picciano. 2004. Dietary supplement use by US adults: Data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol 160(4):339-349. Rockafellow, B. D., and K. K. Saules. 2006. Substance use by college students: The role of intrinsic versus extrinsic motivation for athletic involvement. Psychol Addict Behav 20(3):279287. Scofield, D. E., and S. Unruh. 2006. Dietary supplement use among adolescent athletes in central Nebraska and their sources of information. J Strength Cond Res 20(2):452-455. Tindle, H. A., R. B. Davis, R. S. Phillips, and D. M. Eisenberg. 2005. Trends in use of complementary and alternative medicine by US adults: 1997-2002. Altern Ther Health Med 11(1):42-49. Yu, S. M., R. M. Ghandour, and Z. J. Huang. 2004. Herbal supplement use among US women, 2000. J Am Med Wom Assoc 59(4):17-24.

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INSIGHTS INTO DIETARY SUPPLEMENT USAGE BY U.S. ACTIVE MILITARY PERSONNEL Steve French1 INTRODUCTION Detailed analysis was performed across the portion of the U.S. population that were identified as “currently serving in the military, National Guard, or Reserve” regarding their supplement usage. The sample size of the group is 376 U.S. adults (18 years and older). Comparison of the military population will also be made to the general population of U.S. adults. The scope of the research covered usage of general supplement categories, specific types of supplements, and select supplement brands during a 3- to 6-month period. Specific shopping patterns for nutritional supplements and sports nutrition products were also measured, along with demographic characteristics. (See Box B-3 for research methodology.) Supplement Usage Among Military and Nonmilitary Results showed that almost 7 out of 10 (69 percent) military personnel used dietary supplements in the past 3 months, compared to 73 percent of nonmilitary personnel U.S. adults. Although significant differences do not exist in overall supplement usage between the military and nonmilitary population, military personnel are more likely to use a multivitamin only (23 percent) compared to nonmilitary personnel (18 percent). In addition, military personnel are less likely to be integrated users of dietary supplements with significantly fewer (46 percent) using two or more supplements compared to the nonmilitary population (55 percent) (Figure B-7). BOX B-3 Research Methodology ● NMI periodically surveys more than 50,000 consumers from a nationally representative sample of the U.S. adult population, randomly chosen from an “opt-in panel” of more than 8 million Americans. ● Using an online methodology, these consumers are queried across a range of consumer subsegments, brands, products, and other measures that typically have low incidence within the U.S. adult general population. ● Data is weighted to U.S. Census data across key demographics for U.S. general population incidence projection. ● Statistical accuracy: Given the 50,000+ sample size, the data is statistically valid at the 95 percent confidence level to +/- 0.4 percent. NOTE: ESP (E-Screener Panel) is a proprietary quantitative research tool of the Natural Marketing Institute (NMI). 1

Natural Marketing Institute (NMI), Harleysville, PA

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FIGURE B-7 Supplement usage among military and nonmilitary populations.

There are no significant differences between men and women in the military and their overall usage of supplements. Sixty-eight percent of males in the military use supplements, and 73 percent of females do. However, significantly more nonmilitary women use supplements (77 percent) compared to nonmilitary men (68 percent). Supplement usage for both the military and nonmilitary populations show a direct relationship with age. More specifically, after the age of 45, supplement usage significantly increases among military personnel, with 65 percent of 30- to 44-year-olds using supplements compared to 80 percent among 45-year-olds and older (Figure B-8). This highlights an opportunity to increase supplement usage among military personnel under the age of 45. Conversely, military personnel under the age of 30 are more likely to use supplements compared to the nonmilitary population under the age of 30. Much of the supplement usage for military personnel under age 30 is driven by sports nutrition and muscle building supplements. In fact, 14 percent of military personnel have used protein powders in the past 3 months compared to only 4 percent of the nonmilitary population. Similarly, significantly more military personnel have used sports nutrition supplements compared to the nonmilitary population (8 percent versus 2 percent respectively). On the other hand, military personnel are less likely than the nonmilitary population to use fiber supplements, herbal supplements, and homeopathic remedies (Figure B-9). The military’s high usage of sports nutrition and muscle-building supplements is reflected in their high usage of brands known for their fitness orientation such as GNC and EAS. Military personnel are significantly more likely to use both of these brands compared to the nonmilitary population. However, high usage of these brands may also be a function of commissary availability.

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FIGURE B-8 Supplement usage among military and nonmilitary populations by age group.

In addition to the commissary, military personnel are shopping via several other channels for supplements. Personnel in the 18–29 year-old age range are most likely to shop at GNC (28 percent), compared to 13 percent of 45-year-olds. Although 22 percent of total military personnel shop at GNC, 19 percent shop via the Internet. Internet shopping shows significant increases with age, with 23 percent of 45-year-olds and over shopping via the Internet compared to only 19 percent of 18- to 29-year-olds. Military personnel also shop at natural food supermarkets (9 percent), other nutritional stores besides GNC (9 percent), and through catalog and mail order (5 percent) (Figure B-10). Almost three out of five military personnel (57 percent) use multivitamins, similar to the nonmilitary population (58 percent). However, military personnel are less likely to use single supplements such as calcium, vitamin E, vitamin B, and vitamin D. They are also less likely to use other supplements such as omega-3 fatty acids, fish oil, and glucosamine/chondroitin compared to the nonmilitary population. These less traditional supplements offer a wide range of health benefits, especially to a military lifestyle, offering such benefits as reducing inflammation, increasing energy, improving heart health, helping with joint health and arthritis, improving muscle recovery, and improving concentration to list a few. In essence, this reveals categories of supplements that may need to be explored in more depth for use by military personnel. Profile of Military Supplement Users Compared to military personnel who do not use supplements, military supplement users are more affluent, higher educated, and less likely to have children. The median income of military supplement users is $45,700 compared to $35,400 for nonsupplement users. Over one-third of military supplements users have a college education (36 percent)

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14%

Protein powders

4% 9%

Weight-loss supplements

7% 8%

Herbal supplements

Sports nutrition supplements

12% 8% 2% 4%

Fiber supplements

8% 3% 3%

Children’s supplements

Military Nonmilitary

2%

Homeopathic remedies

4%

Condition specific supplements

2% 3%

= significant difference at 95 percent confidence level

Fi FIGURE B-9 Specific supplement usage.

B 10

compared to only one-quarter of nonsupplement users (26 percent). Significantly more nonsupplement users have children (57 percent) compared to military supplement users (47 percent). More integrated supplement users, who use three or more different types of supplements, also exhibit some demographic differences. Integrated users are older, more affluent, and more highly educated (compared to military personnel who only use multivitamins and military personnel who do not use any supplements) (Figure B-11). Females in the military who use supplements are much lower users of sports nutrition products, yet higher users of herbal supplements. In addition, military personnel using herbals and alternative supplements index high against the general military population for being higher educated.

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APPENDIX B

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FIGURE B-10 Channels shopped for supplements by military population.

Nonsupplement User

(A)

Multivitamin Only User

(B)

3+ Supplement User

(C)

Male: 84% Female: 16%

Male: 81% Female: 19%

Male: 84% Female: 16%

Avg age: 33 yrs old Median income: $35.4K College grad plus: 26% White: 68%

Avg age: 32 yrs old Median income: $38.4K College grad plus: 33% White: 71%

Avg age: 36AB Median income: $48.3K College grad plus: 50%AB White: 75%

FIGURE B-11 Profile of types of supplement users within the military population

Regression Analysis of Dietary Supplement Usage Regression analysis is a statistical technique that identifies the strengths of relationships between variables. More specifically, regression develops an equation that attempts to explain changes in one phenomenon (dependent variable) by looking at changes in other phenomena (independent variables). The regression analysis within this study was designed to explore if a relationship existed between the independent demographic variables and overall supplement usage (dependent variable). The demographic variables used in this analysis included age, gender, race, income, education level, employment, marital status, and children in household.

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Results found that demographic drivers of overall military supplement use carry little weight in determining usage. The only indicator of overall military supplement usage is older age, although the overall strength of predicting the relationship is relatively weak (Figure B-12). Demographic drivers of military supplement category usage (herbals, alternative supplements, sports nutrition, etc.) are also weak with very little predictive value. Conclusions Over two-thirds of the military (69 percent) are using supplements, statistically similar to the nonmilitary population (73 percent). However, military personnel are more likely to be using multivitamins only, highlighting opportunities to increase usage of single supplements, minerals, and other supplements, whose benefits may be advantageous to a military lifestyle. The main driver of overall military supplement usage is older age, but the relationship is relatively weak. High usage of sports nutrition and muscle-building supplements by the youngest age group may be diluting the strength of the relationship. Opportunities, therefore, exist among the younger age groups to increase supplement usage beyond sports and bodybuilding nutrition.

FIGURE B-12 Regression analysis results of the relationship between demographic drivers and supplement usage.

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BEYOND THE DFAC (DINING FACILITY): WHAT SUPPLEMENTS SOLDIERS ARE TAKING AND WHY Sonya Corum1 Prior to going to Fort Jackson and assuming her current position, in 2001 LTC Corum took over as nutrition staff officer at the U.S. Army Center for Health Promotion and Preventive Medicine, replacing LTC Joan Lyon who was actively involved in developing dietary supplement education to include updating Performance Power: The Nutrition Connection series. Included in this series is a module on dietary supplements (module 5). LTC Lyon updated this module as well as authoring a dietary supplement insert for the Soldiers Magazine in 2000. The Department of Defense (DoD) nutrition committee had a strong interest in dietary supplements and educating service members. They asked LTC Corum to chair a working group to develop dietary supplement education. That team put together several different education components including fact sheets, a user brochure, and a series of posters related to dietary supplements. Because of limited resources it was apparent that the dietary supplements education campaign needed to be reviewed. The dietary supplement questionnaire was a result of the need to target the education element. It was necessary to specifically identify what dietary supplements soldiers were taking. Thus, a dietary supplement usage questionnaire was developed. The questionnaire is actually the second version. Major Karen Brassfield did her master's thesis on dietary supplement usage using the first questionnaire version. The current version reflects her lessons learned as well as insights from the working group. The beginning of the questionnaire explains to the soldier what they are filling out and that their answers are anonymous. It also provides the definition of dietary supplements, as it was discovered earlier that not everyone defines the term the same way. Some of the information gathered from the questionnaire includes demographic data, the frequency that a particular supplement is used, and the reasons for use. The supplements were divided into three categories: vitamins and minerals, performance-enhancing supplements, and herbal supplements. Also asked were: where they obtained dietary supplement information, particular adverse events experienced, and where the supplements were purchased. It must be kept in mind that the whole point of this dietary supplement usage questionnaire was to refine dietary supplement education efforts. It was not a research project, but simply meant to focus resources. The format for the questions is the same for all three categories. Each category provided a list of supplements so that respondents could easily select those supplements that they consumed. They were also asked to indicate the frequency of use as well as to choose all the reasons that applied to why they were using that particular supplement. The questionnaire was administered through the Health Promotion and Prevention Initiatives (HPPI) program at the Center for Health Promotion and Preventive Medicine (CHPPM). The HPPI had a small amount of money that they gave to various projects to look at best practices to promote health promotion and prevention. The administration of this questionnaire was one of the projects that they provided funds to support.

1

Army Training and Doctrine Command

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CHPPM-Europe health promotion teams administered the questionnaire to soldiers as a part of their in-processing onto the military base. Sites included Wuerzburg, Germany; Heidelberg, Germany; Landstuhl, Germany; and Vicenza, Italy. Upon completion, the soldiers turned in the questionnaires at the in-processing center. The questionnaires were administered from fiscal year 2003 to fiscal year 2005, with a sample size of about 5,200 (about 77 percent men and about 23 percent females). A few officers completed the questionnaire, but predominantly it was enlisted personnel. About 34 percent were ranked E1 to E3 (privates), about 31 percent were E4 to E5 (E4s are specialists and E5s are entry-level sergeants), and 13 percent were midlevel and senior-level noncommissioned officers. The mean age was 25.4 years with approximately 24 percent 17–21 years old and 23 percent 23– 29 years old. Box B-4 shows the types and percentages of supplements taken. Females predominantly took multivitamins, calcium, and iron. That was a significant difference between the male and the female population. The biggest difference among age groups was that 17- to 30-year-olds were the ones taking zinc; vitamins A, C, or B complex; multivitamin mineral complex; potassium; and calcium. The main reasons stated for taking them were for health and preventing illness. Sports drinks and sports bars were included as part of the ergogenic aids listing. Forty-three percent of those who reported that they were taking supplements said they were using sports drinks and sports bars. The sports drink consumers were more likely to be males 20–30 years old. BOX B-4 Vitamins and Minerals Type of Supplement Multivitamin: 33.8% Vitamin C: 24.4% Calcium: 19.3% Iron: 14.4% Potassium: 12.1% Vitamin A: 12.5% Vitamin B6 : 11.5% Ergogenic Aids Type of Supplement Sports drinks: 42.8% Sports bars: 17.3% Protein: 13.7% Ephedra free: 10.1% Herbal Supplements Type of Supplement Caffeine: 17.5% Ginseng: 6.7% Garlic: 5% Ginkgo: 3.9% Echinacea: 3.6%

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APPENDIX B

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Younger respondents were more likely to take ephedra-free products. They were also taking arginine, creatine, and protein. The major reasons stated were for performance enhancement and strength, and the ephedra-free products for weight loss. In regard to the herbal supplements, the younger population took caffeine as well as echinacea. Females predominantly took garlic and echinacea more so than the males. The older population took garlic and ginkgo. The major reason stated for taking these particular types of supplements was to prevent fatigue. Respondents also said they took ginseng to promote general health. Thirty-six percent of respondents received their information about dietary supplements from friends, almost 32 percent from magazines, 22 percent from the Internet, and 10.4 percent from a sales associate at a store (Figure B-13). A small percentage received their information from their doctors and health care providers, and the smallest percentage received their information through a combination of television, radio, and newspapers. The questionnaire also had a section on adverse effects, and a list was provided to select from. Adverse effects were self-reported. It is important to note that almost 16 percent of respondents reported dehydration as an apparent adverse reaction to supplement usage. For military personnel, this is a significant issue. One of the first things that soldiers receive when they come to Fort Jackson or any Army training centers is their canteens. Soldiers receive guidance about drinking and staying hydrated. It is well documented what effects dehydration has on physical abilities and cognitive performance. Hydration is often difficult to achieve and maintain. If supplements are causing dehydration in soldiers, then it is a concern.

FIGURE B-13 Frequent Sources of Information about Dietary Supplements

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Another significant concern is that of the 951 soldiers who said they experienced other adverse effects. Of that number 9.6 percent of them experienced palpitations, 5.7 percent experienced muscle cramps, and 4.6 percent of them complained of abdominal pain. About 2,241 respondents said they took dietary supplements they bought themselves. The majority of them purchased the supplements from the commissary or the post exchange. Each of these outlets offers a variety of products, particularly multivitamin and mineral complexes. Offpost and on-post purchasing of supplements are about the same; a small percent, about 13 percent, are purchased via mail order and the Internet (Figure B-14).

FIGURE B-14 Supplement Purchase Sites

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DIETARY SUPPLEMENT USE AMONG AIR FORCE PERSONNEL Charity J. Thomasos, Lt Col MIL USAF1 INTRODUCTION Use of complementary and alternative medicine, specifically dietary supplement use, continues to experience tremendous growth. The number of dietary supplements linked to adverse events and undesirable side effects has increased. To date, there has not been a study to determine the extent of dietary supplement use among U.S. Air Force (USAF) active duty personnel. With the Food and Drug Administration’s (FDA’s) ephedra ban challenge, and the androdenestione ban, effective January 2005, the potential impact of these substances on USAF members’ short-term health and mission readiness, plus long-term health effects, has become a highinterest item among USAF leaders. In February 2006, the USAF surgeon general requested an evaluation of dietary supplement use with the purpose of targeting awareness and education efforts. A survey was administered to a sample population to assess the use of dietary supplements and patterns of use within the Air Force. Review of Literature A national survey conducted in 2002 interviewed adults in all 50 states and the District of Columbia; 73 percent of US adults interviewed used a dietary supplement in the past 12 months and 4 percent experienced an adverse event they believed might be related to supplement use. A greater proportion of adverse events was reported by users who were also taking prescription medications (Timbo et al., 2006). After a comprehensive review of studies involving ma huang, ephedra, ephedrine-type alkaloids, and ephedrine, Miller concluded that USAF personnel appear to be following the current USAF policy strongly discouraging the use of dietary supplements containing ephedrine-type alkaloids.. Significant manufacturing quality control issues, limited studies supporting safety and efficacy, and modest results in the context of frequent and serious adverse events are the reasons cited for following the policy (Miller, 2004). A recent case study reported severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement containing synephrine. Many manufacturers of dietary supplements, in response to the ephedra ban, replaced ephedra with synephrine, which is a sympathomimetic amine structurally similar to ephedra. The authors reporting this case study believe military physicians should query personnel on their use of dietary supplements, educate their patients about potential risks, and advocate healthy diets and exercise for weight loss (Burke et al., 2007). A systematic review of supplements for weight reduction showed that adverse events, including hepatic injury and death, have been reported with the use of these supplements. For herbal ephedra and ephedrine-containing supplements, an increased risk of psychiatric, autonomic, and gastrointestinal side effects, as well as heart palpitations have been documented. The risk-benefit profile has shifted regarding these herbal weight-loss supplements (Pittler et al., 2005). Bovill and others examined nutrition knowledge and supplement use among elite U.S. Army soldiers (Bovill et al., 2003). The overwhelming majority of the Army Special Forces soldiers 1

Eglin Hospital, Eglin Air Force Base, Forida

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reported using supplements (90 percent); most incorrectly believed protein is used for energy in short-term events (64 percent) and that vitamins provide energy (58 percent). Magazines and books were the most common information source (75 percent). Experimental Results The survey to assess dietary supplement use among USAF members was adapted from the U.S. Army Center for Health Promotion and Preventive Medicine Dietary Supplement Questionnaire. The survey was modified to group supplements into categories, such as vitamins and minerals, fitness supplements, and so on. Based on rank, active duty personnel at 27 major installations were grouped into one of four categories: junior officers, junior enlisted, senior officers, and senior enlisted. Junior officers hold the rank of 2nd lieutenant, 1st lieutenant, or captain (grades 01 through 03); junior enlisted hold the rank of airman, airman basic, airman 1st class, and senior airman (grades E1 through E4); senior officers hold ranks of major, lieutenant colonel, or colonel (grades 04 through 06; senior enlisted have the rank of staff sergeant, technical sergeant, master sergeant, senior master sergeant, or chief master sergeant (grades E5 through E9. Sampling strata was aggregated within nine major commands (MAJCOMS). Bases are assigned to the respective commands according to the primary mission of the base; the mission of the military installation drives the number of personnel and the USAF specialty codes assigned to the base. The bases were categorized as small, medium or large, dependent upon the number of active duty personnel assigned. Small bases had 5,000 members or less; medium-sized bases had between 5,000 to 10,000 assigned personnel, and large bases had over 10,000 assigned personnel. The survey was administered online during spring and summer of 2006. Personnel in the sample population received an e-mail invitation signed by the USAF surgeon general. The e-mail invitation contained an electronic link to the survey. The e-mail invite and link to the survey were initially sent to the sample populations at each of the nine military installations in February 2006. A computer server malfunction prevented the second invite to be sent the third week after the initial invitation was distributed. A second e-mail invitation to participate in the survey was sent in June 2006 to those members who did not complete the survey. The total number of completed surveys was 11,000. The survey return proportions closely mirror population distributions (Table B-8). Unfortunately, due to repeated computer server malfunctions, the goal of 20,000 completed surveys was not attained. Therefore, the results cannot be extrapolated to the USAF population at large. The findings pertain only to the installations and major commands surveyed. Survey questions assessed the frequency of dietary supplement use, money spent on supplements, where members purchased dietary supplements, sources of information, reasons for use of dietary supplements, perceived and reported side effects, and adverse effects.

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APPENDIX B

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TABLE B-8 Survey Response MAJCOM

USAF Population

Survey Population

ACC AETC AFMC AFSOC AMC FOA/DRU PACAF SPACE USAFE

84,298 64,303 21,187 12,741 49,960 23,060 33,266 18,948 28,187

2,471 1,818 712 665 1,627 988 878 930 896

USAF Pop (%) 23.81 18.17 5.99 3.60 14.11 6.51 9.40 5.35 7.96

Survey Pop (%) 21.57 15.87 6.22 5.81 14.20 8.63 7.66 8.12 7.82

+/2.24 2.30 -0.23 -2.21 -0.09 -2.11 1.73 -2.77 0.14

NOTE: MAJCOM=Major Command; ACC=Air Combat Command; AETC=Air Education & Training Command; AFMC=Air Force Materiel Command; AFSOC=Air Force Special Operations Command; AMC=Air Mobility Command; FOA/DRU=Field Operating Agency/Direct Reporting Unit; PACAF= Pacific Air Forces; SPACE=Air Force Space Command; USAFE=United States Air Forces in Europe.

Discussions and Conclusions Sixty-nine percent of USAF personnel, regardless of the MAJCOM, reported using dietary supplements currently or have used dietary supplements in the past. Thirty-one percent reported never using dietary supplements. Figure B-15 describes supplement use by MAJCOM. The most common supplements reported as being used five or more times per week include multivitamins, multiminerals, creatine, glutamine, vitamin C, caffeine, calcium, protein powders, fish oils, hydroxycut, chondroitin, and NO2 or nitric oxide, as identified in Box B-5. Usage rate was also evaluated based on the members USAF specialty code, or job skill. Security forces, firefighters, communication personnel, and nurses reported the highest use of dietary supplements at 70–75 percent. Physicians had the lowest usage rates reported (46 percent). Across the various ranks there was no statistical difference between usage rates, types of supplements used, or reasons for supplement use. The most common reason for using dietary supplements reported by both senior enlisted and senior officers was to achieve weight loss. This is not an unexpected finding; the military members must meet weight and fitness standards, assessed annually, and the battle against weight gain intensifies with age. The most common supplements used by both junior enlisted personnel and junior officers were those supplements marketed to increase strength and lean body mass. Performance enhancement was the focus among younger personnel. Selected other supplements reported in a free text or comments question are listed in Box B-6. Ninety-six percent reported spending less than $100 per month on dietary supplements. The majority of supplements, 66 percent, are purchased on military installations at stores such as the commissary, base exchange or post exchange, and GNC stores. Very few USAF personnel, 11 percent, reported using the Internet or mail order to purchase dietary supplements. Twenty-three percent purchase supplements off base. Another item of interest was where the airmen went to obtain information on dietary supplements; results are described in Figure B-16. Magazines were the most popular at 19 percent, which is slightly higher than obtaining information from friends or family, at 18 percent. A mere 13 percent report obtaining information on dietary supplements from their health care providers.

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

FIGURE B-15 Supplement use by Major Command (MAJCOM USAF)

Seventy-nine percent reported that they had never attended a briefing on dietary supplements. Only 8 percent reported receiving information on supplements within the past 12 months.

BOX B-5 Most Common Supplements Used 5+ Times/Week Multivitamin Multimineral Creatine Glutamine Vitamin C Caffeine

Calcium Protein powders Fish oils NO2 Chondroitin Hydroxycut

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APPENDIX B

B-63

BOX B-6 Additional Supplement Use Reported Dexitrim Fish oil(s) Flax seed oil Melatonin Acidophilus Aloe vera Biotin CLA Co-Q10 Dandelion Echinacea Garlic pills Milk thistle

Grape seed extract USANA products Oxydrene Lipo-6 Lutein Pomegranate Redline Saw palmetto Selenium Viactiv Water pills ZMA HA-JOINT

Colloidal silver Emergen-C Magnesium glycinate Marine algae Animal cuts powder Bi yan pian Bilberry Brewers yeast Mangosteen Cranberry capsules Red yeast rice Fenugreek Hoodia gordonii

FIGURE B-16 Sources of information on dietary supplements

With the publication of AFI 10-248, the Air Force incorporated guidelines on dietary supplements into their physical training leader programs and handbooks. All airmen have some contact with physical training leaders through mandatory unit physical training sessions. In addition, PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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airmen not meeting fitness standards and weight standards attend mandatory nutrition counseling programs that include guidance on dietary supplements. Reasons for use were consistent across the four categories of supplements, as showed in Figure B-17. The number one reason cited was to promote health (51 percent). The second reason was weight loss, third was increasing strength, lean muscle mass, and stamina, and finally improving memory and increasing cognition and alertness. Only 8 percent of airmen completing the survey reported adverse effects or any adverse reactions. Less than 15 percent of airmen who reported having an adverse reaction or event actually reported this event to a physician. The most common reported side effect was heart palpitations, followed by anxiety and dehydration. Of the four respondents who reported having a heart attack, only three indicated they reported this to their doctor. Heart attacks were in fact the only adverse effect reported to physicians; 85 percent of survey participants did not report heart palpitations. The adverse events reported to health professionals is shown in Figure B-18. In summary, most USAF members, 70 percent, are using some type of dietary supplement. Most spend between $10–$50 monthly on dietary supplements, and most are purchased on the military installation, 60 percent. Members receive information on supplements from magazines and family and friends, not their health care providers. The most common reasons cited for using supplements are to improve health, lose weight, increase lean mass, and gain strength. The majority of USAF members do not report adverse effects; the most common effects were palpitations, anxiety, dehydration, and nausea or vomiting. Seventy-nine percent of responders reported never having received any training on dietary supplements.

FIGURE B-17 Primary reasons for use across supplement categories

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APPENDIX B

B-65

25%

Heart attack (n=4)

75% 83%

Loss of consciousness/fainting (n=6)

17% 57%

Blood in urine (n=7)

43% 89%

Heat exhaustion/heat injuries (n=9)

11% 90%

Visual disturbances (n=20)

10% 92%

Problems with heat tolerance (n=20)

8% 70%

Numbness or tingling of arms or legs (n=25)

30% 79%

Breathing difficulties (n=25)

21% 86%

Chest pain (n=43)

14%

Muscle cramping or pain (n=47)

14%

86% 88%

Tremors (n=76)

12%

Abdominal pain (n=86)

12%

88% 93%

Diarrhea (n=92)

7% 88%

Dizziness or confusion (n=98)

12% 86%

Dehydration (n=116)

14% 89%

Nausea/vomiting (n=137)

11%

Anxiety (n=170)

11%

89% 85%

Palpitations (fast heart beat) (n=182)

15%

0%

10%

20%

30%

40% Reported

50%

60%

70%

Did not report

FIGURE B-18 Adverse effects reports

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80%

90%

100%

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

REFERENCES Bovill, M. E., W. J. Tharion, and H. R. Lieberman. 2003. Nutrition knowledge and supplement use among elite U.S. army soldiers. Mil Med 168(12):997-1000. Burke, J., G. Seda, D. Allen, and T. Knee. 2007. A case of severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement. Mil Med 172(6):656-658. Miller, S. 2004. Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements. Mil Med 169(2):87-93. Pittler, M. H., K. Schmidt, and E. Ernst. 2005. Adverse events of herbal food supplements for body weight reduction: A systematic review. Obes Rev 6(2):93-111. Timbo, B. B., M. P. Ross, P. V. McCarthy, and C. T. Lin. 2006. Dietary supplements in a national survey: Prevalence of use and reports of adverse events. J Am Diet Assoc 106(12):1966-1974.

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REPORTED USE OF DIETARY SUPPLEMENTS IN THE LAST 12 MONTHS AMONG U.S. ACTIVE DUTY MILITARY PERSONNEL IN FOUR SERVICES WORLDWIDE Bernadette M. Marriott, Ph.D.,1,2 Christine Goertz Choate D.C., Ph.D.,3 Laurel Hourani, Ph.D., M.P.H.,4 and Robert B. Bray, Ph.D.4 INTRODUCTION Use of dietary supplements (DS) has been included in nationally representative surveys of the civilian population by the National Center for Health Statistics (NCHS), Center for Disease Control and Prevention (CDC), beginning with the first National Health and Nutrition Examination Survey (NHANES I) (Block et al., 1988) to the currently fielded survey (NCHS, 2005), and in the NCHS’s National Health Interview Surveys (NHIS) in the late 1980s (Subar and Block, 1990) and early 1990s (Slesinski et al., 1995). These surveys have used different time frames of reference for DS use and, while not directly comparable, (Radimer, 2003, 2005; Yetley, 2007) indicate that civilian adult use of vitamin and mineral supplements has increased from approximately 23 percent and 35 percent reporting regular use in the early to late 1970s (Block, 1988; Koplan et al., 1986) to 40 percent and then 52 percent reporting having taken a DS in the last month from the late 1980s through 2000 (Ervin et al., 1999, 2004; Radimer et al., 2004). The NHIS found a slight decline in adult use of vitamin and mineral supplements over the 12 months prior to the survey from 51 percent to 46 percent in the late 1980s to early 1990s (Slesinski et al., 1995; Subar and Block, 1990). The U.S. Department of Agriculture (USDA) also included DS use in their nationally representative Continuing Survey of Food Intake by Individuals (CSFII: 1994–1996) where approximately 56 percent of women and 42 percent of men reported any vitamin or mineral DS with varying frequency categories but no time reference (USDA, 1999). None of the NCHS or USDA surveys include institutionalized persons or military personnel (NCHS, 2002a,b, 2004, 2005). Less data on adult civilian use of botanical and other supplement types is available because these types of DS have only been included in NCHS surveys since 1999 (Radimer, 2003, 2005; Radimer et al., 2000). Other studies have focused on botanical and nutrient DS use by civilians with specific health conditions (Bailey et al., 2003; Barone et al., 2001; Fairfield and Fletcher, 2002; Ford, 2001; Fraunfelder, 2004; Hercberg et al., 2004; Miller et al., 2005; underling in millerUSPSTF, 2003; Yeh et al., 2003) or of specific ages (Executive Summary, 2004; Fiatarone Singh et al., 2000; Houston et al., 1997). A recent National Institutes of Health (NIH) State-ofthe-Science Conference (NIH State-of-the-Science Panel, 2007) discussed the role of multivitamin and mineral DS in chronic disease prevention based on an evidence-based review (Huang et al., 2006, 2007). Few studies outside of the present IOM report have described the use of DS by military personnel (Arsenault and Kennedy, 1999; Bathalon et al., 2000; Bovill et al., 2003; Deuster et al., 2003; Flakoll et al., 2004; Lieberman et al., 2000). Here we describe the use of DS reported by active duty military personnel from four branches of the service as part of a worldwide represenAbt Associates, Inc., Durham, NC 27703, and Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. 2 Corresponding author: Bernadette M. Marriott, Ph.D., Principal Associate/Scientist, Abt Associates Inc., Durham, NC 27703, e-mail: [email protected]. 3 Palmer College of Chiropractic, Davenport, IA 52803. 4 Research Triangle Institute International, Research Triangle Park, NC 27709. 1

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

tative survey of health-related behaviors (Bray et al., 2005). We asked participants about their use of eight DS categories and also their reasons for using supplements. Our data were collected to allow interpretation across multiple timeframes. Here we present the results of once per week or more DS use over the 12 months prior to the survey. Methods Sample and Study Design Questions discussed here on DS use were included in the 2005 Department of Defense (DoD) Survey of Health-Related Behaviors Among Active Duty Military Personnel (Bray et al., 2006). The 2005 survey was the ninth in a survey series that began in 1980. The overall focus of the surveys has been substance use with an emphasis on worldwide active duty personnel’s selfreported use of alcohol, illicit drugs, tobacco, related health effects, and demographics of the respondents. The 2005 survey included questions on substance use and also addressed selected Healthy People 2010 objectives (DHHS, 2000). All respondents completed the questionnaire anonymously and voluntarily. The study was approved by the surgeon general's human subject research review board and Research Triangle Institute’s institutional review board. The sample population for the survey were all active duty military personnel, except recruits, service academy students, individuals absent without official leave, incarcerated individuals, and persons whose station had been changed permanently when the data were collected (1,300,039 persons). The overall sampling design was a stratified cluster sample of worldwide military installations with stratified sample of personnel within clusters (installations). The sampling frame was based on personnel data obtained from the Defense Manpower Data Center. The sampling was done in two stages. In the first sampling stage 60 major military installations with 500 or more personnel were selected. These installations were stratified by service (Army, Navy, Marine Corps, Air Force) and world region (continental United States or outside the continental United States, afloat status for Navy). The second sampling stage was based on selection of military personnel stratified by military pay grade groups, including three enlisted pay grade groups (E1–E3, E4–E6, E7–E9) and three officer pay grade groups (W1–W5, O1–O3, O4–O10) at the selected installations. Due to their smaller numbers in the active duty military, we oversampled women and officers. Military liaison officers at each installation coordinated the survey. Data was collected at group sessions at the selected installations where respondents completed the 50-minute questionnaire, which was administered by civilian project team members. Those eligible personnel who did not attend group sessions at the installations received a questionnaire by mail. Individuals at smaller installations and those living in remote situations also received the questionnaire by mail. The mailed questionnaire packet included full explanation of the survey’s purpose, anonymity, and instructions for voluntarily completing and returning it. The target sample size was 40,000 individuals with 90 percent (36,000) on site at major installations and 10 percent (4,000) by mail at small installations or remote sites. The final sample included 16,146 military personnel (Army: 3,639; Navy: 4,627; Marine Corps: 3,356; Air Force: 4,524). Table B-9 shows basic composition of the sample by service, gender, age, and race or ethnicity. The overall response rate was 51.8 percent. As is not unexpected with surveys of this size, the response rate differed significantly from the sample design. We found higher response rates in females than males (gender), officers than enlisted persons (rank), and Navy and Air Force

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APPENDIX B

B-69

than the Army and Marines (service). To account for this difference in response distribution from the original sample distribution as well as differential answer patterns on the questionnaire, the data for the survey were weighted. Without weighting, there was a potential for nonresponse bias in the data. As an example, the reported prevalence of DS use among junior enlisted persons would be biased if females responded at a higher rate and reported lower levels of DS use than males. Specifically, to account for the potential biasing effects of differential nonresponse, the data for each survey were weighted to represent the population of eligible active duty personnel, and adjustments were made accordingly. To develop the nonresponse adjustment factors we obtained updated counts of military personnel and applied eligibility rates to these new personnel counts for the sampling strata defined by the intersection of service, region, gender, and pay grade groups. Adjustment factors were calculated and applied to the weights to correct for differences in the proportion responding in the sample relative to the proportion in the population. The adjusted sampling weights were used in all data reported in this section. Sample design, weighting, and specific information about the overall calculations are in the final study report (Bray et al., 2006). Variables The self-administered questionnaire included 166 questions and was designed for optical scanning to reduce data entry error. The survey included four questions on DS use: frequency of use of DS categories, reasons for using these DS, sources of DS information, and reporting of DS use to health care professionals. The DS questions on the frequency of use and reason for use of DS specifically queried use of eight intended-use, or ingredient-based (Yetley, 2007) DS categories in the 12 months prior to the survey: multiple vitamins and minerals with at least six ingredients in each product (MVMs) (Lewis et al., 1999), individual vitamins or minerals, antioxidants, body-building supplements, herbal supplements, weight-loss products, joint health and arthritis products, performance-enhancing products, and other supplements not included in the previous categories. These DS questions included selected, specific, nonexhaustive examples of each DS category. For analyses, we combined responses to all categories into “use of any DS.” Use of each DS category was identified by the respondent as two or more times per day, once a day, every other day, once a week, and once a month in the 12 months prior to the survey. Data reported here represent regular DS use at least once a week for the last 12 months.

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

17.6 33.7 27.5 18.1 3.2 60.7 21.8 10.5 7.0

Age 20 or younger 21–25 26–34 35–44 45+

Race/Ethnicity White, non-Hispanic African American, non-Hispanic Hispanic Other 60.9 18.8 8.0 12.4

12.8 30.7 31.0 21.3 4.1 (1.9) [2,658] (1.7) [787] (0.6) [605] (2.0) [577]

(1.5) [307] (1.8) [1,167] (1.7) [1,262] (1.9) [1,467] (0.4) [424]

85.7 (1.3) [3,341] 14.3 (1.3) [1,286]

Navy

Air Force

65.1 11.1 13.7 10.1

21.8 42.9 25.0 9.4 0.9

(2.6) [2,090] 71.5 (2.1) [3,057] (0.7) [466] 14.8 (2.0) [668] (1.8) [528] 5.6 (0.6) [409] (1.1) [263] 8.2 (0.6) [390]

(1.9) [298] 7.9 (0.9) [284] (2.1) [909] 28.6 (2.5) [1,132] (1.5) [941] 34.9 (1.8) [1,117] (0.9) [1,011] 24.5 (1.6) [1,644 (0.1) [197] 4.1 (0.9) [347]

93.9 (0.7) [2,767] 80.4 (1.1) [3,193] 6.1 (0.7) [589] 19.6 (1.1) [1,331]

Marine Corps

64.4 17.6 8.8 9.2

14.1 32.6 30.3 19.7 3.4

(1.2) [9,855] (1.0) [2,633] (0.5) [2,004] (0.6) [1,654]

(1.1) [1,298] (1.2) [4,300] (1.0) [4,312] (1.1) [5,083] (0.4) [1,153]

85.2 (0.7) [12,119] 14.8 (0.7) [4,027]

Total DoD

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*Table displays the percentage of military personnel in each service by characteristic. The standard error of each estimate is presented in parentheses; number of respondents who completed a usable questionnaire is presented in brackets. SOURCE: 2005 Department of Defense (DoD) Survey of Health-Related Behaviors Among Military Personnel.

(2.4) [2,041] (1.8) [712] (0.9) [462] (0.6) [424]

(2.6) [409] (2.2) [1,092] (1.8) [992] (2.4) [961] (0.7) [185]

85.7 (1.6) [2,818] 14.3 (1.6) [821]

Army

Sex Male Female

Characteristic

Service

TABLE B-9 Characteristics of the Eligible Active Duty Military Population Percentage (Standard Error) and [Survey Sample Size] *

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APPENDIX B

B-71

Covariates and Statistical Analyses For this chapter, tables include information on demographic and lifestyle characteristics that civilian studies have previously reported as associated with DS use (Balluz et al., 2000; Block, 1988; Ervin et al., 1999; Koplan et al., 1986; Lyle et al., 1998; Radimer et al., 2004; Rock, 2007; Slesinski et al., 1995; Slesinski et al., 1996; Subar and Block, 1990; USPSTF, 2003). The demographic characteristics: gender, age (< 20, 21–25, 26–34, 35–43, 44+ years), race/ethnicity (white, non-Hispanic; black, non-Hispanic; Hispanic; and other), education (high school or equivalent or less, some college no degree, 4-year college degree or equivalent or higher), and body mass index (BMI) (< 25.0; > 25.0 <30.0; >30.0) are presented. BMI (weight in kilograms divided by squared height in meters) was calculated using respondents self-reported height (in feet and inches) and weight (in pounds) without shoes. At least annually, military personnel have their height and weight measured. Most military personnel more closely monitor their weight than civilians because of concerns about meeting military body composition standards (Marriott and Grumpstrup-Scott, 1992). Also included in the tables that follow are data on four lifestyle characteristics previously associated with DS use: leisure time physical activity (none, less than moderate, moderate, vigorous), diet: consuming fruit and vegetables (<3 times/day, > 3 times/day), cigarette use (never, former, current), and alcohol consumption in the last 30 days (never, 1–3 times/month, > 4 times per month). The data were analyzed using SUDAAN (SUrvey DAta ANalysis) software release 9.0 (RTI, 2004). We used t-tests to assess statistical difference. Statistically significant results at the P < .05 level are reported. Results Over 60 percent of active duty military personnel reported using a DS at least once a week over the last 12 months. (See Table B-10.) For all service branches MVMs were most commonly used. However, fewer army personnel reported using a DS in general and MVMs in particular than personnel in the other services. A higher percent of Marine Corps personnel reported using bodybuilding, weight loss, and performance-enhancing supplements than did the personnel in the other services. Figure B-19 illustrates the gender differences in categorical DS use. A significantly higher percent of female personnel reported using any DS, MVMs, individual vitamin and minerals, and weight-loss DS (P < .05); whereas significantly more male personnel reported using bodybuilding and performance-enhancing DS (P < .05). Earlier logistic regression analysis confirmed this association (Marriott et al., 2008). Table B-11 presents nine demographic and lifestyle characteristics and use of the eight DS categories, other DS, and any DS among active duty personnel. Age was significantly associated with use of specific DS categories (Marriott et al., 2008). Older (44+ yrs.) personnel were more likely to use individual vitamin and mineral DS, antioxidants, and joint health/arthritis products, whereas younger personnel were more likely to use bodybuilding supplements (< 20 through 43 years), weight-loss products, and performance-enhancing supplements (both categories: < 20 through 34 years). Military personnel who did not currently smoke cigarettes, drink alcohol, and who consumed more fruit and vegetables, and engaged in moderate or vigorous leisure time physical activity were significantly more likely to use DS (Marriott et al., 2008).

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DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

8.8 (0.4)

(1.1) (1.7) (1.3) (1.4) (1.0) (0.9) (0.5) (1.1)

10.4 (1.2)

47.5 28.3 22.8 19.1 18.8 13.0 9.9 8.7

Navy 61.3 (1.1)

11.6

41.8 24.6 20.3 28.4 21.1 12.2 8.2 10.9 576,284.37

257,137.05 198,792.38 196,583.17 112,160.03 81,686.442 172,205.17 80,448.30 86,875.39

Marine Corps 61.3 434,580.20

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(1.5) (0.8) (0.6) (1.0) (1.0) (0.7) (0.6) (0.7) 7.2 (0.5)

49.9 28.0 20.9 17.8 15.9 11.3 7.6 5.6

Air Force 63.3 (1.2)

PREPUBLICATION COPY: UNCORRECTED PROOFS

SOURCE: 2005 Department of Defense (DoD) Survey of Health-Related Behaviors Among Military Personnel.

Other supplements

39.8 25.8 19.1 20.9 18.0 10.8 8.4 9.7

Multivitamin/multimineral DS Individual vitamin and mineral DS Antioxidants Bodybuilding DS Weight-loss DS Herbal supplements Joint health/arthritis products Performance enhancing DS

(1.6) (1.0) (0.6) (1.5) (0.8) (0.6) (0.7) (1.2)

Army 56.3 (1.6)

DS Category Any supplements

Service

(1.0) (0.6) (0.5) (0.7) (0.5) (0.4) (0.3) (0.6) 9.1 (0.4)

45.0 26.9 20.8 20.5 18.0 11.7 8.5 8.4

Total DoD 60.3 (0.8)

86,875

434,580 257,137 198,792 196,583 172,205 112,160 81,686 80,448

Weighted sample size 576,284

TABLE B-10 Percentage (with Standard Error in Parentheses) of Category of Dietary Supplement Use at Least once a Week over Previous 12 Months Among Active Duty Military Personnel by Service

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APPENDIX B

Whether compared within pay grade or current military position, DS use by officers and enlisted personnel is similar (see Table B-12). More officers reported using MVMs, individual vitamins and minerals, and joint health and arthritis DS than did enlisted personnel. Body building DS, weight loss supplements and performance-enhancing DS were reported more often by enlisted personnel than officers. Odds ratios in a earlier publication indicated that younger age was a predictor for use of the same DS categories as enlisted personnel whereas being in the oldest age group (44+) was significantly associated with use of individual vitamins and minerals, antioxidants, and joint health and arthritis products (Marriott et al., 2008). Figure B-20 illustrates the reasons stated for using DS. Military male and female personnel reported that they predominantly use DS to improve their health or supplement their diet. However, 25 percent stated that they used DS to improve physical performance, while 19 percent reported taking DS to lose weight. More women stated that the reason they took DS was to lose weight and improve their overall health; whereas more men than women stated improving physical performance was their reason for DS use.

FIGURE B-19 Reported use of dietary supplement categories at least once a week over previous 12 months among active duty military personnel by gender.

PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

Characteristic Gender Male Female Age (years) < 20 21–25 26–34 35–43

Race/ethnicity White, non-Hispanic Black, non-Hispanic Hispanic Othera Education High school equivalent or less Some college, no degree 4-year college or higher

44+

DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

46.3 (1.06)

42.6 (1.52)

40.3 (1.71) 44.6 (2.22)

35.1 (1.07)

46.7 (0.98)

53.3 (1.94)

58.3 (1.39)

58.2 (1.79) 62.1 (1.57)

52.5 (1.14)

62.6 (0.77)

65.0 (2.45)

58.4 (1.90)

60.8 (0.90)

68.3 (1.76)

33.0 (2.22) 41.4 (1.35) 48.7 (1.25) 50.9 (0.94)

43.0 (0.89) 56.2 (1.55)

58.3 (0.78) 71.4 (1.32)

53.4 (2.05) 58.4 (1.59) 62.0 (1.17) 63.8 (0.88)

Multivitmin/ Multimineral Supplements

Any Dietary Supplment

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20.1 (1.51)

21.9 (0.76)

17.6 (0.71)

20.6 (1.66) 23.7 (1.61)

20.2 (0.94)

20.5 (0.47)

32.1 (2.09)

19.1 (1.69) 19.8 (0.83) 19.9 (0.89) 22.4 (0.87)

20.5 (0.53) 22.4 (0.89)

19.1 (2.08)

21.5 (0.78)

22.9 (1.03)

23.2 (1.26) 21.8 (1.13)

19.0 (1.35)

20.3 (0.81)

6.5 (1.08)

25.7 (1.59) 25.6 (1.09) 19.9 (1.02) 12.1 (0.71)

23.0 (0.78) 6.2 (0.59)

13.2 (1.75)

20.5 (0.66)

19.1 (0.77)

23.2 (1.14) 18.3 (1.72)

18.6 (0.91)

17.1 (0.47)

8.9 (1.70)

17.9 (1.37) 20.0 (0.71) 19.0 (0.78) 15.3 (0.73)

16.8 (0.48) 25.0 (1.08)

9.2 (0.95)

12.8 (0.74)

11.2 (0.65)

12.5 (0.94) 14.1 (1.07)

11.8 (0.97)

11.2 (0.48)

12.9 (1.51)

10.9 (1.02) 13.3 (0.92) 10.2 (0.82) 11.7 (0.66)

11.8 (0.45) 11.0 (0.76)

PREPUBLICATION COPY: UNCORRECTED PROOFS

26.4 (1.87)

28.1 (0.66)

23.7 (0.94)

27.2 (1.71) 31.5 (1.49)

27.8 (1.23)

26.0 (0.72)

37.5 (1.90)

24.4 (1.70) 27.8 (1.08) 24.6 (0.90) 28.6 (1.13)

25.2 (0.67) 36.6 (1.12)

Individual Weight-loss Herbal Vitamin & Antioxidants Bodybuilding Supplements Supplements Mineral Supplements Supplements

9.6 (1.10)

8.3 (0.47)

7.1 (0.49)

8.3 (0.76) 9.2 (1.14)

7.6 (0.75)

8.7 (0.42)

5.4 (0.94) 7.2 (0.59) 8.0 (0.53) 12.2 (0.59) 16.5 (1.23)

8.8 (0.35) 7.1 (0.61)

Joint Health/ Arthritis Products

6.5 (0.90)

8.1 (0.72)

11.0 (0.80)

10.5 (1.19) 9.3 (1.18)

8.1 (1.00)

8.1 (0.56)

3.9 (0.87)

10.9 (1.51) 11.7 (0.79) 7.1 (0.78) 4.0 (0.40)

9.4 (0.63) 2.4 (0.36)

PerformanceEnhancing Supplements

6.8 (1.14)

9.5 (0.52)

10.3 (0.67)

11.6 (1.37) 10.8 (1.37)

9.6 (0.73)

8.5 (0.41)

9.2 (0.96)

10.3 (1.40) 10.5 (0.55) 8.7 (0.58) 6.8 (0.48)

9.3 (0.42) 8.2 (0.62)

Other Supplements

TABLE B-11 Percentage (with Standard Error in Parentheses) of Category of Dietary Supplement Use at Least Once per Week over Previous 12 Months by Active Duty Military Personnel, by Demographic and Lifestyle Factors

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25.0–29.9 > 30.0 Physical Activityc None Less than moderate Moderate Vigorous

Characteristic BMIb < 25.0

41.8 (1.57) 47.6 (0.77)

40.1 (1.16) 48.4 (1.26)

47.1 (1.14) 46.1 (1.78)

53.6 (1.25) 62.3 (1.29)

63.5 (1.03) 65.1 (1.54)

58.9 (1.43)

69.0 (1.43)

55.4 (1.57) 63.5 (0.68)

Multivitmin/ Multimineral Supplements

Any Dietary Supplment

TABLE B-11 continued

APPENDIX B

Copyright © National Academy of Sciences. All rights reserved.

23.1 (0.65) 22.5 (1.08)

17.5 (0.99) 19.1 (1.04)

19.0 (0.80) 21.9 (0.87)

25.3 (1.06)

25.7 (0.92) 21.4 (1.53)

11.6 (0.93) 16.4 (1.28)

18.7 (0.87) 21.8 (1.04)

11.7 (0.87)

20.2 (0.67) 35.6 (1.15)

13.9 (1.05) 17.1 (0.93)

10.2 (0.50) 20.4 (0.94)

10.2 (0.63)

13.3 (0.53) 12.8 (1.10)

8.6 (0.64) 10.2 (0.97)

10.5 (0.56) 12.5 (0.72)

11.2 (0.73)

PREPUBLICATION COPY: UNCORRECTED PROOFS

29.4 (0.62) 26.4 (1.38)

22.0 (1.27) 26.3 (1.36)

26.0 (1.09) 28.0 (0.90)

31.6 (1.21)

Individual Weight-loss Herbal Vitamin & Antioxidants Bodybuilding Supplements Supplements Mineral Supplements Supplements

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9.5 (0.44) 13.1 (1.06)

5.4 (0.52) 8.9 (0.70)

12.3 (0.87) 6.2 (0.35) 9.5 (0.49)

Joint Health/ Arthritis Products

10.7 (0.70) 9.1 (0.99)

4.6 (0.75) 5.8 (0.70)

7.1 (0.65) 9.4 (0.78)

4.1 (0.62)

PerformanceEnhancing Supplements

10.6 (0.59) 12.5 (1.15)

6.1 (0.74) 8.1 (0.81)

7.6 (0.69) 9.6 (0.56)

6.9 (0.70)

Other Supplements

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

23.2 (0.62)

20.3 (0.81) 17.7 (1.04) 20.2 (0.76)

20.2 (0.47) 20.9 (0.77) 21.6 (1.34)

34.2 (3.00) 12.4 (2.15)

Antioxidants

23.2 (1.14)

21.5 (1.16) 17.2 (1.05) 19.4 (0.91)

20.1 (0.73) 19.8 (0.87) 20.8 (1.63)

29.5 (2.67) 11.9 (1.73)

Bodybuilding Supplements

18.7 (0.70)

19.5 (0.70) 14.8 (0.81) 19.4 (0.87)

17.9 (0.46) 17.1 (0.73) 18.1 (1.25)

21.0 (2.96) 12.9 (1.77)

WeightLoss Supplements

13.1 (0.57)

12.4 (0.58) 10.3 (0.66) 11.2 (0.67)

11.3 (0.40) 11.0 (0.57) 12.7 (1.14)

19.4 (2.33) 11.1 (2.01)

Herbal Supplements

9.4 (0.57)

6.9 (0.51) 6.7 (0.58) 8.9 (0.52)

8.4 (0.33) 8.7 (0.45) 11.6 (0.97)

13.1 (2.17) 8.9 (1.31)

Joint Health/ Arthritis Products

10.4 (0.85)

9.1 (0.72) 6.3 (0.88) 7.6 (0.77)

8.2 (0.59) 7.6 (0.67) 9.7 (1.01)

12.7 (2.25) 6.0 (1.37)

PerformanceEnhancing Supplements

Self-reported height and weight were converted to body mass index (kg/m2).

Copyright © National Academy of Sciences. All rights reserved.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Reported leisure time physical activity for 20 minutes or more for 3 or more days per week: moderate burns 3.5–7kcal/min or the equivalent of 3 to 6 metabolic equivalents (METS); vigorous burns more than 7 kcal/min or the equivalent of 6 or more METS. SOURCE: 2005 Department of Defense (DoD) Survey of Health-Related Behaviors Among Military Personnel, From Marriott et al (2008).

c

b

9.7 (0.67)

9.5 (0.65) 8.2 (0.66) 9.2 (0.44)

8.9 (0.35) 8.9 (0.57) 9.4 (0.98)

14.5 (2.24) 8.8 (2.21)

Other Supplements

Other Race/ethnicity includes American Indian, Alaska native, Asian (e.g., Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese), Native Hawaiian, other Pacific Islander (e.g., Samoan, Guamanian, Chamorro) and other.

28.2 (0.96)

44.9 (1.26)

61.0 (1.18)

a

24.8 (1.14) 25.8 (1.06) 26.5 (0.87)

38.3 (1.35) 42.7 (1.58) 46.9 (1.35)

Total

26.3 (0.64) 28.2 (0.84) 27.3 (1.35)

41.0 (2.45) 20.9 (2.32)

58.1 (2.47) 28.3 (2.31) 44.4 (0.99) 47.9 (1.02) 49.7 (1.81)

Any Dietary Supplement

Individual Vitamin & Mineral Supplements

Multivitamin/ Multimineral Supplements

DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

Characteristic Diet (Fruits & veg) < 3 times/day 69.2 (2.38) > 3 times/day 43.0 (2.91) Cigarette smoking Never 59.9 (0.86) Former 62.4 (1.01) Current 64.3 (1.94) Alcohol consumption in last 30 days Never 55.2 (1.14) 1–3 times/month 57.6 (1.58) > 4 times/month 61.5 (1.09)

TABLE B-11 continued

B-76

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B-77

3,954 399 1,442 2,113

Total Officer* W1–W5 O1–O3 O4–O10

Current Military Job Total Enlisted Infantry, gun crew, or seamanship specialist Electronic equipment repairman Communications Health care specialist Other technical Functional support Electrical/mechanical Craftsman Service and Supply Nonoccupational

57.9 (0.8) 54.1 (1.6) 59.0 (0.8) 61.1 (1.3)

12,190 2,593 6,376 3,221

Characteristic Pay Grade Total Enlisted E1–E3 E4–E6 E7–E9

Copyright © National Academy of Sciences. All rights reserved.

57.7 (2.7) 56.4 (2.0) 59.9 (2.3) 59.7 (2.3) 60.1 (1.8) 57.3 (1.5) 56.9 (1.0) 53.0 (2.9) 58.3 (2.0) 52.3 (4.2)

1,393

905 1,237 1,032 900 2,074 1,712 482 1,149 402

41.8 (2.1) 42.2 (2.8) 45.0 (2.8) 45.7 (2.5) 43.7 (1.8) 42.2 (1.1) 40.2 (3.0) 40.8 (1.5) 37.1 (3.5)

38.7 (2.8)

41.9 (1.0)

58.4 (1.3) 57.7 (4.5) 58.9 (2.1) 57.5 (1.5)

42.2 (0.9) 35.5 (1.7) 44.0 (1.0) 49.3 (1.6)

22.6 (1.8) 27.1 (2.5) 27.4 (2.0) 29.1 (2.0) 25.9 (1.6) 25.8 (1.6) 23.6 (2.8) 27.1 (1.6) 23.2 (3.3)

24.7 (2.1)

25.9 (0.7)

29.9 (1.1) 32.0 (2.5) 28.3 (1.7) 31.8 (1.6)

26.3 (0.7) 25.8 (1.4) 26.5 (0.7) 26.8 (1.1)

19.5 (1.7) 18.8 (1.5) 19.8 (1.8) 22.6 (1.7) 16.7 (1.0) 21.8 (1.4) 17.6 (2.0) 20.0 (1.4) 22.5 (2.7)

20.6 (1.9)

19.9 (0.5)

22.8 (0.9) 25.7 (3.3) 20.2 (1.3) 26.3 (1.6)

20.3 (0.5) 19.3 (1.0) 20.8 (0.6) 20.7 (0.7)

Antioxidants

22.6 (2.0) 20.3 (1.6) 17.1 (2.1) 22.4 (1.8) 14.3 (1.1) 23.6 (1.1) 19.3 (2.1) 18.9 (1.6) 20.4 (3.6)

28.8 (2.4)

21.1 (0.7)

15.8 (1.3) 15.3 (3.3) 20.9 (1.7) 7.9 (0.8)

21.4 (0.7) 24.4 (1.3) 21.8 (0.9) 12.8 (0.8)

Bodybuilding DS

19.2 (1.6) 18.5 (1.4) 18.8 (1.5) 22.3 (2.2) 18.2 (0.9) 20.2 (1.0) 18.3 (2.2) 21.8 (2.1) 16.9 (2.9)

19.4 (1.2)

19.5 (0.5)

9.9 (0.7) 11.2 (1.5) 11.5 (1.1) 6.9 (1.0)

19.7 (0.5) 18.4 (1.1) 21.2 (0.5) 15.3 (0.8)

WeightLoss DS

PREPUBLICATION COPY: UNCORRECTED PROOFS

57.6 (0.9)

11,286

68.4 (1.3) 68.1 (4.4) 69.2 (2.3) 67.2 (1.5)

Any DS

Sample Size

Multivitamin/ Multimineral Supplements

Individual Vitamin & Mineral DS

10.8 (1.2) 11.9 (1.3) 11.7 (1.4) 13.0 (1.4) 9.2 (0.8) 12.8 (1.3) 10.9 (1.5) 10.5 (1.1) 12.9 (2.1)

13.0 (1.5)

11.7 (0.4)

10.1 (0.7) 10.2 (2.0) 9.7 (0.9) 10.7 (0.8)

12.0 (0.4) 12.6 (0.9) 12.2 (0.6) 9.8 (0.6)

Herbal DS

6.9 (0.9) 8.5 (1.1) 7.7 (1.2) 9.4 (1.3) 6.3 (0.7) 7.8 (0.8) 9.2 (1.5) 5.8 (0.7) 8.2 (2.3)

7.8 (1.3)

7.6 (0.4)

12.0 (0.7) 17.0 (2.3) 9.5 (1.1) 15.0 (0.8)

7.8 (0.3) 6.5 (0.6) 7.6 (0.3) 12.3 (0.7)

Joint Health/ Arthritis Products

7.6 (1.2) 8.1 (1.4) 4.8 (1.1) 10.6 (1.6) 5.7 (0.9) 9.6 (1.2) 6.8 (1.4) 7.6 (0.9) 9.0 (2.5)

14.2 (1.6)

8.7 (0.6)

5.0 (0.7) 5.1 (1.0) 6.4 (1.0) 3.0 (0.6)

9.1 (0.6) 10.7 (1.0) 9.3 (0.8) 4.1 (0.5)

PerformanceEnhancing DS

TABLE B-12 Percentage (with Standard Error in Parentheses) of Dietary Supplement Use at Least Once a Week over Previous 12 Months as Reported by Active Duty Military Personnel, by Pay Grade and Current Military Job

APPENDIX B

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Individual Vitamin Multivitamin/ & Mineral Multimineral DS Supplements 58.4 (1.3) 30.0 (1.2) 57.3 (7.0) 28.0 (4.7) 56.1 (2.7) 27.5 (2.0) 63.1 (6.5) 19.5 (3.8) 54.0 (3.3) 28.7 (2.1) 57.0 (3.4) 27.7 (2.6) 60.6 (2.9) 37.5 (3.3) 63.5 (3.6) 27.8 (3.8) 60.9 (5.4) 39.0 (3.2) Antioxidants 22.8 (0.9) 27.3 (5.0) 19.0 (1.6) 19.6 (4.7) 19.9 (2.0) 25.4 (2.6) 30.7 (3.0) 21.8 (3.4) 27.5 (3.3)

Bodybuilding DS 15.6 (1.2) 4.3 (1.8) 18.8 (2.4) 16.6 (5.7) 13.8 (1.9) 8.8 (2.5) 12.0 (1.8) 17.9 (4.6) 16.6 (3.2)

WeightLoss DS 9.8 (0.7) c 8.3 (1.5) 8.5 (3.0) 11.7 (2.2) 5.4 (2.0) 10.1 (1.4) 10.5 (2.2) 11.1 (1.9)

DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

Herbal DS 10.0 (0.7) 12.0 (5.0) 7.6 (1.2) 8.5 (2.9) 11.4 (2.3) 15.0 (3.7) 8.1 (2.1) 13.7 (3.6) 9.1 (1.5)

a

Copyright © National Academy of Sciences. All rights reserved.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Totals are not equal due to missing data on some individual questionnaires. Excludes two individuals who were trainees where the sample size was too small to present estimates. b Excludes 53 officers whose military job was classed as nonoccupational where the sample size was too small to present estimates. c Estimate suppressed due to small sample size. SOURCE: 2005 Department of Defense (DoD) Survey of Health-Related Behaviors Among Military Personnel.

%

Sample Any Characteristic Size DS Total Officer+ 3,384 68.5 (1.4) General officer 212 71.2 (5.1) Tactical operations 1,050 66.9 (2.5) Intelligence 182 71.1 (6.3) Engineering/maintenance 601 63.7 (3.1) Scientist or professional 272 66.4 (4.1) Health care 270 72.3 (3.1) Administrator 477 72.0 (2.5) Supply, procurement, or 320 68.7 (5.2) allied officer

TABLE B-12 Continued

B-78

Joint Health/ Arthritis Products 12.0 (0.8) 16.9 (4.7) 12.0 (1.6) 15.1 (4.4) 8.9 (1.2) 10.4 (2.0) 13.3 (1.7) 10.4 (1.7) 13.1 (3.1)

PerformanceEnhancing DS 4.8 (0.6) 3.7b (2.0) 6.2 (1.2) 3.0 (1.6) 3.6 (1.0) 3.0 (1.4) 3.6 (1.4) 4.8 (2.0) 6.1 (1.8)

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

APPENDIX B

B-79

Males Females

69.4

77.6

80

67.7

Total

11.9 18.2 12.9

29.6 19.8

17.8

3

18.9

25.5 14.2

7.4

7.7 6.3

20

5.2 7.1

27.9

40

22.2

60

7.4

Percent Personnel

100

0 Supplement diet/ improve health

Improve mental health

Improve cognitive function

Improve physical performance

Increase muscle mass

Lose weight

Help with special health problem

Reasons for DS Use

FIGURE B-20 Reported reasons for use of any dietary supplement in the last 12 months among active duty military personnel by gender

Table B-13 shows that of those personnel who used DS, approximately 31 percent took a supplement daily in the last 12 months. Almost 13 percent reported taking DS two or more times each day. Statistically significant differences exist in frequency of use among personnel in the service branches. Nearly 37 percent of personnel told their physician about their use of DS, with 28 percent reporting that they told a nurse practitioner/physician assistant and 13 percent stating that they entered their use of DS into their medical record. More female personnel than male personnel reported telling health care professionals about their DS use (Table B-14), and older personnel more commonly told health care professions about their DS use than did younger personnel (Marriott et al., 2008).

PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

6.8 (0.5)d 7.6 (0.4) 27.0 (1.3)b, d 13.2 (0.7)c, d

Once a week

Every other day

Once a day

Two times or more a day

12.4 (1.0) c

31.7 (1.1)a, c, d

8.1 (0.6)

7.6 (0.5)

7.3 (0.7)a, c

Navy

17.4 (1.4)a, b, d

26.1 (0.8)b, d

8.6 (0.6)d

6.9 (0.6)d

9.6 (0.9)b, d

Marine Corps

Copyright © National Academy of Sciences. All rights reserved.

Air Force

10.6 (0.8)a, c

35.9 (1.0)a, b, c

7.1 (0.4)c

8.6 (0.6)a, c

7.3 (0.4)a, c

PREPUBLICATION COPY: UNCORRECTED PROOFS

SOURCE: 2005 Department of Defense (DoD) Survey of Health-Related Behaviors Among Military Personnel.

b

Estimate is significantly different from the Army at the 95% confidence level. Estimate is significantly different from the Navy at the 95% confidence level. c Estimate is significantly different from the Marine Corps at the 95% confidence level. d Estimate is significantly different from the Air Force at the 95% confidence level.

a

9.6 (0.7)b, d

Once a month

Any Supplement Use

Army

12.8 (0.5)

30.7 (0.7)

7.7 (0.2)

7.6 (0.3)

8.3 (0.4)

Total DoD

TABLE B-13 Percentage (with Standard Error in Parentheses) of Frequency of Any Dietary Supplement Use over Previous 12 Months Among Active Duty Military Personnel by Service

B-80

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Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

B-81

APPENDIX B

TABLE B-14 Percentage (with Standard Error in Parentheses) of Active Duty Military Personnel Who Reported Informing Health Care Professionals About Dietary Supplement Use, by Gender, Service, and Health Professional Type2005 Department of Defense (DoD) Survey of HealthRelated Behaviors Among Military Personnel Service Health Care Type

Army

Medical Doctor Males 27.9 (2.2) Females 49.7 (3.9) Total 31.5 (2.4) Nurse Practitioner or Physician Assistant Males 17.5 (1.8) Females 37.9 (2.7) Total 20.9 (1.9) Psychiatrist Males Females Total Dentist Males Females Total Other Military Health Professionals Males Females Total Other Nonmilitary Health Professionals Males Females Total Indicated Use on Personal Health Record Males Females Total

Navy

Marine Corps

Air Force

Total DoD

29.7 (2.4) 47.3 (3.0) 32.6 (2.3)

24.0 (1.9) 42.4 (2.6) 25.3 (1.8)

46.1 (3.4) 60.8 (3.5) 49.6 (2.9)

33.0 (1.5) 53.3 (2.1) 36.6 (1.4)

14.6 (1.3) 24.0 (1.9) 16.2 (1.2)

10.7 (2.1) 25.4 (2.9) 11.7 (2.0)

27.5 (3.0) 43.1 (2.1) 31.3 (2.6)

18.6 (1.1) 35.9 (1.5) 21.7 (1.1)

3.7 (0.4) 5.6 (1.3) 4.0 (0.5)

3.7 (0.6) 5.5 (0.7) 4.0 (0.5)

2.3 (0.9) 8.0 (1.6) 2.7 (0.9)

3.5 (0.5) 4.8 (0.7) 3.8 (0.5)

3.5 (0.3) 5.4 (0.5) 3.8 (0.3)

9.4 (1.0) 17.5 (1.9) 10.8 (1.1)

8.9 (0.9) 15.1 (1.5) 10.0 (0.9)

7.7 (0.8) 10.6 (2.2) 7.9 (0.8)

16.1 (2.9) 25.8 (2.0) 18.4 (2.5)

10.9 (0.9) 20.0 (1.2) 12.5 (0.9)

10.8 (1.1) 16.3 (2.4) 11.7 (1.1)

12.5 (1.3) 14.9 (1.1) 12.9 (1.0)

12.2 (0.8) 17.4 (2.4) 12.6 (0.8)

11.9 (1.3) 16.0 (1.6) 12.9 (1.0)

11.8 (0.6) 15.9 (1.0) 12.5 (0.5)

6.2 (1.0) 11.3 (2.2) 7.1 (1.0)

5.6 (0.7) 7.2 (1.4) 5.9 (0.6)

3.7 (0.4) 10.2 (1.6) 4.2 (0.4)

4.4 (0.4) 6.4 (1.7) 4.9 (0.5)

5.2 (0.4) 8.2 (1.0) 5.7 (0.4)

7.8 (0.9) 16.3 (2.2) 9.2 (1.0)

9.5 (1.0) 20.6 (2.0) 11.3 (1.0)

7.3 (1.4) 15.7 (2.2) 7.9 (1.2)

17.8 24.7 19.5

(2.7) (1.1) (2.1)

11.0 (0.9) 20.8 (1.0) 12.8 (0.8)

NOTE: Only those who reported supplement use in the past 12 months are included. All items in table had a nonresponse rate >= 10%.

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B-82

DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

Discussion These data from a large (16,146 individuals), carefully structured, worldwide survey of active duty personnel indicated that 60 percent reported using at least one of eight categories of DS at least once a week over the previous 12 months. Multivitamin/multimineral, individual nutrient, and antioxidant DS were the most widely used supplement categories. Although internal military communications and media have indicated the potential health risk of bodybuilding, weight-loss, and performance-enhancing DS (Miller, 2004; Oh and Henning, 2003; Whitehead, 2000), many active duty service members reported using them. Based on this survey and our weighting of the data we estimated that approximately 198,600, 196,600, and 172,200 active duty personnel are currently regularly using bodybuilding, weight-loss and performanceenhancing DS, respectively. Herbal supplements are used relatively less frequently by active duty personnel (an estimated 112,160 individuals) perhaps as a result of both media attention to adverse events and negative results of clinical trials (Bent et al., 2006; Ernst, 1998; Hypericum Depression Trial Study Group, 2002; Turner et al., 2005; Valli and Giardina, 2002) as well as military policies on the use of some nonnutrient DS products (Farmer, 2002; Johnston, 2002; Miller, 2004). Individual surveys of specific military units have reported similar results to this worldwide survey. Among 2,215 male army cadets entering US Army Special Forces and Ranger training programs, 64 percent reported using DS at least once per week in the 3 months prior to the survey with almost 40 percent reporting using MVMs and 29 percent reporting performanceenhancing supplements and spending an average of $26 per month on DS (Arsenault and Kennedy, 1999). In highly trained Special Forces personnel (N=157) 90 percent reported using DS regularly but less than once per week in the 6 months prior to the survey; fewer of Special Forces support personnel reported DS use (76 percent) (Bovill et al., 2003). In a comparison of army studies reported by Lieberman and colleagues in this report (Lieberman et al., 2007) male personnel’s regular weekly use of DS over the 6 months prior to each survey differed with age and job type: 58 percent (2006–2007 armywide survey: n=553; mean age 30.9 yr; all job categories), 66 percent (2000 Special Forces: n=152; mean age=31.3; experienced soldiers with high physical and mental job demands); 72 percent (1999 Army War College: n=284; mean age= 44 yr; high mental job demands); 82 percent (1999 Ranger Unit: n=768; mean age: 23.6 yr; new soldiers with extremely high physical job demands). In an initial review of the data from the ongoing army-wide survey, more army women (71 percent) than men (58 percent) in all job categories reported DS use. Lieberman and colleagues similarly found that more army women (82 percent) than men (72 percent) who attended the Army War College reported taking DS. Soldiers invited to attent the ArmyWar College are typically older than the average soldier and have high mental job demands. Similar to the findings in our worldwide multiservice study, for both genders in all of these army studies, more individuals (23 to 52 percent) reported using MVMs than other DS categories (Lieberman et al., 2000, 2007). More civilians and military thus reported using nutrient supplements than any other categories of DS (Coates et al., 2007; Huang et al., 2006; NIH State-of-the-Science Panel, 2007). In our survey the weighted estimate of active duty personnel using nutrient supplements was 990,500 individuals compared with an estimated prevalence of 730,000 using the combined other six categories and unnamed other supplements5. In another analysis (Marriott et al., 2008) we found that when the data for these active duty military personnel respondents was adjusted to match the 5

These weighted estimates reflect that respondents can report using DS from more than one DS category.

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APPENDIX B

B-83

demographics of the civilian population in the U.S. census, that military personnel had a significantly higher prevalence of DS use than the most recently published data on civilians collected through the National Health and Nutrition Examination Survey (NHANES). Although 70 percent of active duty respondents indicated that their reason for using any DS was to improve overall health or supplement their diets, 26 percent also indicated that they used DS to improve physical performance. Increasing muscle mass and improving physical performance may be two reasons why military personnel have a higher prevalence of DS use than civilians. Similar to civilians, military personnel contend with the same day-to-day professional demands; in addition, military personnel must meet the requirements of regular physical performance testing and body composition standards. In a recent NIH State-of the-Science Conference, few positive associations were found for MVMs or single nutrients and health outcomes. The conference participants also cautioned against healthy individuals taking MVMs and single nutrients at above nationally recommended levels (Huang et al., 2006; Mulholland and Benford, 2007; NIH State-of-the-Science Panel, 2007; Rock, 2007; Yetley, 2007). Following the assessment of this conference, with at least 20 percent of active duty personnel living in remote areas or extreme environments (Defense Manpower Data Center, 2005) and over 575,000 active duty personnel using DS regularly each week, it is important for military health care providers to initiate discussion with their clients about their DS use. Over one-third of military personnel report that they are telling their doctors about their DS use, yet these individuals tend to be older personnel; whereas it is the younger personnel who report using those DS with higher health risk. Therefore, it is also important for military policy makers to more thoroughly examine the risks and benefits of DS use for military health and performance.

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REFERENCES Arsenault, J., and J. Kennedy. 1999. Dietary supplement use in U.S. Army Special Operations candidates.Mil Med 164(7):495-501. Bailey, L. B., G. C. Rampersaud, and G. P. A. Kauwell. 2003. Folic acid supplements and fortification affect the risk for neural tube defects, vascular disease and cancer: Evolving science. J Nutr 133(6):1961S-1968S. Balluz, L. S., S. M. Kieszak, R. M. Philen, and J. Mulinare. 2000. Vitamin and mineral supplement use in the United States. Results from the third National Health and Nutrition Examination Survey. Arch Fam Med 9(3):258-262. Barone, G. W., B. J. Gurley, B. L. Ketel, and S. R. Abul-Ezz. 2001. Herbal supplements: A potential for drug interactions in transplant recipients. Transplantation 71(2):239-241. Bathalon, G. P., S. M. McGraw, L. D. Hennessy, W. F. Barko, J. F. Creedon, and H. R. Lieberman. 2000. Comparison of reported nutritional supplement intake in two Army populations. JADA 100(9):A102. Bent, S., C. Kane, K. Shinohara, J. Neuhaus, E. S. Hudes, H. Goldberg, and A. L. Avins. 2006. Saw palmetto for benign prostatic hyperplasia. N Engl J Med 354(6):557-566. Block, G., C. Cox, J. Madans, G. B. Schreiber, L. Licrita, and N. Melia. 1988. Vitamin supplement use by demographic characteristics. Am J Epidemiol 127(2):297-309. Bovill, M. E., W. J. Tharion, and H. R. Lieberman. 2003. Nutrition knowledge and supplement use among elite U.S. army soldiers. Mil Med 168(12):997-1000. Bray, R. M., L. L. Hourani, K. L. Rae, J. A. Dever, J. M. Brown, A. A.Vincus, M. R. Pemberton, M. E. Marsden, D. L. Faulkner, and R. Vandermaas-Peeler. 2006. 2005 Department of Defense Survey of Health-Related Behaviors Among Active Duty Military Personnel. Final report. U.S. Department of Defense, Cooperative Agreement No. DAMD17-00-2-0057. Research Triangle Park, NC: RTI International. Coates, P. M., J. T. Dwyer, and A. L Thurn. 2007. Introduction to State-of-the-Science Conference: Multivitamin/mineral supplements and chronic disease prevention. Am J Clin Nutr 85(Suppl):255S-256S. Defense Manpower Data Center Statistical Information Analysis Division. 2005. Active duty military personnel strengths by regional area and by country (309a) September 30, 2005. http://siadapp.dior.whs.mil/personnel/MILITARY/history/hst0905.pdf (accessed March 23, 2007). Deuster, P. A., A. Sridhar, W. J. Becker, R. Coll, K. K. O'Brien, and G. Bathalon. 2003. Health assessment of U.S. Army Rangers. Mil Med 168(1):57-62. DHHS (Department of Health and Human Services). 2000. Healthy People 2010. 2nd ed. With understanding and improving health and objectives for improving health. Washington, DC: U.S. Government Printing Office. Ernst, E. 1998. Harmless herbs? A review of the recent literature. Am J Med 104(2):170-178. Ervin, R. B., J. D. Wright, and J. Kennedy-Stephenson. 1999. Use of dietary supplements in the United States, 1988-94. Vital Health Stat 11(244):i-iii, 1-14. Ervin, R. B., J. D. Wright, C. Y. Wang, and J. Kennedy-Stephenson. 2004. Dietary intake of selected vitamins for the United States population: 1999-2000. Adv Data (339):1-4. Executive summary. 2004. Conference on dietary supplement use in the elderly—Proceedings of the conference held January 14-15, 2003, Natcher Auditorium, National Institutes of Health, Bethesda, MD. Nutr Rev 62(4):160-175.

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Fairfield, K. M., and R. H. Fletcher. 2002. Vitamins for chronic disease prevention in adults: Scientific review. JAMA 287(23):3116-3126. Farmer, K. L. 2002. Reporting data on use of medication and nutritional supplements by patients with heat injuries and illnesses. Department of the Army memorandum. http://www.apgea.army.mil/doem/pgm34/HIPP/MemoDietarySupplements.pdf (accessed January 8, 2008). Fiatarone Singh, M. A., M. A. Bernstein, A. D. Ryan, E. F. O'Neill, K. M. Clements, and W. J. Evans. 2000. The effect of oral nutritional supplements on habitual dietary quality and quantity in frail elders. J Nutr Health Aging 4(1):5-12. Flakoll, P. J., T. Judy, K. Flinn, C. Carr, and S. Flinn. 2004. Postexercise protein supplementation improves health and muscle soreness during basic military training in Marine recruits. J Appl Physiol 96(3):951-956. Ford, E. S. 2001. Vitamin supplement use and diabetes mellitus incidence among adults in the United States. Am J Epidemiol 153(9):892-897. Fraunfelder, F. W. 2004. Ocular side effects from herbal medicines and nutritional supplements. Am J Ophthalmol 138(4):639-647. Hercberg, S., P. Galan, P. Preziosi, S. Bertrais, L. Mennen, D. Malvy, A. M. Roussel, A. Favier, and S. Briançon. 2004. The SU.VI.MAX Study: A randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med 164(21):2335-2342. Houston, D. K., M. A. Johnson, T. D. Daniel, and L. W. Poon. 1997. Health and dietary characteristics of supplement users in an elderly population. Int J Vitam Nutr Res 67(3):183-191. Huang, H.-Y., B. Caballero, S. Chang, A. J. Alberg, R. D. Semba, C. Schneyer, R. F. Wilson, T.Y. Cheng, G. Prokopowicz, G. J. Barnes, II, J. Vassy, and E. B. Bass. 2006. Multivitamin/mineral supplements and prevention of chronic disease. Evidence Report/Technology Assessment No. 139. (Prepared by The Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-0018). Rockville, MD: Agency for Healthcare Research and Quality. Huang, H.-Y., B. Caballero, S. Chang, A. J. Alberg, R. D. Semba, C. Schneyer, R. F. Wilson, T.Y. Cheng, G. Prokopowicz, G. J. Barnes, II, J. Vassy, and E. B. Bass. 2007. Multivitamin/mineral supplements and prevention of chronic disease: Executive summary. Am J Clin Nutr 85(suppl):265S-268S. Hypericum Depression Trial Study Group. 2002. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: A randomized controlled trial. JAMA 287(14):1807-1814. IOM (Institute of Medicine). 1992. Body composition and physical performance: Applications for the military services. Washington, DC: National Academy Press. Johnston, D. T. 2002. Miscellaneous pharmaco-active substances and nutritional supplements: Education and policy for aircrew members. www.nomi.med.navy.mil/NAMI/WaiverGuideTopics/pdfs/Waiver percent20Guide percent20- percent20Supplements.pdf (accessed April 2, 2007). Koplan, J. P., J. L. Annest, P. M. Layde, and G. L. Rubin. 1986. Nutrient intake and supplementation in the United States (NHANES II). Am J Public Health 76(3):287-289. Lewis, C. J., N. T. Crane, D. B. Wilson, and E. A. Yetley. 1999. Estimated folate intakes: Data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr 70(2):198-207. Lieberman, H. R., G. P. Bathalon, G. Bathalon, J. Creedon, M. Bovill, and S. McGraw. 2000. Use of dietary supplements in elite U.S. Army populations.

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http://ods.od.nih.gov/news/conferences/Lieberman_Supplements_REV1_PEP.pdf (accessed February 12, 2008). Lieberman, H. R., T. B. Stavinoha, S. M. McGraw, and L. D. Sigrist. 2007. Appendix B. Use of dietary supplements in the U.S. Army. Lyle, B. J., J. A. Mares-Perlman, B. E. K. Klein, R. Klein, and J. L. Greger. 1998. Supplement users differ from nonusers in demographic, lifestyle, dietary and health characteristics. J Nutr 128(12):2355-2362. Marriott, B., C. G. Choate, et al. 2008. Dietary supplement use among active duty military personnel: Data from a worldwide survey. Unpublished. Miller, S. C. 2004. Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements. Mil Med 169(2):87-93. Miller, E. R., III, R. Pastor-Barriuso, D. Dalal, R. A. Riemersma, L. J. Appel, and E. Guallar. 2005. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142(1):37-46. Mulholland, C. A., and D. J. Benford. 2007. What is known about the safety of multivitaminmultimineral supplements for the generally healthy population? Theoretical basis for harm. Am J Clin Nutr 85(Suppl):318S-322S. NCHS (National Center for Health Statistics). 2002a. MEC in-person dietary interviewers procedures manual. http://www.cdc.gov/nchs/data/nhanes/nhanes_01_02/dietary_year_3.pdf (accessed January 8, 2008). NCHS. 2002b. NHANES 2001-2002. Public data release file documentation. http://www.cdc.gov/nchs/about/major/nhanes (accessed October 25, 2004). NCHS. 2004. NHANES analytic guidelines. http://www.cdc.gov/nchs/about/major/nhanes/currentnhanes.htm#Interviewer (accessed October 25, 2004). NCHS. 2005. Analyic and reporting guidelines: The National Health and Nutrition Examination Survey. http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/nhanes_analytic_guidelines_dec_2005. pdf (accessed January 8, 2008). NIH State-of-the-Science Panel. 2007. National Institutes of Health State-of-the-Science Conference Statement: Multivitamin/mineral supplements and chronic disease prevention. Am J Clin Nutr 85(Suppl):257S-264S. Oh, R. C., and J. S. Henning. 2003. Exertional heatstroke in an infantry soldier taking ephedracontaining dietary supplements. Mil Med 168(6):429-430. Radimer, K. L. 2003. National nutrition data: Contributions and challenges to monitoring dietary supplement use in women. J Nutr 133(6):2003S-2007S. Radimer, K. L. 2005. Methodological issues in assessing dietary supplement use in children. J Am Diet Assoc 105(5):703-708. Radimer, K. L., A. F. Subar, and F. E. Thompson. 2000. Nonvitamin, nonmineral dietary supplements: Issues and findings from NHANES III. J Am Diet Assoc 100(4):447-454. Radimer, K., B. Bindewald, J. Hughes, B. Ervin, C. Swanson, and M. F. Picciano. 2004. Dietary supplement use by US adults: Data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol 160(4):339-349. RTI (Research Triangle Institute). 2004. SUDAAN User's Manual. Release 9.0. Research Triangle Park, NC: RTI.

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Rock, C. L. 2007. Multivitamin-multimineral supplements: Who uses them? Am J Clin Nutr 85(Suppl):277S-279S. Slesinski, M. J., A. F. Subar, and L. L. Kahle. 1995. Trends in use of vitamin and mineral supplements in the United State: The 1987 and 1992 National Health Interview Surveys. J Am Diet Assoc 95(8):921-923. Slesinski, M. J., A. F. Subar, and L. L. Kahle. 1996. Dietary intake of fat, fiber and other nutrients is related to the use of vitamin and mineral supplements in the United States: The 1992 National Health Interview Survey. J Nutr 126(12):3001-3008. Subar, A. F., and G. Block. 1990. Use of vitamin and mineral supplements: Demographics and amounts of nutrients consumed. The 1987 Health Interview Survey. Am J Epidemiol 132(6):1091-1101. Turner, R. B., R. Bauer, K. Woelkart, T. C. Hulsey, and J. D. Gangemi. 2005. An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med 353(4):341-348. USDA (U.S. Department of Agriculture). 1999. Supplementary data tables: USDA’s 1994-1996 Continuing Survey of Food Intake by Individuals. Table Set 12. http://www.ars.usda.gov/SP2UserFiles/Place/12355000/pdf/Supp.pdf (accessed June 22, 2007). USPSTF (U.S. Preventive Services Task Force). 2003. Routine vitamin supplementation to prevent cancer and cardiovascular disease: Recommendations and rationale. Ann Intern Med 139(1):51-55. Valli, G., and E. G. Giardina. 2002. Benefits, adverse effects and drug interactions of herbal therapies with cardiovascular effects. J Am Coll Cardiol 39(7):1083-1095. Whitehead, R. G. 2000. Dietary supplements: Is your health at risk? Hot Topics, Current Issues for Army Leaders. http://www.army.mil/publications/soldiersmagazine/HotTopics/media/fall00.pdf (accessed April 2, 2006). Yeh, G. Y., D. M. Eisenberg, T. J. Kaptchuk, and R. S. Phillips. 2003. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care 26(4):12771294. Yetley, E. A. 2007. Multivitamin and multimineral dietary supplements: Definitions, characterization, bioavailability, and drug interactions. Am J Clin Nutr 85(Suppl):269S-276S. ACKNOWLEDGEMENTS General survey design, data collection, and data analyses were supported by the Department of Defense under Cooperative Agreement No. DAMD17-00-2-0057 to RTI, International. Inclusion of specific survey questions on dietary supplements, their analyses, and interpretation of the results were supported by the Samueli Institute through Department of the Army Award No. W81XWH-06-2-0009 to the Samueli Institute (the U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office for this award), and under the Samueli Institute's contract P4805.039 to RTI International and under RTI subcontract 3-312-0209842 to Abt Associates, Inc. The content of this information does not necessarily reflect the position or the policy of the government, and no official endorsement should be inferred The authors acknowledge Kelly Close for her conduct of original data analysis; Andrew J. Young, Ph.D., and Wayne B. Jonas for their interest in this project and review of the preliminary data; Tom V. Williams, Ph.D., for his role in the conceptualization of the project; Patricia A. PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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Deuster, Ph.D., MPH, and COL Gaston P. Bathalon, Ph.D., RD, for their assistance in crafting the dietary supplement survey questions; William Schlenger, Ph.D., and Michael Finch, Ph.D., for their careful review of the earlier manuscripts and suggestions on data analysis; and Joan A. G. Walter, JD, PA-C, for program management at the Samueli Institute.

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SURVEY OF ARMY HEALTH CARE PROVIDERS CONCERNING DIETARY SUPPLEMENTS Danny Jaghab1 The focus of the study was very simple—targeting the type of information that should be given to health care providers. The U.S. Army Center for Health Promotion and Preventive Medicine (CHPPM), provides the “War Fighters Guide for Dietary Supplements,” which is a type of brochure that can be put into the pockets of battle dress uniforms (BDUs). The Department of Defense (DoD) dietary supplement committee wanted to have a similar type of product for health care providers. The goal of the study was to take a look at what health care providers know about dietary supplement usage with regard to soldiers and to specifically compare physicians’ knowledge to that of other health care providers. An electronic survey was used on the Army Medical Department (AMEDD) Knowledge Management website. The survey was for senior leaders. It is a simple survey consisting of only seven questions. The link was e-mailed to 8,000 health care providers, 4,000 physicians, and 4,000 ancillary health care providers (dieticians, occupational therapists, physical therapists, nurses, and physician’s assistants [PAs]), with a 15 percent return rate. It is important to mention that these health care providers—88 percent of physicians and 77 percent of the others—have been deployed, because dietary supplement usage is a concern in a deployed environment. The results of the survey show that there is little difference between physician’s knowledge of dietary supplements and that of the ancillary group. The researchers were concerned that the soldiers would be afraid to tell the physicians about certain dietary supplements they were using, or that they would be afraid to tell the ancillary group. The ancillary group included the medical service corps. These are the men and women who are commanders and in medical administrative positions. The researchers were concerned that the soldiers might not reveal what they were taking to the medical service corps, but that was not the case. For the herbals, the five most popular were ginkgo biloba, green tea, melatonin, St.-John'swort, and echinacea. The top five by brand, as reported by the physicians and the ancillary group, are listed in Box B-7. The top five reasons the soldiers took the supplements are listed in Box B-8. Please notice that weight loss is a concern, especially during deployment. The top five sources soldiers were buying their supplements from are listed in Box B-9. As noted in the box, a major concern is that these supplements are sold in the open market in Iraq. These supplements come from Amman, Jordan, and it is unknown what is in them, but soldiers are buying them. The top 10 concerns of health care providers regarding supplement usage by soldiers are listed in Box B-10. The concerns of the physicians and the ancillary group are very similar. It was the goal of the researchers to find out what the concerns were, and then put it in the format of an education product for health care providers as well as soldiers.

1

Directorate of Health Promotion and Wellness, U.S. Army Center for Health Promotion and Preventive Medicine

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BOX B-7 Top Five Brands, From Most to Least Physicians (n=573) ● Ripped Fuel (n=51) 8.9% ● Hydroxy Cut (n=34) 5.9% ● MEGA Man (n=8) 1.4% ● Xenadrine (n=6) 1% ● Myoplex (n=5) 0.9% Ancillary (n=614) ● Hydroxy Cut (n=71) 11.6% ● Ripped Fuel (n=49) 8% ● Cell-Tech (n=12) 2% ● Xenadrine (n=9) 1.5% ● Myoplex (n=6) 1% SOURCE: U.S. Army CHPPM.

BOX B-8 Top Five Reasons Soldiers Took Dietary Supplements, Most to Least Physicians (n=573) ● Performance enhancer (n=301) 52.5% ● Gain weight (n=139) 24.3% ● Lose weight (n=137) 23.9% ● Increase muscle mass, conditioning, strength (n=35) 6.1% ● Cognitive enhancer, stay awake (n=21) 3.7% Ancillary (n=614) ● Performance enhancer (n=298) 48.5% ● Lose weight (n=166) 27% ● Gain weight (n=136) 22.1% ● Increase muscle mass, conditioning, strength (n=40) 6.5% ● Supplement diet, health maintenance (n=22) 3.6%

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BOX B-9 Top Five Places Soldiers Buy Dietary Supplements, Most to Least Physicians (n=573) ● PX (n=298) 52% ● Online (n=203) 35.4% ● GNC (n=126) 22% ● Given or sent (n=75) 13.1% ● Unknown (n=67) 11.7% Disturbing: ● Local economy (such as Mexico and Iraq markets) (n=16) 2.8% Ancillary (n=614) ● PX (n=364) 59.3% ● Online (n=245) 39.9% ● GNC (n=92) 15% ● Given or sent (n=87) 14.2% ● Unknown (n=30) 4.9% Disturbing: ● Local economy (such as Mexico and Iraq markets) (n=11) 1.8%

The top education suggestions are listed in Box B-11. From this study, it was concluded that there were really more similarities than differences between the physicians and the other health care providers in their understanding of the usage of the dietary supplements with the soldiers, and that we needed to use this information when we build educational tools at the CHPPM for our service members and health care providers. Every branch of the armed services has an Internet portal. The Army Knowledge Online (AKO) is the army Internet portal. On the first of February, the Defense Knowledge Online (DKO) portal merged with the AKO. The DKO administration permitted the AKO to have 200,000 accounts from all of the other services. That means that a navy person or an air force person could come into the AKO and gain access to whatever information that was on that portal. Every branch of the armed services has an Internet portal. The Army Knowledge Online (AKO) is the army Internet portal. On the first of February, the Defense Knowledge Online (DKO) portal merged with the AKO. The DKO administration permitted the AKO to have 200,000 accounts from all of the other services. That means that a navy person or an air force person could come into the AKO and gain access to whatever information that was on that portal.

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BOX B-10 Top Ten Concerns for Usage, Most to Least Physicians (n=573) ● Interaction of supplements with medications or other supplements (n=123) 21.5% ● Side effects (general) (n=117) 20.4% ● Dehydration (n=99) 17.3% ● Renal or kidney functions including stones (n=82) 14.3% ● Heat injury or heat stress (n=57) 9.9% ● Supplements are not regulated by the FDA (n=52) 9.1% ● Safety of taking supplements (n=46) 8% ● Cardiac issues (n=45) 7.9% ● Overuse of supplements (n=43) 7.5% ● Soldiers don’t understand the risks and complications of the supplements (n=43) 7.5% Ancillary (n=614) ● Dehydration (n=129) 21% ● Side effects (general) (n=124) 20.2% ● Interaction of supplements with medications or other supplements (n=100) 16.3% ● No concerns (n=72) 11.7% ● Safety of taking supplements (n=42) 6.8% ● Heat injury or heat stress (n=41) 6.7% ● Cardiac issues (n=34) 5.5% ● Overuse of supplements (n=33) 5.4% ● Renal or kidney functions including stones (n=28) 4.7% ● Long-term effects (n=26) 4.2%

BOX B-11 Top Four Education Suggestions, Most to Least Physicians (n=573) ● Which supplements work or do not work (n=67) 11.7% ● Better nutrition in general (n=34) 5.9% ● General risks of taking supplements (n=32) 5.6% ● Weight-loss supplement education (n=10) 1.7% Ancillary (n=614) ● Which supplements work or do not work (n=49) 8% ● None or N/A (n=41) 6.7% ● Better nutrition in general (n=28) 4.6% ● General risks of taking supplements (n=19) 3.1%

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Every branch of the armed services has an Internet portal. The Army Knowledge Online (AKO) is the army Internet portal. On the first of February, the Defense Knowledge Online (DKO) portal merged with the AKO. The DKO administration permitted the AKO to have 200,000 accounts from all of the other services. That means that a navy person or an air force person could come into the AKO and gain access to whatever information that was on that portal. The researchers for the survey asked the AKO administration if they could have 500 accounts per service for their online communities. To find the Ultimate Warrior community, go to the Self-Service page and click on the My Medical page. It is incredible to see how many people visit these web pages at all times of the day or night. Over the Christmas holiday usage statistics were checked to see if people were actually visiting this site. They were coming Sunday nights. They were coming Christmas Eve. They were coming at all times of the day and night. This is worldwide and the training occurs in real time. Now, this is the Ultimate Warrior community. We started with Weigh to Stay. Referring again to the website, on the left is a section covering weight management. When we formed that community, a significant response were soldiers asking why the focus of the community was on weight loss when so many soldiers were concerned about gaining strength and adding weight. In response, we formed a second community, Hooah Bodies. Hooah Bodies was launched December 4, 2007, and it is growing at a quicker rate than the Weigh to Stay community. Weigh to Stay is typically a 3-hour program in weight management. The first hour covers general nutrition, the second hour is physical fitness and exercise, and the third hour is a combination of information covering nutrition, exercise, and behavior change. We added a fourth hour to the program that focuses strictly on behavior management. We have a licensed psychologist who teaches this part, and we recruited a motivational speaker who produced 15 short videos for us. This man has lost over 260 pounds and has maintained it for over 5 years to join the army, and he is studying to become a nurse. Any soldier can go online and register for this course. To register, soldiers fill out a mandatory HIPAA-required form and they complete an electronic survey. The soldier must complete this process for each different community he joins through this portal. Next the soldier can schedule a session, and check to see what courses are offered at the time of the session. Instructors for the courses are stationed across the globe; the time differences allow classes to be available around the clock. Classes are available on weekends as well. Soldiers receive an e-mail the first day of the class that reminds them that class is about to start. Once the soldier logs on, he or she is connected to a kind of virtual classroom. The instructor is live, wherever he or she may be. Soldiers can see the presentation the instructor is giving and can ask the instructors questions via telephone. The website also offers information on nutrition. This allows soldiers who are deployed in Iraq to have access to nutritional guidance without having to travel back from the front to a combat support hospital, which can be risky. The website also offers product reviews performed by the U.S. Army Research Institute of Environmental Medicine (USARIEM). Soldiers’ input helps guide what products are reviewed. For example, a soldier posted a comment stating that Red Line energy drink “was working out really great for me.” Such comments raise red flags for the researchers running the website. In this instance, within a couple of days a product review of Red Line was performed by

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USARIEM and posted on the Weigh to Stay site, and the soldier who originally posted the comment was informed of the new review. On the Hooah Body site, channels are available for each of the Armed Services. In early 2008 there should be a course of instruction available online. Soldiers may also try programs offered by different branches of service, such as changing from the army’s Weigh to Stay program to the navy's Ship Shape program. Each of these online communities are linked to each other. Each community covers exercise and fitness. RSS feeds from reputable sources, such as the Mayo Clinic, are provided on the website; these change every day and keep the website fresh. Many of the RSS feeds offer recipes. There are a total of 12 instructional classes offered. This community is over 1,200 strong so far. The Weigh to Stay community is over 5,200 strong. This is growing at a fast rate, and these courses are all developed by our dieticians who specialize in sports nutrition. Such courses allow soldiers to learn about nutrition in-depth, far beyond the basic food pyramid. The program has also contacted the surgeon general's office to investigate offering continuing medical education (CME) credit for physicians. If that is possible, course work can be developed for physicians who are deployed and who have difficulty obtaining CMEs in the field. These courses are all reviewed by our credentialing board at the AMEDD center. One of our instructors is also an army champion bodybuilder. She is a registered dietician with a masters in sports nutrition. Soldiers respect such instructors and accept the information they have to offer more readily. At a recent meeting of the DoD Dietary Supplement Committee, it was decided to put a link to Medwatch on the Dietary Supplement page of the portal so soldiers have a way to report adverse reactions.

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USE OF DIETARY SUPPLEMENTS IN THE U.S. ARMY Harris R. Lieberman, Trisha B. Stavinoha, Susan M. McGraw, Lori D. Sigrist1 INTRODUCTION Use of dietary supplements is largely unregulated in U.S. military and civilian populations (De Smet, 2002; Noonan and Noonan, 2006) (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress). Many dietary supplements are ineffective, and some have been found to be dangerous (Gardner et al., 2007; Hypericum Depression Trial Study Group, 2002; Lonn et al., 2005; Solomon et al., 2002). In addition, some dietary supplements interact with prescribed medications (Scott and Elmer, 2002; Wilson, et al., 2006). As noted in two recent reports from the Institute of Medicine (IOM), the lack of data regarding dietary supplement use in military personnel, and the possibility that consumption of certain products might have detrimental effects on health and physical and cognitive performance, establishes a requirement for collection of military-specific survey data (IOM, 2006a,b). Despite safety and efficacy concerns, dietary supplement use in the United States has grown substantially over the last 15 years, due in part to passage of the Dietary Supplement Health and Education Act of 1994 (Millen et al., 2004; Noonan and Noonan, 2006) (Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 108 Stat 4325, 103rd Congress). For example, sales of supplements have reached over $21 billion in the United States, with over $4 billion spent on herbal supplements in 2005, a 2 percent increase from 2004 (Blumenthal et al., 2006; Nutrition Business Journal, 2007). It is likely that increasing supplement use in the general population will be reflected by similar increases in military populations. To date, use of dietary supplements in the U.S. Army has only been assessed in select populations (Arsenault and Kennedy, 1999; Bovill, et al., 2003; Brasfield, 2004). The most recent survey, conducted by Brasfield in 2002, assessed enlisted soldiers from 16 different locations, but did not include warrant or commissioned officers (Brasfield, 2004). Previous studies from the U.S. Army Research Institute of Environmental Medicine (USARIEM) examined supplement use in nonrepresentative samples, such as the Special Forces, Army Ranger units, trainees in a Special Forces qualification course, and high-ranking officers at the Army War College (Arsenault and Kennedy, 1999; Bathalon et al., 2000; Bovill, et al., 2003; Brasfield, 2004; McGraw et al., 2000). In these groups, the percent of soldiers using supplements, defined as consumption of at least one supplement per week, was 66 percent in Special Forces, 82 percent in Rangers, and 77 percent in Army War College officers. Surveys of the general U.S. population report that 40–60 percent of U.S. adults take supplements, indicating that elite army soldiers consume more supplements than the general population (Balluz et al., 2005; Fragakis and Thomson, 2007; Rock, 2007). In some respects, soldiers in many elite units resemble athletes due to the physical demands of their duties, and several reports suggest competitive athletes are avid users of dietary supplements (Erdman et al., 2006; Striegel et al., 2006). For example, a recent survey at a National Collegiate Athletic Association Division I university found that 89 percent of athletes took dietary supplements (Froiland et al., 2004). Although the appropriate use of certain supplements might provide health benefits, unrestrained and unguided consumption of dietary supplements is a concern for military officials. 1

Military Nutrition Division U.S. Army Research Institute of Environmental Medicine, Natick, MA

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Depending on the pattern of use, certain dietary supplements carry health risks and might also alter the bioavailability or action of other bioactive compounds. The recent IOM report, Nutrient Composition of Rations for Short-Term, High-Intensity Combat Operations, expressed concern regarding the efficacy and safety of certain dietary supplements popular among soldiers (IOM, 2006a). For a number of popular supplements, the physical or cognitive performance benefits are questionable (see Appendix B Limited efficacy of dietary supplements for physical and cognitive performance enhancement in military operations by H. R. Lieberman). In addition, there appear to be safety concerns over: the metabolic effects of long-term use of some supplements, such as creatine; potential interactions with other components of the diet or medications; and withdrawal effects (Ciocca, 2005; Juliano and Griffiths, 2004; Mayhew et al., 2002). Methods Over the past 10 years, multiple surveys have been conducted by USARIEM scientists and collaborators to assess dietary supplement use and related factors in various U.S. Army populations (Arsenault and Kennedy, 1999; Bathalon et al., 2000; Bovill, et al., 2003; Brasfield, 2004; McGraw et al., 2000). The results of four separate surveys are presented in this chapter. These surveys assessed different army populations and used different survey tools, although three of the four questionnaires were similar. The most current and representative data presented here are from an armywide study that is still underway (Stavinoha et al., 2007). The surveys presented here were embedded in larger studies addressing other issues with the exception of the ongoing armywide supplement survey. Planning for the armywide survey was initiated in 2006 in anticipation of the formation of a dietary supplement subcommittee of the Committee on Military Nutrition Research. The survey is only partially complete at this time, so the data presented should be considered preliminary. Some differences are to be expected when the survey is completed and a larger population sample is obtained. The armywide survey is sampling a heterogeneous population in many occupational specialties, including enlisted soldiers, warrant officers, and commissioned officers. To date, this survey excludes soldiers from the Special Forces, Rangers, and high-ranking officers (O-6 and above), but these groups make up a very small proportion of the army and were surveyed previously (Arsenault and Kennedy, 1999; Bathalon et al., 2000; Bovill et al., 2003; McGraw et al., 2000; Office of Army Demographics, 2005). Table B-15 summarizes key aspects of the surveys presented here. The Special Forces group surveyed is an elite volunteer unit with substantial army experience (U.S. Army, 2007). Their training and the operations they typically conduct require extremely high levels of physical and cognitive performance. Like the Special Forces group, the Rangers are also an elite volunteer unit. However, in contrast to Special Forces, Rangers are young and relatively new to the army and are predominantly lower-ranking enlisted soldiers. There are extremely high physical demands associated with their training and operations (Bryant and Bryant, 2005; Lieberman et al., 2002; 2005; U.S. Army, 2007). Volunteers surveyed from the Army War College are comparable to middle- and high-level managers in the civilian population (Bathalon et al., 2000). Physical demands placed on them are moderate compared to Rangers or Special Forces soldiers; however, mental demands are high.

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APPENDIX B

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TABLE B-15 Key Characteristics of the Surveys Used and Population Samples Assessed Armywide Date Number of volunteers Number of questions asked Number of supplements individually listed Proportion of females Proportion of officers Mean age (± SD)

2006–2007 667 43 92 11% 21% 30 ± 9.2

Ranger 1999 758 51 14 0% 6% 24 ± 4

Special Forces 1999 152 109 70 0% 15% 31 ± 6.1

Army War College 1999 315 13 61 10% 100% 44 ± 4

An Armywide Survey: September 2006–February 2007 The conduct of this anonymous survey was approved by the USARIEM Human Use Review Committee. Survey Design. A 43-question survey instrument was used for this armywide assessment. The survey items were selected based in part on a questionnaire used in a previous USARIEM study conducted by Bovill and associates described below (Bovill et al., 2003). The armywide survey was modified to collect additional demographic information and assess caffeine intake from beverages, foods, and drugs, as well as supplements. Supplements listed on the armywide questionnaire were updated to reflect current patterns of supplement use based on data from the Army Air Force Exchange System (AAFES) and General Nutrition Center (GNC) stores located on and off military installations. Ninety-two of the most popular supplements were listed. Prior to distribution to participating units, a pilot survey was conducted with local army volunteers to assess their comprehension of study questions and determine the time required to complete the survey. Questions on this survey assessed types of supplements used, frequency of use, reason for use, where supplements were purchased, sources used to obtain information on supplements, and amount of money spent on supplements. Demographic factors, including rank, age, gender, military specialty, and exercise frequency and intensity were also surveyed. Sampling Procedures. Sample size calculations were performed using the EpiInfo (Version 6) program to estimate the power required for a population survey using random sampling. An N of 1760–2000 was estimated to be adequate to permit detection of use of a specific supplement in 5 percent of the population with a 95 percent confidence interval (CI). Our intent, therefore, is to obtain over 2,000 surveys from up to 11 U.S. locations and 4 foreign locations. This preliminary report includes data from 667 volunteers collected at 7 sites. Appropriate sites for this survey were selected based on the soldier population present. Army school settings were selected for many of the sites. Schools provide an excellent environment for conducting surveys. Soldiers must attend to maintain job skills, stay in the army, and be eligible for promotion. Schools, as well as other sites, were selected to sample soldiers with various ranks, job types, and to represent geographically dispersed locations. We did not survey Basic Combat Training (BCT) soldiers or Advanced Individual Training (AIT) soldiers as trainees in these schools are not permitted to consume supplements. Survey Administration At each study site, a point of contact (POC), typically a dietitian or other health care professional, administered the questionnaire. The POC made contact with the unit commander or class leader and arranged for a time and place to distribute the survey. In PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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most cases, the POC conducted the survey in person in a classroom setting. The POC presented a standard presentation provided by USARIEM to describe the purpose and contents of the survey, its confidential nature (no identifying data were collected), and to clarify potentially complicated questions. All returned surveys were reviewed for completeness. Data were scanned and tabulated using ScanTools Plus and SPSS 15.0 software programs, as employed previously in multiple USARIEM studies (Lieberman et al., 2005, 2006; McClung et al., 2006). Special Forces Survey: July 2000 This survey was part of a larger study assessing the nutritional status of Special Forces soldiers (Tharion et al., 2004). Two surveys contained a total of 109 questions relating to health, fitness, injury, energy balance, nutrition knowledge, and dining facility usage, in addition to supplements consumed (Bovill et al., 2003). The surveys were administered in a classroom setting by USARIEM staff. Types of supplements used, frequency of use, reason for use, side effects, and money spent on supplements were surveyed. A list of 70 different supplements was provided on the survey. Demographic and lifestyle factors, including rank, age, gender, military specialty, exercise frequency, and living arrangements were assessed. Participants were 119 Special Forces soldiers from the 10th Special Forces Group and 38 additional soldiers assigned to their unit based in Ft. Carson, Colorado. Army War College Survey: 1999–2001 This 13-question survey instrument was one of many administered as part of a Health and Fitness Assessment (HFA) at the Army War College (Bathalon et al., 2000). The HFA gathered health and fitness information on a high-level officer population. Questions on the survey addressed types of supplements used, frequency of use, reason for use, and cost. A list of 61 different supplements was included. Participants were 315 students attending the Army War College. The sample consisted of senior-level officers age 44, plus or minus 4 years. Staff from the Army Physical Fitness Research Institute and the Army War College administered the survey. Ranger Survey: April 1999 This 51-question survey instrument evaluated the use of 14 categories of supplements. The survey assessed various demographic factors, frequency of supplement use, reason for use, side effects, and money spent on supplements. Participants were 768 Army Rangers assigned to the 75th Ranger Regiment and were aged 24, plus or minus 4 years. Results Armywide Survey Table B-16 presents the demographic characteristics of soldiers assessed in the armywide survey compared to the characteristics of the whole army. As of December 2006, there were 498,168 active duty personnel in the army, 16 percent were officers and 15 percent were females (DoD, 2006). The armywide sample presented here consists of 21 percent officers and 11 percent females. The greatest difference between our survey sample and the total army population is an overrepresentation of more highly educated soldiers in our sample. Since our survey is still underway, we have not as of yet corrected for this imbalance, but will do so, if necessary, using appropriate statistical methods in the final publication presenting the study results. Table B-17 prePREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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APPENDIX B

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sents data on frequency of supplement used by participants in the armywide survey, stratified across various demographic factors, as well as use of three of the most popular supplements. At least 50 percent of every demographic or occupational group consumed at least one supplement a week, with the exception of those individuals who never engaged in strength training, although 45 percent of this group did use supplements (Table B-17). Chi square analyses were performed to determine if there were associations between supplement use, defined as using any supplement at least once a week, and demographic variables of interest. The criterion for significance was defined as P < .05. Use, defined as taking a supplement at least once a week, varied with sex (P = .011), with females typically consuming more supplements (71 percent) than males (58 percent). Use also varied with age (P = .001) and educational level (P < .001), with the greatest use in the group aged 30–39 years (69 percent) and least in soldiers who were less than 20 years old (57 percent). Among soldiers who had some high school education or a GED, 52 percent took supplements, while 78 percent of soldiers with a bachelor’s degree reported taking supplements (Table B-17). Rank was also associated with supplement use (Table B-17), with the lowestranking soldiers (E1–E4) generally using less supplements then higher ranking soldiers (P < .001). Occupational category, broadly defined as combat arms, combat support, or combat service support, also had an influence on supplement use (P < .001). Strength training had more of an influence on supplement use (P < .001) than aerobic training (NS, P = .091). The most widely used supplements across all demographic and occupational groups were multivitamins and sport drinks. Protein/amino acid mixtures were also popular, and many soldiers were using calcium and individual vitamins (Table B-17). Table B-17 also presents the mean amount of money spent by soldiers stratified by demographic factors and exercise frequency. Table B-18 presents all supplements used by at least 1 percent of the soldiers in the armywide survey. TABLE B-16 Demographic Comparison of Armywide Survey Population to Current Army Statistics E1–E4 E5–E9 WO 1–5 O1–O3 O4–O6 Female Officers < 20 21–29 30–39 > 40 High school or GED Some college or associate Bachelor degree Graduate degree a b

Armywide Survey (%) 48 31 15 5 1 11 21 11 47 22 20 31 46 16 6

2006 data. 2005 data

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Army Overall Population 45a 38 a 3a 8a 6a 15 a 16 a 14b 49 b 28 b 10 b 69 b 8b 13 b 6b

DIETARY SUPPLEMENT USE BY MILITARY PERSONNEL

At Least Once/ Week (%) 1–2 Supplements/ Week (%)

Copyright © National Academy of Sciences. All rights reserved.

20 15 15 10 14 16 13 8 15 15 13 15 15 13 19 0 21 12 15 8 13 19

9 10 17 19 8 12 24 39 10 16 15 9 16 18 22 40 3 17 12 9 16 14

19 36 40

35 40 28

24 39 43 50 40

29 36 33

21 33 52 41

24 26 44 43

32 37

Multivitamin Use (%)

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15 14

5+ Supplments/ Week (%)

12 20

3 –-4 Supplements/ Week (%)

Male 553 58 31 Female 63 71 37 Age 70 < 20 57 28 21–29 283 59 28 30–39 143 69 35 > 40 133 63 40 Education High school or GED 194 52 27 Some college/associate 289 64 32 degree 107 78 40 Bachelor degree 39 72 40 Graduate degree Occupation 219 57 33 Combat armsa Combat support b 214 61 31 Combat service support c 192 60 32 Rank E1–E4 298 53 30 E5–E9 195 61 31 WO1–WO5 100 67 36 O1–O3 31 88 47 O4–O6 5 60 20 Exercise—Aerobic 28 52 28 None 234 66 38 < 4 days a week > 5 days a week 361 56 29 Exercise—Strength 176 45 28 None 141 62 34 < 2 days a week > 3 days a week 306 67 34 a Infantry, armor, field artillery, air defense, special forces, aviation. b Engineer, chemical, military intelligence, military police, signal, civil affairs. c Ordinance, quartermaster, transportation, legal, medical, finance, chaplain

Sex

Total N

14 28 19

14 21 19

21 14 15 38 40

19 21 19

14 20 25 23

17 21 19 16

19 20

Sport Drinks Use (%)

4 10 22

7 16 13

12 16 13 22 0

16 16 10

12 14 17 15

9 13 18 13

14 10

Protein Amino Acid Mix Use (%)

TABLE B-17 Supplement Use in the Armywide Survey Stratified by Age, Education, Occupation, Rank, and Exercise Frequency

B-100

73 46 55

31 48 66

59 67 48 32 40

64 51 59

46 71 53 25

56 47 67 67

58 58

Money Spent per Month ($)

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TABLE B-18 Top 40 Supplements Used by 1% or More of Soldiers in the Armywide Sample Rank 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Product Multivitamin Sport drink Protein powder Vitamin C Calcium Vitamin E Vitamin D Vitamin A Caffeine Creatine Sport bar Iron Mega-vitamin Potassium Antioxidant mix Magnesium Chromium Folate Zinc B-complex B12 Amino acid mix Glucosamine B6 Riboflavin Meal replacement Beta carotene Niacin Phosphate Selenium Garlic Hydroxycut Nitro Tech Cell Tech Fish body oil Arginine Glutamine Xenadrine Ginseng Ephedra

Percent 33.7 19.3 13.8 12.9 7.8 7.1 6.2 5.6 5.1 4.5 4.4 4.4 4.0 4.0 3.6 3.6 3.6 3.6 3.5 3.3 3.2 3.2 3.0 2.9 2.9 2.7 2.6 2.6 2.4 2.4 2.0 2.0 2.0 1.8 1.7 1.7 1.5 1.4 1.4 1.4

NOTE: Supplements that fell into the “other” category included bee pollen, prenatal vitamins (PNV), flaxseed oil, omega-3 fish oil, fiber, GNC Mega Man, Censor, Nature’s Plus, Cell Tech, Muscle Milk, estrogen, Vagisal, aspirin, Amplify, NO Xplode, Valtrax, Nitro Tech, Lipo 6, and Nitrix. None of these supplements were taken by more than 1% of the population except for Mega Man and prenatal vitamins, which both had categories.

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Frequency of Supplement Use, Top Supplements Used, and Reason for Use in All Populations Table B-19 presents frequency of supplement use across the various populations surveyed, stratified by sex if females were assigned to the unit or school surveyed. Extent of participation in exercise, either aerobic or strength training, is also presented in Table B-21. Over 50 percent of the soldiers in all groups consumed a supplement at least once a week, while over 30 percent in all groups surveyed took more than one supplement once a week. The aggregate frequency of supplement use for the armywide sample is somewhat of an overestimate since, as noted above, the surveyed population was somewhat better educated that the general population and such individuals tend to use more supplements (Table B-16). The most popular supplements across all groups surveyed were multivitamins and sport drinks. Tables B-20 through B-22 present the 10 most widely used supplements by group surveyed, stratified by sex if the population had females. Table B-23 presents the top five reasons cited by soldiers for supplement use across all groups. The most common reason for supplement use was to improve health and increase energy. TABLE B-19 Supplement Use and Exercise Frequency Among Survey Populations Armywide

Use supplements at least once a week Use 1–2 different supplements per week Use 3–4 different supplements per week Use 5+ different supplements per week Multivitamin use Sport drinks use Protein/amino acid mixture use Creatine use Aerobic exercise > 3 times/week Aerobic exercise > 5 times/week Strength training > 3 times/week

Army War College Male Female (%) (%) 72 82 29 36

Male (%) 58 31

Female (%) 71 37

12

20

14

15

14

12

32 37 39 19 20 10 14 10 3 5.2 0 2 Exercise Frequency 91 90 75 60 50 N/A 50 31 34

Ranger Male (%) 82 45

Special Forces Male (%) 66 41

6

19

14

23

15

7

52 0 0 0

23 41 18 19

32 36 17 16

N/A N/A N/A

98 N/A 45

96 65 36

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APPENDIX B

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TABLE B-20 Top 10 Supplements Used at Least Once a Week by the Armywide Survey Straitfied by Gender Male

N = 583 (%)

Multivitamin Sports drink Protein powder Vitamin C Calcium Vitamin E Vitamin D Vitamin A Caffeine Creatine

32 19 14 13 7 7 6 5 5 5

Female Multivitamin Sports drink Calcium Vitamin C Folate Iron Protein powder Vitamin D Vitamin E Vitamin A

N = 70 (%) 37 20 32 16 14 11 10 10 10 7

TABLE B-21 Top 10 Supplements Used at Least Once a Week by the Army War College Sample Stratified by Gender Male

N = 284 (%) 39 22 17 10 7 6 6 5 5 5

Multivitamin Vitamin E Vitamin C Sport drink Antioxidants B-complex Garlic Beta-carotene Ginkgo biloba Calcium

Female Multivitamin Calcium Vitamin E Vitamin C Antioxidants Beta-carotene Magnesium Folate B-complex B6

N = 31 (%) 52 32 32 29 23 16 13 13 13 10

TABLE B-22 Top 10 Supplements Used at Least Once a Week by the Special Forces and Rangers Samples Special Forces Sport drink Multivitamin Protein powder Creatine Sport bar Vitamin C Meal replacement drink Vitamin E Antioxidants Androstenedione

N = 15 (%) 36 32 16 16 15 11 9 7 6 6

Rangers Sport drink Multivitamin Creatine Protein/amino acids Antioxidants Herbs Carbohydrate beverage Androstenedione Sport bar Sport gel

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N = 758 (%) 41 23 19 18 14 9 7 7 6 3

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TABLE B-23 Top Five Reasons for Supplement Use, Across All Groups Surveyed Rangers 1. Energy 2. Health 3. Muscle strength 4. Other 5. Physician Recommended Armywide—Male 1. Health 2. Muscle strength 3. Performance 4. Other* 5. Energy Armywide—Female 1. Health 2. Other* 3. Energy 4. Weight loss 5. Performance

% 58 47 33 29 .4 % 61 20 20 18 17 % 50 26 24 12 10

Special Forces 1. Health 2. Performance 3. Energy 4. Other 5. Physician recommended Army War College—Male 1. Health 2. Other 3. Performance/Energy 4. Poor Diet 5. Physician Recommended Army War College—Female 1. Health 2. Performance/energy 3. Other 4. Poor diet 5. Physician recommended

% 72 64 45 26 5 % 62 18 13 6 4 % 71 16 10 3 3

*Other reasons for use by the armywide sample include: pregnancy, recovering from surgery, to lower cholesterol, heartburn, bone/joint health, to consume protein w/o calories, good taste, thirsty, hydration, to mix with alcohol, and to gain weight. Perceived Governmental Role in Supplement Regulation As part of the armywide survey participants were asked their opinion regarding the U.S. government’s role in monitoring supplements. As shown in Figure B-21a, only 4 percent of soldiers believe the U.S. government requires all dietary supplements to work as promised. The remainder either believed the government did not require supplements to work as promised or did not know what the government required (47 percent and 49 percent respectively). Twenty-seven percent of soldiers believed the U.S. government requires that dietary supplements sold be safe for consumption (Figure B-21b). However, the majority was not sure or believed the government had no such requirement.

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APPENDIX B

B-105

Percent

60

47

50 40 30 20 10 0

49

4

All subjects Yes

No

I don't know

FIGURE B-21a Perceived governmental role in supplement regulations in the armywide survey 50

44

Percent

40 30

28.8

27.2

20 10 0

All Subjects Yes

No

I don't know

FIGURE B-21b Perceived governmental role in supplement regulations in the armywide survey

Supplement Knowledge and Confidence Among Supplement Users Supplement users in the armywide survey were asked about their knowledge of the ingredients in the products they use and their confidence regarding the efficacy and safety of these products. Less than 50 percent of supplement users reported they knew all or most of the ingredients in the supplements they were taking (Figure B-22a) and over 60 percent were doubtful their supplements work as claimed or were safe to consume (Figures B-22b, B-22c).

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FIGURE B-22a Supplement knowledge among supplement users in the armywide survey

FIGURE B-22b Supplement knowledge among supplement users in the armywide survey

FIGURE B-22c Supplement knowledge among supplement users in the armywide survey

Spending on Supplements Each survey assessed monthly expenditures of the participants on supplements, as shown in Figure B-23. The armywide survey had the largest proportion of individuals who reported not spending any money on supplements (61 percent), but 13 percent of that sample reported spend-

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APPENDIX B

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Percent

ing more than $100 per month (Figure B-23a). Since more than half of this group reported consuming at least one supplement per week, they appear to be obtaining supplements without purchasing them, presumably from garrison feeding facilities. Average monthly spending by soldiers in the armywide survey was $58. Rangers and Special Forces soldiers reported spending more money on dietary supplements than the general army population sample (Figures B-23b, B23c). Few soldiers attending the Army War College were spending more than $25 a month on supplements (Figure B-23d). 70 60 50 40 30 20 10 0

61

None

6

9

<$20

$21–40

13

6

4

1

$41–60

$61–80

$81–100

Armywide

FIGURE B-23a Monthly expenditures on supplements in all groups surveyed

FIGURE B-23b Monthly expenditures on supplements in all groups surveyed

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>$100

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FIGURE B-23c Monthly expenditures on supplements in all groups surveyed

FIGURE B-23d Monthly expenditures on supplements in all groups surveyed

Discussion The results of the various surveys presented here demonstrate that use of dietary supplements is common among U.S. Army soldiers. Extent of use varies substantially depending on various demographic and occupational factors. Females use more supplements than males, consistent with patterns of use in the civilian U.S. population (Table B-17) (Fennell, 2004). The youngest, least educated soldiers use less supplements than their more educated, older colleagues, which is also similar to the pattern seen in the general population (Table B-17) (Fennell, 2004). Soldiers in Special Forces units and Rangers appear to use more supplements more frequently than soldiers in conventional units (Table B-19). Individuals in these elite units report engaging in more aerobic exercise and strength training (Table B-19), factors that are associated with more extensive supplement use in the general army sample, especially with respect to strength training (Table B-17). For 67 percent of soldiers in the armywide population sample, spending on dietary supplements was modest, less then $20 month (Figure B-23a), although 18 percent reported spending over $61 per month, and the mean level of expenditure was $58. It therefore appears that a rela-

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B-109

tively small proportion of the general army population is responsible for spending most of the money on supplements. Foods and beverages containing dietary supplements, such as sport drinks and sport bars, were included in the survey, so this level of use is somewhat less disturbing than it appears. However, it may be excessive given the lack of evidence that most dietary supplements provide health or performance benefits (see Appendix B Limited efficacy of dietary supplements for physical and cognitive performance enhancement in military operations by H. R. Lieberman) (Gardner et al., 2007; Hypericum Depression Trial Study Group, 2002; Solomon et al., 2002). Spending on dietary supplements in the Special Forces and Rangers was greater than the general army population and, therefore, even more of a concern. Seventeen percent of Special Forces soldiers reported spending more than $81 per month and 19 percent of Rangers were spending more than $61 per month. This is a significant portion of their disposable income, particular the Rangers, who are young and of low rank. Young, low-ranking soldiers in the general army population were typically using fewer supplements than their older colleagues, due perhaps to lack of disposable income and less concern about their general health. Rangers selected “increasing energy” as their most frequent reason for use of dietary supplements, while the general army sample listed general health as their primary reason for using supplements (Table B-23). The extent of dietary supplement use among all groups and the high level of expenditure by special operations soldiers (Rangers and Special Forces), and a subset of the general army population, is somewhat surprising given the skepticism expressed by soldiers with regard to the efficacy and safety of dietary supplements. Among supplement users in the general army survey, only 31 percent indicated they were either extremely or very confident that their own dietary supplements worked as claimed, and only 39 percent were confident the dietary supplements they were using are safe (Figures B-22b and B-22c). Given this level of skepticism, efforts to provide soldiers with accurate information regarding the safety and efficacy of dietary supplements may help reduce the use of ineffective and potentially dangerous supplements. However, it should also be noted that national surveys of dietary supplement users indicate that individuals who regularly consume supplements report they would continue using them regardless of the advice of medical professionals or scientific evidence indicating they were not effective (Blendon et al., 2001). Acknowledgements The opinions or assertations contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the U.S. Army or the Department of Defense. Human subjects participated after giving their free and informed voluntary consent. The investigators adhered to the policies for protection of human subjects as prescribed in Army Regulation 70-25, and the research was conducted in adherence with the provisions of 32 CFR Part 219. Citations of commercial organizations and trade names in this report do not constitute an official endorsement or approval of the products or services of these organizations.

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REFERENCES Arsenault, J., and J. Kennedy. 1999. Dietary supplement use in U.S. Army Special Operations candidates. Mil Med 164(7):495-501. Balluz, L. S., C. A. Okoro, B. A. Bowman, M. K. Serdula, and A. H. Mokdad. 2005. Vitamin or supplement use among adults, behavioral risk factor surveillance system, 13 states, 2001. Pub Health Rep 120(2):117-123. Bathalon, G. P., S. M. McGraw, L. D. Hennessy, W. F. Barko, J. F. Creedon, and H. R. Lieberman. 2000. Comparison of reported nutritional supplement intake in two army populations. Supplement to JADA 100:A102. Blendon, R. J., C. M. DesRoches, J. M. Benson, M. Brodie, and D. E. Altman. 2001. Americans’ views on the use and regulation of dietary supplements. Arch Intern Med 161(6):805-810. Blumenthal, M., G. K. L. Ferrier, and C. Cavaliere. 2006. Total sales of herbal supplements in United States show steady growth. Herbal Gram 71:64-66. Bovill, M. E., W. J. Tharion, and H. R. Lieberman. 2003. Nutrition knowledge and supplement use among elite U.S. army soldiers. Mil Med 168(12):997-1000. Brasfield, K. 2004. Dietary supplement intake in the active duty enlisted population. U.S. Army Med Dept J 10-12:44-56. Bryant, R., and S. Bryant. 2005. 75th Rangers. St. Paul: Zenith Press. Ciocca, M. 2005. Medication and supplement use by athletes. Clin Sports Med 24(3):719-738. DoD (Department of Defense). 2006. Active duty military personnel by rank/grade. http://siadapp.dior.whs.mil/personnel/MILITARY/rg0612.pdf (accessed December 2006). De Smet, P. A. 2002. Herbal remedies. N Engl J Med 347(25):2046-2056. Erdman, K. A., T. S. Fung, and R. A. Reimer. 2006. Influence of performance level on dietary supplementation in elite Canadian athletes. Med Sci Sport Exerc 38(2):349-356. Fennell, D. 2004. Determinants of supplement usage. Prev Med 39(5):932-939. Fragakis, A. S., and C. Thomson. 2007. Popular dietary supplements, 3rd ed. Chicago, IL: American Dietetic Association. Froiland, K., W. Koszewski, J. Hingst, and L. Kopecky. 2004. Nutritional supplement use among college athletes and their sources of information. Int J Sport Nutr Exerc Metab 14(1):104120. Gardner, C. D., L. D. Lawson, E. Block, L. M. Chatterjee, A. Kiazand, R. R. Balise, and H. C. Kraemer. 2007. Effect of raw garlic vs. commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: A randomized clinical trial. Arch Int Med 167(4):346-353. Hypericum Depression Trial Study Group. 2002. Effect of Hypericum perforatum (St. John’s Wort) in major depressive disorder: A randomized controlled trial. J Am Med Assoc 287(14): 1807-1814. IOM (Institute of Medicine). 2006a. Nutrient composition of rations for short-term, highintensity combat operations. Washington, DC: The National Academies Press. IOM. 2006b. Mineral requirements for military personnel: Levels needed for cognitive and physical performance during garrison training. Washington, DC: The National Academies Press. Juliano, L. M., and R. R. Griffiths. 2004. A critical review of caffeine withdrawal: Empirical validation of symptoms and signs, incidence, severity and associated features. Psychopharmacology 176(1):1-29.

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Lieberman, H. R., C. M. Falco, and S. S. Slade. 2002. Carbohydrate administration during a day of sustained aerobic activity improves vigilance, as assessed with a novel ambulatory monitoring device, and mood. Am J Clin Nut 76(1):120-127. Lieberman, H. R., G. P. Bathalon, C. M. Falco, F. M. Kramer, C. A. Morgan III, and P. Niro. 2005. Severe decrements in cognition function and mood induced by sleep-loss, heat, dehydration and undernutrition during simulated combat. Biol Psych 57(4):422-429. Lieberman, H. R., P. Niro, W. J. Tharion, B. C. Nindl, J. C. Castellani, and S. J. Montain. 2006. Cognition during sustained operations: Comparison of a laboratory simulation to field studies. Aviat Space Environ Med 77(9):929-935. Lonn, E., J. Bosch, S. Yusuf, P. Sheridan, J. Pogue, J. M. Arnold, C. Ross, A. Arnold, P. Sleight, J. Probstfield, G. R. Dagenais, HOPE and HOPE-TOO Trial Investigators. 2005. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. J Am Med Assoc 293(11):1338-1347. Mayhew, D. L., J. L. Mayhew, and J. S. Ware. 2002. Effects of long-term creatine supplementation on liver and kidney functions in American college football players. Int J Sport Nutr Exerc Metab 12(4):453-460. McClung, J. P., L. J. Marchitelli, K. E. Friedl, and A. J. Young. 2006. Prevalence of iron deficiency and iron deficiency anemia among three populations of female military personnel in the US Army. J Am Coll Nutr 25(1):64-69. McGraw, S. M., W. J. Tharion, and H. R. Lieberman. 2000. Use of nutritional supplements by U.S. Army Rangers. FASEB Journal 14:A742. Millen, A. E., K. W. Dodd, and A. F. Subar. 2004. Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey results. J Am Diet Assoc 104(6):942-950. Noonan, C., and W. P. Noonan. 2006. Marketing dietary supplements in the United States: A review of the requirements for new dietary ingredients. Toxicology 221(1):4-8. Nutrition Business Journal. 2007. Nutrition Business Journal. http://www.nutritionbusiness.com (accessed March 23, 2007). Office of Army Demographics. 2005. Army Profile FY05. Washington, DC: Office of Army Demographics. Rock, C. L. 2007. Multivitamin-multimineral supplements: Who uses them? Am J Clin Nutr 85(suppl):277S-279S. Scott, G. N., and G. W. Elmer. 2002. Update on natural product-drug interactions. Am J Health Syst Pharm 59(4):339-347. Solomon, P. R., F. Adams, A. Silver, J. Zimmer, and R. DeVeaux. 2002. Ginkgo for memory enhancement: A randomized controlled trial. J Am Med Assoc 288(7):835-840. Stavinoha, T. B., S. McGraw, and H. R. Lieberman. 2007. Dietary supplement use in the U.S. Army. Sports, Cardiovascular and Wellness Nutritionists (SCAN) 2007 Symposium, Austin, Texas, April 13-15. Striegel, H., P. Simon, C. Wurster, A. M. Niess, and R. Ulrich. 2006. The use of nutritional supplements among master athletes. Int J Sports Med 27(3):236-241. Tharion, W. J., C. J. Baker-Fulco, M. E. Bovill, S. M. Montain, J. P. DeLany, C. M. Champagne, R. W. Hoyt, and H. R. Lieberman. 2004. Adequacy of garrison feeding for Special Forces soldiers during training. Mil Med 169(6):483-490. U.S. Army. 2007. Special forces. http://www.goarmy.com/special_forces/ (accessed April 3, 2007).

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Wilson, K. M., J. D. Klein, T. S. Sesselberg, S. M. Yussman, D. B. Markow, A. E. Green, J. C. West, and N. J. Gray. 2006. Use of complementary medicine and dietary supplements among U.S. adolescents. J Adolesc Health 38(4):385-394.

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EVALUATING SAFETY OF DIETARY SUPPLEMENTS: A SUMMARY, WITH INTERPRETATION, OF THE 2005 INSTITUTE OF MEDICINE REPORT ON DIETARY SUPPLEMENTS: A FRAMEWORK FOR EVALUATING SAFETY Elizabeth Jeffery, Ph.D.1 INTRODUCTION The increased use of supplements since the passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA), and the broad spectrum of products that qualify as dietary supplements as defined by the DSHEA, make the determination of risk to the health of the consumer a sizeable task. This is particularly true given that the DSHEA requires that the Food and Drug Administration (FDA) determine what is unsafe, without providing to the FDA the ability to require that specific information on safety be presented by manufacturers prior to marketing, or even that manufacturers submit to the FDA any serious adverse event reports they receive on dietary supplement use. It was against this backdrop of incomplete information that the FDA requested the Institute of Medicine (IOM) and the National Research Council of the National Academies to propose a framework for evaluation of the safety of dietary supplement ingredients. (It should be noted that since that time, in December 2007, the law has changed, requiring manufacturers to submit to the FDA any reports they receive of serious adverse events). The IOM committee’s tasks were the following: 1. Develop a framework for categorizing and prioritizing dietary supplement ingredients sold in the United States, based on safety issues. 2. Describe a process for developing a system of scientific reviews. 3. Utilize the proposed framework to develop at least six scientific reviews or monographs as prototypes. 4. Revise the framework based on comments received. This latter request resulted in an interim report, public and FDA comment, and finally reassembly with new expertise to revise the report. The following summary will not dwell on the third and fourth sections, but on the proposed framework to categorize, prioritize, and review the safety of dietary supplements, published as a final report in 2005. Regulatory Background Current regulatory approaches to the safety evaluation of dietary supplements in the United States are a product of several key pieces of legislation that span the 20th century, culminating in the passage of the DSHEA in 1994. Since the passage of the 1938 Federal Food, Drug, and Cosmetic Act (FDCA), the FDA has wrestled with the most appropriate approach to regulating die1

University of Illinois, Urbana, Illinois

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tary supplements, and several attempts have been met with resistance by industry as well as by segments of the public. In 1958, the Food Additives Amendment to the FDCA defined food additives and provided that they must undergo a premarket approval process unless they are considered to be generally recognized as safe (GRAS). However, the FDA’s attempts to regulate botanical products as unapproved food additives were halted by the courts, based on the product’s intended use, as determined by the labeling and advertising claims, to be a supplement to the diet. In 1994, the DSHEA established the legal definition of dietary supplements as foods (see Box B-12), and defined the FDA’s authority over these products: the FDA bears the burden of proof in determining that a dietary supplement ingredient presents a “significant or unreasonable risk of illness or injury” (see Box B-13), rather than the manufacturer being responsible for providing safety data (the law for drugs and other nonfood items). For dietary ingredients new to the U.S. market since 1994, manufacturers or distributors must notify the FDA at least 75 days before introducing a dietary supplement ingredient, and must provide the FDA with the information that is the basis upon which they have concluded that the new ingredient can “reasonably be expected to be safe.” The most common basis for GRAS is historical use, although regulations do not presently limit GRAS to similar processing/preparation (e.g., hot water extract versus whole plant material) or even the same plant parts as the “historically safe” food.

BOX B-12 Legal Definition of a Dietary Supplement as Defined by the Dietary Supplement Health and Education Act of 1994 The term dietary supplement: (1) means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E). Dietary supplements are further defined as products that are labeled as dietary supplements and are not represented for use as a conventional food or as a sole item of a meal or the diet. Supplements can be marketed for ingestion in a variety of dosage forms including capsule, powder, softgel, gelcap, tablet, liquid, or, indeed, any other form so long as they are not represented as conventional foods or as sole items of a meal or of the diet (FDCA, as amended, § 402).

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BOX B-13 Safety Standards for Dietary Supplements as Established by the DSHEA Section 4. Safety of Dietary Supplements and Burden of Proof on FDA. DSHEA amends § 402 (21 U.S.C. 342) by adding the following: (f) (1) If it is a dietary supplement or contains a dietary ingredient that— (A) presents a significant or unreasonable risk of illness or injury under – (i) conditions of use recommended or suggested in labeling, or (ii) if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use; (B) is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury; (C) the Secretary declares to pose an imminent hazard to public health or safety, except that the authority to make such declaration shall not be delegated and the Secretary shall promptly after such a declaration initiate a proceeding in accordance with sections 554 and 556 of title 5, United States Code to affirm or withdraw the declaration; or (D) is or contains a dietary ingredient that renders it adulterated under paragraph [402](a)(1) under the conditions of use recommended or suggested in the labeling of such dietary supplement. In any proceeding under this paragraph, the United States shall bear the burden of proof on each element to show that a dietary supplement is adulterated. The court shall decide any issue under this paragraph on a de novo basis. (2) Before the Secretary may report to a United States attorney a violation of the paragraph (1)A for a civil proceeding, the person against whom such proceeding would be initiated shall be given appropriate notice and the opportunity to present views, orally and in writing, at least 10 days before such notice, with regard to such proceeding. SOURCE: FDCA, P.L. 75-717 § 402, AS AMENDED 21 U.S.C. § 342(F) (2001).

The Safety Framework The framework consists of two sections: (1) a process for prioritizing, evaluating, and describing available information about risk of harm; and (2) a set of science-based principles for interpreting this incomplete dataset and for evaluating risk to human health. The committee kept in mind that “risk” is a likelihood measure, not a proven effect. Section 1—The Process The safety framework has three components: signal detection, identification of level of concern in an initial review, and integrative evaluation, as well as consideration of how these components feed into the FDA’s decision to take action (Figure B-24). PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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Signal Detection

Proactive Initiation

Initial Review

Concern Level Lower..............................Higher

Integrative Evaluation Gather Data -Categories -Prevalence of Use -Use by Vulnerable Groups

MONITOR Draft Monograph Continue to Collect Data

TAKE ACTION

Integrate Data

Use Expert Advisory Committee

Concern Level Lower..............................Higher

FIGURE B-24 Diagram of the three components of the safety framework: signal detection, identification of level of concern in an initial review, and integrative evaluation, as well as consideration of how these components feed into the FDA’s decision to take action

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Signal detection. Many, even the vast majority, of dietary supplement ingredients available in the United States appear safe when used as directed, and because of the limited resources available to the FDA, may never undergo safety evaluation. However, even those that appear safe under most circumstances may prove of concern to specialty groups such as pregnant women, the elderly, or the military in active service. Signal detection describes cause for an ingredient’s safety to be reviewed. The credibility of the signal and its relationship to any serious adverse effect(s) in humans must next be confirmed. Confirmation that a serious2 health problem may result due to ingestion of a dietary supplement ingredient signals the need for further study. In addition to signal detection, a proactive review of the safety of a dietary supplement ingredient may be appropriate, particularly where there is high prevalence of use among a potentially vulnerable population. Due to the large number and diversity of dietary supplements available, varied formulations and poor documentation of safety issues, no further prioritization was recommended. Initial review of available information. Following review of the nature (e.g., quality of the report, applicability to humans, route of exposure, confounding exposures) of a signal to determine the appropriate level of concern regarding a risk to human health, available data on safety should be collected for evaluation and generation of a monograph. It is proposed that data are collected in four categories; human data, animal data, data on related substances, and in vitro data. Integrative evaluation. Integration of available data into an analysis, and possibly referring the draft monograph and accompanying information to an expert advisory committee for additional input prior to the FDA determining whether to take regulatory action, completes the monograph production process. An integrative evaluation might be focused, reacting to concern over a specific signal of high concern, or broad, searching for any risk associated with use of a particular dietary supplement ingredient. Integrating the data to determine risk. Given the incompleteness of safety information, a causal model was developed as a tool to integrate multiple different categories of available data in order to establish risk. Evidence-based principles were used for considering these various categories of data and for methods of integration among and within categories of data during the integrative evaluation (Figure B-25). At any point during monograph construction and data integration, should evidence indicate a lower level of concern, the FDA could choose to place the draft on reserve, together with triggers (such as My NCBI and other automated search tools) to alert the FDA should the level of concern rise in the future. It is necessary for the FDA to do this since, although the industry is required to perform postmarketing surveillance in the case of drugs, postmarketing surveillance is not required for dietary ingredients. Recently, the FDA added the category “dietary supplements” to their online adverse event reporting system MedWatch, available for manufacturers, distributors, and consumers as well as physicians. Whether this generates quality data will depend upon the quality of data input.

2

Serious—any experience resulting in any of the following outcomes: death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the individual and may require medical or surgical intervention to prevent one of the outcomes previously listed (in accordance with 21 C.F.R. § 600.80 [2002] and 21 C.F.R. § 314.80 [2002]).

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FIGURE B-25 Illustration of a causal model used to integrate different types of data. Panel A describes categories of available data that are not independently very strong or conclusive regarding ingredient X’s relationship to adverse effect Y. Panel B describes data that, when integrated across the different categories, allow for a stronger conclusion by strengthening the linkages between ingredient I and adverse effect Y. Dashed arrows indicate weak or inconclusive data

Section II—Applying Science-based Principles to Establish Risk In determining the risk for serious harm from exposure to a specific dietary supplement ingredient, the framework provides guiding principles for the use of available scientific information from all four categories of data: human data, animal studies, information on related substances, and in vitro experiments (Box B-14). The report also describes how to consider the potential for dietary supplement interactions with drugs and other xenobiotics. Quantitative evaluation of risk is limited to level of concern, initially based on the signal detected, and later on the integrated product of all high-quality scientific data. Thus a high level of concern, indicating a more immediate priority for investigating further to determine if an unreasonable risk to public health exists, may be generated by even a single unconfounded serious health problem. Alternatively, in the absence of clear human data, a high level of concern may only be evident following integration of data from other categories of data. The necessity for an integrated

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evaluation is based on the very real lack of human safety data for most dietary supplement ingredients. Key Principles for Considering Data. The following three questions are asked when considering data: •

Is there a concentration of substances at the sites of action? A critical factor in determining toxicity of an ingredient is not necessarily the ingested amount, but the concentration of a dietary supplement’s active constituents, in active form, at their sites of action.

•

Is there an absence of evidence? Absence of evidence of risk does not indicate that there is no risk. Even if a study showing lack of adverse effects is reported, if the study is not adequately designed to identify risk (e.g., not sufficiently powered, incompletely reported, does not include positive controls, or otherwise has inadequate mechanisms for detecting adverse events), it is not scientifically valid to use such information to mitigate suggested risk from other sources.

•

Is there consistency and biological plausibility? Data can be collated within the same category and across categories to determine level of concern. In integrating observations across categories of data, consistency and evidence of biological plausibility should raise the level of concern, facilitated, and conceptually illustrated, by the use of causal evidence models. Examples of monographs and integrated causal evidence models are available at www.iom.edu/fnb.

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BOX B-14 Guiding Principles for Evaluating Data to Determine Unreasonable Risk •

•

• •

•

General principles - Absence of evidence of risk does not indicate that there is no risk. - Proof of causality or proof of harm is not necessary to determine unreasonable or significant risk. - Integration of data across different categories of information and types of study design can enhance biological plausibility and identify consistencies, leading to conclusions regarding levels of concern for an adverse event that may be associated with use of a dietary supplement. Human data - A credible report or study finding of a serious adverse event in humans raises concern about the ingredient’s safety and requires further information gathering and evaluation; final judgment, however, will require consideration of the totality of the evidence. - Historical use should not be used as prima facie evidence that the ingredient does not cause harm. - Considerable weight can be given to a lack of adverse events in large, highquality, randomized clinical trials or epidemiological studies that are adequately powered and designed to detect adverse effects. Animal data - Even in the absence of information on adverse events in humans, evidence of harm from animal studies is often indicative of potential harm to humans. Related substances - Scientific evidence for risk can be obtained by considering if the plant constituents are compounds with established toxicity, are closely related in structure to compounds with established toxicity, or the plant source of the botanical dietary supplement itself is a toxic plant or is taxonomically related to a known toxic plant. - Supplement ingredients that are endogenous substances or that may be related to endogenous substances should be evaluated to determine if their activities are likely to lead to serious effects. Considerations should include the substance’s ability to raise the steady-state concentration of biologically active metabolites in tissues and whether the effect of such increases would be linked to a serious health effect. In vitro data - Validateda in vitro studies can stand alone as independent indicators of risk to human health if a comparable exposure is attained in humans and the in vitro effects correlate with a specific adverse health effect in humans or animals.

__________ a

In this report, in vitro assays are considered validated when their results have been proven to predict a specific effect in animals and/or humans with reasonable certainty (not necessarily universally accepted or without detractors).

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Limitations of the Framework The framework as presently described has limitations: it cannot be used to consider any possible benefits of consuming dietary supplements; it is focused on ingredients rather than products available in the marketplace; it is not a measure of safety or hazard—only of risk, that is of “potential” for hazard; and it does not offer a quantitative measure of risk. If in the future, more data, particularly human data, are available, then more complete prediction capabilities, and requirements for such, could be included in an updated framework. However, dietary supplements, by virtue of the DSHEA, have been assumed to be safe—they have not been required to be proven safe. Thus, the appropriate scientific standard to be used to overturn this basic assumption of safety is to demonstrate significant or unreasonable risk, not proof that an ingredient is unsafe. In developing the framework, approaches to the evaluation of safety of dietary supplements taken by other organizations and governmental bodies, both within and outside the United States, were reviewed and found to vary in their relevance to the protection of the American public from risks associated with consumption of dietary supplement ingredients. The completed framework placed high importance on reliance of high-quality scientific data, consideration of all categories of such data (including animal data, in vitro data, data about the safety of related substances, as well as data on human use), use of appropriate expertise, and objectivity, as they gleaned ideas from other approaches. Often the approaches were neither sufficiently detailed nor sufficiently transparent to give a complete picture of the data considered, how sparse data were weighed and considered, the rationale behind the conclusions, or other questions regarding safety. Thus the review of other approaches was useful for not only identifying components to include in the framework, but also to identify necessary components absent from other reports. Recommendations to the FDA were included. Although most of these have not yet been carried out, due in part to lack of human and financial resources, the FDA has commenced collection of voluntary adverse event reports. It is very challenging for the FDA to carry out the mandate of the DSHEA given the limitations that the DSHEA imposes on the few requirements of data from the manufacturer and thus on the quantity and quality of currently available scientific data related to the safety of dietary supplement ingredients. One of the key premises of the DSHEA is that history of use is evidence of safety when applied to dietary supplements; yet there are significant scientific problems with this assumption, including lack of similarity in formulation between the supplement and the historical food. In line with these findings, members of the scientific and medical community have strongly advised that the regulatory mechanisms for monitoring the safety of dietary supplements, as currently defined by the DSHEA, be revised. The constraints imposed on the FDA with regard to ensuring the absence of unreasonable risk associated with the use of dietary supplements make it difficult for the health of the American public to be adequately protected.

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APPROACHES FOR POSTMARKETING ADVERSE EFFECT SURVEILLANCE OF DRUGS AND BIOLOGICALS Gerald J. Dal Pan1 Monitoring and understanding the safety of drug and therapeutic biologic products is a process that proceeds throughout the product’s life cycle, spanning the period prior to first administration to humans through the entire marketing life of the product. This chapter will present a brief overview of the Food and Drug Administration’s (FDA’s) programs to monitor the safety of drugs and therapeutic biologics after approval. This chapter will not be an all-inclusive discussion of the topic, which is broad, and has been covered in detail elsewhere (Ahmad et al., 2005; Arlett et al., 2005). Rather, the fundamental structure of the system will be reviewed. Preapproval drug safety assessment includes animal toxicology and pharmacology studies, clinical pharmacology studies (also known as phase 1 studies), proof-of-principle studies for the disease or condition under study (also known as phase 2 studies), and confirmatory studies of safety and efficacy (also known as phase 3 studies). In each of these stages of drug development, important drug safety information is obtained. These topics have been covered elsewhere in detail (FDA, 2002; IOM, 2006) and will not be further addressed here. At the time a drug product is approved, there is a substantial amount of data regarding its safety profile. In the preapproval review process, the FDA reviews these data, along with data on the product’s efficacy, to determine if the potential benefits of the drug exceed the potential risks for its intended use. As part of the approval process, the FDA reviews the product’s professional labeling (also referred to as the package insert), to ensure that, amongst other things, the product’s uses and its risks are explained. Risks of the products are presented in the following sections of the label: Highlights, Boxed Warnings, Contraindications, Warnings and Precautions, and Adverse Reactions. Though the preapproval testing of a drug is very rigorous, and the review of the data is very thorough, there are still some uncertainties about the complete safety profile of a drug when it is brought to market. Several factors contribute to these uncertainties. First, the number of patients treated with the drug prior to approval is limited, generally from several hundred to a few thousand. Second, patients in clinical trials tend to be more carefully selected for treatment, and thus more clinically homogeneous, than patients treated in the course of clinical practice once a drug is marketed. Compared to patients in clinical trials, patients treated in clinical practice may have a broader range of comorbidities, take a wider variety of concomitant medications, and have a different spectrum of the underlying disease being treated. Third, additional populations of patients, such as children or the elderly, who may not have been studied in large numbers in clinical trials, may be treated with the product once it is marketed. In addition, marketed drug products are often used for diseases or conditions for which they are not indicated, or at doses outside of the approved range (“off-label use”), thus making patients treated in clinical practice more diverse than those treated in clinical trials. No drug product is free of harm in all persons who take it. Rather, the term safe is used to indicate that the potential benefits of the product outweigh its potential risks. The goal of the post1

Director, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD.

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marketing, or postapproval, safety program is to identify adverse events that were not identified prior to approval, and to understand better the spectrum of adverse events associated with the drug, including adverse events recognized prior to approval. A core aspect of the postapproval drug safety system is the reporting of adverse events to the FDA. In the United States, suspected adverse events in individual patients are generally identified at the point of care. Patients, physicians, nurses, pharmacists, or anyone else at the point of care who suspects that there may be an association between an adverse event and a drug or therapeutic biologic product can, but are generally not required, to report the adverse event to either the manufacturer or to the FDA. The public can send reports directly to the FDA via the MedWatch program (http://www.fda.gov/medwatch/), which was established in 1993 to allow health care providers and consumers to send a report about serious problems that they suspect are associated with any medical product (e.g., drug, biologic, device) directly to the FDA. In addition, the MedWatch program also sends information about newly identified safety findings and new safety-related labeling changes to those who join its e-mail list. Members of the public can also report suspected adverse events to a product’s manufacturer, which is then subject to regulations regarding the submission of these reports to the FDA. The person or company that owns an approved New Drug Application (NDA) (21 C.F.R. §314.80) or Abbreviated New Drug Application (ANDA) (21 C.F.R. §314.98) have postmarketing safety reporting responsibilities. Additionally, “any person other than the applicant (nonapplicant) whose name appears on the label of an approved drug product” also has postmarketing safety reporting responsibilities [21 C.F.R. §314.80 (c)(1)(iii)]. The licensed manufacturer that holds a Biological License Application (BLA) (21 C.F.R. §600.80) or any person whose name appears on the label of a licensed biological product as its manufacturer, packer, distributor, shared manufacturer, joint manufacturer, or any other participant involved in divided manufacturing has postmarketing safety reporting responsibilities [21 C.F.R. §600.80(c)(1)(iii)] (FDA, 2007). In addition, other entities have postmarketing safety reporting responsibilities. Manufacturers are required to submit postmarketing expedited safety reports to the FDA for prescription drug products marketed for human use without an approved application [21 C.F.R. §310.305(a)]: “any person whose name appears on the label of a marketed drug as its manufacturer, packer, or distributor” [21 C.F.R. §310.305(c)(1)(i)] has postmarketing safety reporting responsibilities. For simplicity, this section uses the term manufacturer to indicate those with reporting responsibilities. When the manufacturer of a product receives an adverse event report, that manufacturer is required to report the event to the FDA. The specific reporting requirements depend both on the regulatory status of the product and on the nature of the event. In general, adverse events are defined as “serious” if they result in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive

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treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse [21 C.F.R. §314.80 (a) Similar language in 21 C.F.R. §310.305(b) and 21 C.F.R. §600.80(a)]. “Adverse events” are also defined as “unexpected” if they are not listed in the current labeling for the drug product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an adverse drug experience that has not been previously observed (i.e., included in the labeling) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product” [21 C.F.R. §314.80 (a) Similar language in 21 C.F.R. §310.305(b) and 21 C.F.R. §600.80(a)]. From a public health perspective, adverse events that are both serious and unexpected are of the greatest concern, and information about such events may require regulatory action, such as a labeling change or dissemination of information to the public, on the part of the FDA, the manufacturer, or both. For products that are the subject of an approved application (i.e., an approved New Drug Application [NDA], licensed Biological License Application [BLA], or approved Abbreviated New Drug Application [ANDA]), the manufacturer must report any event that is both serious and unexpected to the FDA within 15 days; in addition, any follow-up information about serious and unexpected events must also be submitted within 15 days. Other adverse event reports must be submitted on a periodic basis [21 C.F.R. §314.80 (c) (2) for NDAs and ANDAs and 21 C.F.R. §600.80 (c) (2) BLAs]. Over-the-counter (OTC) drug products can be marketed either under an approved NDA or ANDA, or under an OTC drug monograph. Those marketed under an approved NDA or ANDA follow the same reporting requirements as prescription products marketed under NDAs or ANDAs. Up until recently there were no postmarketing safety reporting requirements for monograph OTC products. In late 2006 Public Law 109-462 was passed that requires those responsible for monograph OTC drug products to submit reports of all serious adverse events to the FDA within 15 days, and to submit follow-up reports within 15 days. (The law has similar requirements for dietary supplements, though discussion of this provision is beyond the scope of this chapter). There are also adverse event reporting requirements for manufacturers of unapproved prescription products, which are generally products that were brought to the market before the Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act in 1962. For these products, only original and follow-up reports of adverse events that are both serious and unlabeled must be sent to the FDA [21 C.F.R. §310.305 (a)]. The above system of adverse event reporting is sometimes called a passive, spontaneous reporting system. It is passive because FDA receives this information, rather than actively seeking it out. It is spontaneous because the persons who initially report the adverse events to either the FDA or to the manufacturer choose what events to report. It is generally recognized that there is substantial underreporting of adverse events to FDA.

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The adverse event reports that the FDA receives from the public and from the manufacturers are entered into a database known as the Adverse Event Reporting System (AERS). The FDA receives over 400,000 reports a year; about 94 percent of them are from manufacturers, and the remainder are directly from the public via the MedWatch system. Many manufacturers submit reports to the FDA electronically, using the standards set forth by the International Conference on Harmonization (ICH), which includes regulators and industry representatives from three regions—the United States, Japan and the European Union (FDA, 2005a). Adverse events in AERS are coded using a system called MedDRA, the Medical Dictionary for Regulatory Activities that was developed under the auspices of the International Conference on Harmonisation (ICH, 2007). For reports received directly from the public via MedWatch, there is a manual triage process performed by a trained pharmacist who looks at every report to ensure that each goes to the right database(s), since the reported adverse event may relate to a drug or therapeutic biologic, a blood product, a vaccine, a medical device, or a dietary supplement. The FDA reviews the reports it receives and pays particular attention to those of adverse events that are both serious and unexpected. An important part of the review focuses on the narrative report that is included. The quality of these narratives varies from one report to the next. In general, the more complete the clinical data in the narrative, the more useful the report is. Reports with little or no clinical data are of limited value. Manufactures are required by regulation [21 C.F.R. §314.80(c)(1)(ii), §600.80(c)(1)(ii), and §310.305(c)(2)] to pursue follow-up of adverse event reports. The FDA does not have the resources to pursue follow-up in all cases, but does pursue follow-up in selected cases. The review of adverse event reports is a complex process, and can not be covered here in detail. It has, however, been reviewed elsewhere (Ahmad et al., 2005), and has been the subject of public discussion (FDA, 2005b). In brief, the ability to make an inference about the causal relationship of an adverse event to a drug or therapeutic biologic product is greatest for adverse events that are rare, that are generally the result of drug treatment, and don't have a high background rate. Examples of such types of adverse events include acute liver failure (without any other obvious cause), aplastic anemia that has no other obvious cause, agranulocytosis, certain skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis, and certain arrhythmias that result from QT interval prolongation. On the other hand, the review of individual case reports is generally not helpful in evaluating the causal relationship of an event that is already common in the underlying population. For example, if a drug is given to patients for the treatment of high blood pressure, individual case reports of myocardial infarction will be difficult to interpret, since high blood pressure is a risk factor for myocardial infarction. Similarly, if a drug is given primarily to patients between the ages of 50 and 70 years old, case reports of myocardial infarction will again be difficult to interpret, since myocardial infarction has a high background rate in this population. To help place reports of adverse events in a broader context, data on drug utilization are often incorporated into the analysis. Typically, these data provide information on the number of prescriptions dispensed for a given drug, not the number of persons who have taken the drug. These data, which are obtained from commercial vendors, are used to calculate a reporting rate. The reporting rate is calculated by dividing the number of cases in the FDA’s AERS database of an adverse event in persons taking a given drug by the number of prescriptions dispensed for that drug in a given time period. It is important to note that the reporting rate is not an incidence rate.

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The calculation of an incidence rate requires knowledge of the total number of cases of the adverse event in the population as well as knowledge of the total number of persons and the duration of drug exposure in the population taking the drug. Because the AERS system only receives a small fraction of all drug-related adverse events occurring in the population, the total number of cases of the adverse event of interest is not available. In addition, the drug utilization data available to the FDA has reported drug utilization in terms of number of dispensed prescriptions, not in terms of number of actual persons taking the medication. For these reasons, a reporting rate is not the same as an incidence rate. (Data on the number of persons taking a given drug has recently become available, though experience with this measure to date is limited.) Nonetheless, despite some well-recognized limitations (Ahmad et al., 2005; Rodriguez et al., 2001), reporting rates are useful for placing adverse event reports in a population-based context and for following trends over time (Ahmad et al., 2005). Data mining is an additional tool that can be used to evaluate data in the AERS database. Briefly, data mining refers to the application of computer algorithms to a database to identify patterns and associations that are not otherwise easily apparent. This method can be used to search the AERS database for combinations of drugs and adverse events that occur more frequently than would be expected based solely on data from the AERS database. The mathematical basis of this approach is beyond the scope of this paper, but is well described elsewhere (Almenoff et al., 2005). It is important to note that a signal identified through data mining does not imply a causal relationship between a drug and an adverse event. Rather, it is a signal that further evaluation of the individual cases is required. As such, data mining is only the first step in a process that requires detailed review of the cases that give rise to the data mining signal. In addition to the AERS database, there are other sources of data and other methodological approaches used in the evaluation and quantification of suspected adverse drug events. Observational epidemiological studies, which include case-control studies and cohort studies, are approaches that can confirm an association between a drug and an adverse event, and can also provide a quantitative measure of that association. In addition, properly designed observational studies can control for potentially confounding factors that might otherwise result is an inaccurate measure of association between the drug and the adverse event. A variety of data sources can be used for these studies. Data from electronic health records and from linked medical claims and pharmacy claims databases have been used for these purposes (Graham et al., 2004; Hennessy, 2006). In addition, data collected specifically for a drug safety study can be used (Writing Group, 2002). Observational epidemiological studies are time consuming and costly, and are thus used to examine important drug safety questions that can not be answered with data from spontaneous report systems. Clinical trials provide another approach to examining drug safety questions. Many clinical trials are designed primarily to examine a drug efficacy question, but nonetheless collect safety information. In addition, some clinical trials are designed primarily to examine a specific safety question. Active surveillance systems are also being explored to identify and examine drug safety issues. Drug safety active surveillance systems, which take advantage of large repositories of automated health care data, are now being developed and tested by multiple organizations. The commonality of these systems is that they do not rely on health care providers or patients to recognize and report adverse events that may be related to medication use. Rather, these systems often use sophisticated statistical methods to actively search for patterns in linked prescription, outpatient, and inpatient utilization of care data that might suggest the occurrence of an adverse

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event related to drug therapy. This lack of reliance on health care providers or patients to detect the event, relate it to a drug, and then report it to FDA, along with its prospective nature, is what makes these systems “active” rather than “passive” in their scope. However, one system is unlikely to address all drug safety problems or all patient populations. While there is much interest in developing these systems, there is also much work to be done in the validation of these systems. Monitoring and evaluating new safety signals of drugs and therapeutic biologics after they have been approved is part of a lifecycle approach to drug safety. While the spontaneous reporting system has been the cornerstone of the postapproval drug safety system in the United States for several decades, new approaches based on large population-based databases will be explored in the coming years and will likely play an increasingly important role in this system.

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REFERENCES Ahmad, S. R., R. A. Goetsch, and N. S Marks. 2005. Spontaneous reporting in the United States. In Pharmacoepidemiology, 4th ed., edited by B. L. Strom. : New York: John Wiley & Sons. Pp. 135-159. Almenoff, J., J. M. Tonning, A. L. Gould, A. Szarfman, M. Hauben, R. Ouellet-Hellstrom, R. Ball, K. Hornbuckle, L. Walsh, C. Yee, S. T. Sacks, N. Yuen, V. Patadia, M. Blum, M. Johnston, C. Gerrits, H. Seifert, and K. LaCroix. 2005. Perspectives on the use of data mining in pharmacovigilance. Drug Safety 28:981-1007. Arlett, P., M. Mosely, and P. J. Seligman. 2005. A view from regulatory agencies. In Pharmacoepidemiology, 4th ed., edited by B. L. Strom. New York: John Wiley & Sons. Pp. 103-130. FDA. 2001. Guidance for industry: Postmarketing safety reporting for human drug and biological products including vaccines. http://www.fda.gov/cder/guidance/4177dft.pdf (accessed July 9, 2007). FDA (Food and Drug Administration). 2002. The FDA’s drug review process: Ensuring drugs are safe and effective. FDA Consumer Magazine. July-August. Pub No. FDA05-3242. http://www.fda.gov/fdac/features/2002/402_drug.html (accessed July 9, 2007). FDA. 2005a. Guidance documents on E2B and E2BM, International Conference on Harmonization; Guidance on data elements for transmission of individual case safety reports. http://www.fda.gov/cder/guidance/1861fnl.pdf (accessed February 2008). FDA. 2005b. Drug Safety and Risk Management Advisory Committee meeting. May 18–19, 2005. http://www.fda.gov/OHRMS/DOCKETS/98fr/05-7458.htm (accessed July 9, 2007). Graham, D. J., J. A. Staffa, D. Shatin, S. E. Andrade, S. D. Schech, L. La Grenade, J. H. Gurwitz, K. A. Chan, M. J. Goodman, and R. Platt. 2004. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292(21):2585-2590. Hennessy, S. 2006. Use of health care databases in pharmacoepidemiology. Basic Clin Pharmacol Toxicol 98:260-265. ICH (International Conference on Harmonisation). 2007. MedDRA—the Medical dictionary for regulatory activities. http://www.meddramsso.com/MSSOWeb/index.htm (accessed February 2008). IOM (Institute of Medicine). 2006. The future of drug safety: Promoting and protecting the health of the public. Washington, DC: The National Academies Press. Rodriguez, E. M., J. A. Staffa, and D. J. Graham. 2001. The role of databases in drug postmarketing surveillance. Pharmacoepidemiol Drug Saf 10:407-410. Writing Group for Women’s Health Initiative Investigators. 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288(3):321-333.

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FDA POSTMARKETING SURVEILLANCE: ISSUES FOR DIETARY SUPPLEMENTS Vasilios H. Frankos, Ph.D., and Robert Mozersky, D.O.1 The Center for Food Safety and Applied Nutrition (CFSAN) within the Food and Drug Administration (FDA) regulates foods, color, and cosmetics. Although dietary supplements are considered a food, there are laws that are unique and specific to dietary supplements. On October 15, 1994, the Dietary Supplement Health and Education Act amended the Food Drug and Cosmetic Act. This amendment defined a dietary supplement as: a product (other than tobacco) intended to supplement the diet that bears one or more of the following dietary ingredients: a vitamin; mineral; herb or botanical; dietary substance for use by man to supplement the diet by increasing the total dietary intake; and a concentrate, metabolite, constituent of any of the above” 21 U.S.C §321(ff) (1). Congress intended the law to limit impediments to marketing and promotion of dietary supplements, and expand the universe of lawfully marketed dietary supplement products. The law also made it clear that dietary supplements were not subject to premarket approval. The FDA could only take action against a dietary supplement when it could demonstrate that the supplement was unsafe. Lastly, nowhere in the law did it state that any adverse events associated with dietary supplements had to be reported to the FDA. Presently, adverse events related to dietary supplements are reported to the FDA on a voluntary basis. Any individual can submit an adverse event associated with a dietary supplement by using one of the following methods: going to the MedWatch website (http://www.fda.gov/medwatch/report/hcp.htm), by phoning 1-800-FDA-1088, or by submitting the MedWatch report in its document form. The entry point of most dietary supplement adverse events is within the Center for Drugs Evaluation and Research (CDER). Here it receives a unique MedWatch identification number and is forwarded to the center that regulates the product associated with the adverse event. Prior to June 2003, CFSAN was using a database called the Special Nutritional Adverse Event Monitoring System (SN/AEMS). SN/AEMS collected and manually entered into an Access database all adverse events related to dietary supplements. In June of 2003, CFSAN’s Adverse Event Reporting System (CAERS) became operational. This new database combined the Cosmetic Adverse Reaction Monitoring System, the Adverse Reaction Monitoring System that monitors adverse events associated with foods, and SN/AEMS into one database. The CAERS system is an electronic database and was designed to receive MedWatch reports related to products CFSAN regulates. Once in a while, an adverse event is reported directly to the CAERS system via e-mail, a phone call, or a letter. Regardless of the method by which CAERS receives the

Division of Dietary Supplement Products, Office of Nutritional Products, Labeling, and Dietary Supplements, Center for Food Safety and Applied Nutrition.

1

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adverse event the report is given a unique CAERS identification number, is MeDRA2 coded, and forwarded to the appropriate reviewer. The reviewer of an adverse event can request follow-up information regarding the case or complete his evaluation from the material present in the report. Usually a follow-up is requested when the adverse event is so severe or uncommon that immediate investigation of the product’s safety is warranted. Examples of such uncommon adverse events would be sudden death, liver or kidney failure, aplastic anemia, or Steven Johnson Syndrome. When such a severe type of adverse event is reported to the agency an expedited safety evaluation is undertaken. As part of such an evaluation, the FDA would contact any other federal agency, such as the Centers for Disease Control and Prevention, the Department of Defense, or a foreign regulatory agency to determine if they have evaluated a similar case. Foreign regulatory agencies that CFSAN consults with include Health Canada, MedSafe of New Zealand, Therapuetic Goods of Australia, and others. Examples of actions that the FDA has taken when it has identified a problem related to a dietary supplement include the banning of the selling of ephedrine alkaloids (February 11, 2004); a letter to industry, health care providers, and consumer advisory regarding the safety of aristolochic acid in April of 2001; and consumer advisory regarding the safety of LipoKinetix; usnic acid; kava; and many other dietary supplements. These and other actions can be found at http://www.cfsan.fda.gov/~dms/ds-warn.html. More often less unique and more common adverse events are reported to the FDA. Examples of such events are heart attack, stroke, or a consumer falling and fracturing a hip. One important resource that is considered during a review of these types of adverse events is whether one or more similar adverse event(s) have been reported in the medical literature. If similar adverse events related to a product have been identified, the reviewer may contact the author of the paper to obtain more details regarding the case(s). Next, literature regarding animal studies is evaluated to see if any animals exposed to the product in question experienced similar adverse events. Review of the pharmacology literature can also inform the reviewer whether the adverse reaction experienced by the consumer is biologically plausible. Finally, weekly, monthly, biannual, or annual reports are generated by querying the CAERS database; this often helps to identify trends that would otherwise not be seen. These types of reports are used to determine whether a specific product or specific adverse events occurs at an unusually high rate. Although these techniques are employed, rarely is a significant pubic health issue related to dietary supplements identified. Some of the reasons that affected the number of adverse events reported to CFSAN are: (1) patients may be embarrassed to admit to using alternative treatment to their health care provider, (2) consumers may be less likely to report herbal adverse event associations because many consumers believe dietary supplements are inherently safe or “natural,” and (3) an adverse event may be reported to a health care provider but not to the agency. Other problems with reports that are submitted for review is that the reports are incomplete. A report is considered incomplete unless it contains all of the following information: a reporter, an injured consumer, a CFSAN regulated product, and an adverse event. Even if all of the aforementioned information is included in the report, other significant information relating to the adverse event may not be present in the report. Such information includes formulation of the product. The term formulation of a product or the term proprietary blend often appears on the label of a dietary supplement. When this term is used, the quantity of each ingredient in the blend 2 Medical Dictionary Regulatory Activities (MeDRA) terms. The International Conference on Harmonization (ICH) developed MedDRA, which is a standardized dictionary of medical terminology.

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is not provided. Additional helpful information that is often not part of the report includes serving size of the product, and whether confounding factors, (e.g. whether the consumer had a prior medical condition, or was taking numerous dietary supplements or medications) were present at the time that the event occurred. Because the CAERS database relies strictly on reports that are submitted on a voluntary basis, and the fact that many of the reports submitted are incomplete, trends regarding adverse events are not easily identified. A method that could increase the ability of the database to detect serious adverse events would be to require adverse event reporting to be mandatory. On December 12, 2006, Congress enacted the Dietary Supplement and Nonprescription Drug Consumer Protection Act. This new law mandates that the individual’s whose name appears on the label of a nonprescription drug (also known as an over-the-counter drug) or a dietary supplement is responsible for reporting any serious adverse event associated with their product to the agency via a MedWatch 3500A form within 15 business days of the responsible party learning of the adverse event. A manufacture’s, packer’s, distributor’s, or retailer’s name and address must appear on the product’s label that is considered the responsible party. The law goes on to state that a product’s label must accompany the MedWatch report. Any new medical information related to a submitted serious adverse event must be reported to the FDA within 1 year of the initial report. The notifier must maintain records of a serious adverse event for a 6 years period and permit the FDA to have access to these records. The new law defined a serious adverse event as: death, a life-threatening experience, persistent or significant disability or incapacity, congenital abnormality or birth defect, and finally an event that requires based on reasonable medical judgment, a medical or surgical intervention to prevent an outcome described under one of the above examples. How will the new Dietary Supplement and Nonprescription Drug Consumer Protection Act help CFSAN regarding dietary supplement safety evaluations? The new law mandates manufacturers of dietary supplements to report serious adverse events using the MedWatch 3500A form. Because of this, CAERS will have an increase in the number of adverse events to review. It is also likely that these mandated reports will have more information then the voluntary reports CFSAN presently receives. Having a more robust database will allow a higher quality analysis of adverse events related to dietary supplements. In conclusion, the monitoring and trending of adverse events relating to dietary supplements will most likely improve. This is due to the fact that the new law mandates industry to report all serious adverse events it becomes aware of, and industry will be required to complete specific fields on the MedWatch 3500A form. With the increase in number and quality of adverse event reports, CFSAN will have a greater ability to detect dietary supplements that are causing or may lead to a public health concern.

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CORPORATE APPROACHES TO SAFETY AND POSTMARKET ADVERSE EVENT SURVEILLANCE OF DIETARY SUPPLEMENTS Rick Kingston1 INTRODUCTION Since the inception of the Dietary Supplement Health and Education Act (DSHEA), dietary supplement manufacturers have been challenged to implement systems of postmarket surveillance in order to monitor the safety of products marketed and distributed to consumers. Despite the appearance of numerous supplement safety-related issues, the most notable involving the botanical ephedra, no single system or approach to surveillance has emerged. For the most part, manufactures have relied on passive systems of surveillance to alert them to safety or product integrity issues that may or may not involve their specific products or ingredients. These passive systems of surveillance typically have involved media reports, isolated anecdotal case reports in the medical literature, spurious reports of poor product performance received and documented in complaint logs through corporate customer service lines, incidents that are the subject of litigation, spontaneously reported adverse events received and documented by poison control centers, and reports of safety issues forwarded to the manufacturer after being received by regulators who have been notified by consumers or health professionals. Reports of adverse events received through the Food and Drug Administration’s (FDA’s) MedWatch system have been forwarded to the Center for Food Safety and Applied Nutrition (CFSAN) for inclusion in the CFSAN Adverse Event Reporting System (AERS). Although the CFSAN AERS has been tabulating reports of adverse events, the system has not been readily accessible by manufactures or others that have been interested in reviewing information contained in that data collection system. Supplement AERs had previously been accessible from the FDA website but were subsequently removed due to concerns regarding the lack of validation, evaluation, and report accuracy. Although there are many possible avenues whereby manufacturers may learn of product issues, there has been no systematic effort to implement an industry standard of practice whereby manufactures can receive, document, manage, and analyze reported adverse effects potentially associated with supplement products. There are numerous reasons to account for the fact that no system of surveillance has emerged and there remains no system of “sharing” adverse events with regulators, consumers, academics, and others interested in monitoring or confirming the inherent safety profile of supplement products and their ingredients. First, most manufacturers have not perceived a need to implement comprehensive methods of postmarket surveillance to monitor for adverse effects given the inherently wide margin of safety associated with the majority of marketed dietary supplements. Most of the ingredients in dietary supplements have either achieved GRAS status (generally recognized as safe) or enjoy a well-documented history of safe use. Secondly, there has been no mandatory requirement that manufactures collect, document, and report supplement-related adverse events to any regulatory body, and those manufacturers that have implemented systems of surveillance have been reluctant to share their experience in any meaningful way without a level playing field with those that do not collect or share their experience. 1

SafetyCall International Poison Control Center, Bloomington, MN.

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Given the perception of inherent safety, lack of a supported regulatory system of surveillance sponsored by governmental agencies, and the fact that there has been no regulatory requirement for manufacturers to report, in those instances where products have been suspected to result in adverse events there have not been consistently available avenues for consumers or health professionals to report their experience. For those passive systems of surveillance that have been used, there have been significant limitations regarding their utility. Recent legislation will likely have a significant impact on dietary supplement postmarket surveillance. Twelve years after the passage of the DSHEA and an act of Congress largely supported by the dietary supplement industry, the introduction and passage of the Dietary Supplement and Nonprescription Drug Consumer Protection Act (DSNDCPA) was accomplished. The last bill of the 109th Congress, the DSNDCPA was passed and signed into law December 22, 2006. Upon full implementation on December 22, 2007, all dietary supplement manufacturers will be required to report to the FDA within 15 business days any allegation of a serious adverse event involving the manufacturer’s products. Although a system of postmarket surveillance is vital to ensuring product safety and quality, significant challenges will be faced by an industry ill prepared to receive, document, and manage all reports of adverse events for the prescribed 6 year required archiving period. Companies will need to identify and train personnel, develop a tracking system, maintain records, and meet short reporting deadlines. Despite these challenges, this new system of surveillance will offer substantial opportunities for manufacturers to share their safety experience with regulators, health professionals, consumers, and others interested in monitoring the safety of supplements. It will also be important for those interested in monitoring supplement safety to understand the existing systems of consumer product postmarket surveillance and how they might fit into the new supplement adverse event reporting paradigm or how their experience in monitoring product safety might apply. Existing Systems of Postmarket Surveillance for Consumer Products and Sponsoring Agencies or Organizations Consumer Product Safety Commission (CPSC) The CPSC has been monitoring product-related injuries resulting in hospitalization for decades. These incidents have been monitored through the National Electronic Injury Surveillance System (NEISS) and more recently the Cooperative Adverse Drug Event Surveillance project (CADES), which has been documenting drug and dietary supplement-related incidents that result in hospital visits. This system monitors a representative subset of U.S. hospitals for patient visits related to consumer product use. The recent addition of drug and supplement-related incidents may provide additional insight into those visits involving drugs or supplements. A limitation of this system relates to the fact that supplement-related hospital visits are relatively infrequent. Additionally, given that many consumers either do not share supplement use with their mainstream health care providers, or medical professionals do not ask about supplement use, those incidents potentially involving supplements may go undetected. It is also often times difficult for medical providers to find product information regarding various supplements that patients might report using. And lastly, in those instances where supplement use is reported or suspected to be associated with a hospital visit, there is no systematic method to code the supplement or its ingredients in order to track other potential sentinel events. Although there are limitations to its use, the CADES system might help identify and track more significant incidents involving specific supplements. Other CPSC product safety monitoring systems such as general consumer PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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communications or manufacturer communications are unlikely to apply to dietary supplement systems of safety surveillance. Environmental Protection Agency (EPA) FIFRA 6(a)(2) System of Mandatory Adverse Event Reporting Products regulated by the EPA are subject to mandatory adverse event reporting by manufactures under the Federal Insecticide Fungicide Rodenticide Act (FIFRA) 6(a)(2) rule. Although unrelated to the proposed supplement AERS, the 6(a)(2) rule is most similar to the new mandatory AERS for dietary supplements. Manufacturers subject to this rule are required to receive, document, categorize, and report any allegation of injury resulting from pesticide, herbicide, antibacterial, or other EPA-regulated product. The rule is quite similar to the supplement adverse event legislation but provides much more detail regarding exactly what incident elements must be collected and reported. The rule is also similar in that the majority of reported incidents come directly from consumers rather than health professionals that report incidents to drug manufacturers, which is typical of drug-related adverse events reported to the FDA. Incidents involving EPA-registered products that may be more accurately confirmed as regulated products have product registration numbers associated with every product and ingredient. These registration numbers allow accurate documentation and coding of involved products as well as allow benchmarking and tracking of sentinel events potentially associated with these products. This system of surveillance was modified in 1998 to its current format, which continues to be in place today. An additional similarity to the supplement AERS relates to how the system maximally engages the manufacturer to serve as a primary contact point for reported events. Pesticide manufactures do not typically employ health professionals skilled in responding to and documenting adverse events. Thus, manufacturers routinely outsource this function to outside medical entities or poison control centers that have this skill set and help the manufacturer meet reporting requirements while also helping the manufacturer understand their own experience. Typically, consumers are directed to the manufacturer’s AERS through a toll-free number on the product labeling or material safety data sheet (MSDS). The phone number may go directly to the manufacturers adverse event call center or be routed to the adverse event call center through the manufacturers customer service line. In any event, manufacturer employees are specifically trained to ensure that any allegation of a medical adverse event be directed to the proper channel to allow documentation and reporting within specific timeframes specified in the 6(a)(2) rule. The experience related to this system of surveillance will likely be similar to that of the dietary supplement industry. Consumers and health professionals have come to expect the manufacturer to provide information and support for any product associated injury, misadventure, or unintended consequence. Pesticide manufactures routinely receive and respond to medical-related inquiries of this nature. This system of surveillance has maximally engaged the manufacturer to collect, respond to, document, report, and analyze their ongoing postmarket experience. The safety of EPA-regulated products has typically been attributed to both premarket assessment and postmarket confirmation of an acceptable safety profile. Entities outside of the pesticide industry that utilize these products often use data collected through the 6(a)(2) reporting system to evaluate the safety of these products.

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FDA Systems of Surveillance Including the MedWatch and CFSAN Adverse Event Reporting System The MedWatch system of drug safety collects information from a variety of mandatory reporting channels involving the manufacturer and is most represented by three types of data: reports from clinical trials (high-quality reports from health professions well educated on the clinical pharmacology and actions of the drug in question), spontaneous reports from health professionals (often lower-quality reports from health professionals questioning a relationship), and spontaneous reports directly from consumers (lowest-quality report, no benefit of health professional “managing the event”). The majority of adverse event incident data represented in the MedWatch system is represented by these three categories of data in the listed respective order. It is also estimated that 94 percent of MedWatch incident data comes through the manufacturer (mandatory reporting) as opposed to being received directly from consumers or health professionals. Additionally, given that most drug use is supervised, monitored, or assisted by a learned and licensed professional who ultimately reports adverse event incidents to manufactures or through other venues, it is more common that reports from these entities are more likely to yield higher-quality data. Although less frequent as compared to mandatory reporting, MedWatch also receives data through non-company-sponsored reporting channels either directly from consumers or health professionals. This system is passive and less conducive to the collection of higher-quality data. Spontaneous reports depend on either the patient or a health care practitioner to identify an effect, identify a suspected cause, question a relationship, and report it to a governmental body. In these instances reporting is typically a one-way street (not designed to engage the caller and provide clinical advice, but rather record historical events after the fact). This nature of spontaneously reported data is most subject to misinterpretation. American Association of Poison Centers (AAPCC) Data Poison centers throughout the United States routinely provide telephone-based poison information services to the general public and health professionals regarding any incident involving substances potentially capable of resulting in unintended adverse consequences. Although likely not best suited for monitoring supplement adverse effects from routine product use, poison control center incident data is one of the most frequently cited databases regarding supplement toxicity issues and is routinely accessed by the public, health professionals, manufacturers, and regulators when questions of product-related adverse effects or toxicity are of concern. For those that report incidents to poison centers, there is no preregistration, payment, or any other requirement of those who use the service. Calls or reports to the centers are voluntary as there are no local or national requirements that any given incident must be reported and calls can also be made anonymously. The center’s phone lines are considered “hotlines,” and some centers align themselves or colocate service with nurse “advice line” programs, drug information centers, industry product surveillance services, or community 911 emergency phone operations. Since 1984, the experience of poison centers has been shared through the publication of an annual report. Prior to 2005 the report was published in the September issue of the American Journal of Emergency Medicine. The report is now being published in the journal Clinical Toxicology. All incidents reported to poison centers are tabulated in a standardized format and aggregated by the American Association of Poison Centers into a single database. This database was previously known as the Toxic Exposure Surveillance System (TESS) and has recently been renamed the National Poisoning and Exposure Database. Data from the poison control database PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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have been quoted in numerous publications addressing issues of toxicology and the epidemiology of poisoning in the United States. The annual report summarizes “exposure” calls where an individual has ingested or otherwise been exposed to a substance in an unintended or excessive manner, or routine product use has potentially resulted in adverse effects. The 2005 annual report identifies the majority of calls to poison centers as acute in nature (91.5 percent) as compared to chronic (1.9 percent) or acute on chronic (5.8 percent), which is defined as continuous or repeated exposures occurring over a period exceeding 8 hours (Lai et al., 2006). When calls are received, the poison center specialist assesses the incident and determines the need for treatment and/or referral. Recognizing the limitations of telephone-based patient assessment, it is usually the practice of poison specialists to consider a worst-case scenario regarding the incident in question. This may result in referral of individuals without the presence of any adverse effects in questionably toxic situations so that health care providers can provide a more in-depth, hands-on patient assessment. Not all exposure-related reports to poison centers represent poisoning. In more than 72 percent of exposure-related inquiries, no adverse clinical effects are reported, and when including cases in which no more than minor effects are reported, the total represents more than 87 percent of all calls. Additionally, not all reported incidents are equal in intensity, especially in those incidents classified as “adverse effects” secondary to drugs, chemicals, or other agents. Each case is assessed as to its overall clinical outcome (e.g., no effect; minor effect; moderate effect; major effect; unrelated effect; death, no follow-up; nontoxic, no follow-up; minimal toxicity, no follow-up; potentially toxic). Unless specifically coded as “unrelated,” the severity rating implies that the overall outcome is the result of the exposure to the substance(s) identified in the incident. Although a causal link is suggested with this type of classification system, many epidemiologists do not believe that incidents reported in this manner are amenable to determination of cause-and-effect relationships and at best, may only suggest an association between a given substance and a certain effect or outcome. As most incidents are reported by consumers, information must be taken at face value from individuals that may not be knowledgeable of all the exposure circumstances, clinical effects, and treatments that have been rendered. In the vast majority of reported incidents there is no attempt or ability to authenticate or validate individual reports. Poison center data has been inadvertently misrepresented in both science and public venues and are subject to both strengths as well as significant limitations. As an example, Bent et al. (2003) compared the number of reported incidents involving ephedra-containing products to other herbs. This article implied that the reported incidents coded as “adverse reaction” and contained in TESS were adjudicated as attributable to products involved in the incident. As spontaneously reported incidents, none were investigated nor validated in such a way so as to allow a cause-and-effect determination. Misunderstanding of the database structure and reporting format by the authors contributed to other errors in analysis and interpretation that were represented in the article (Kingston and Borron, 2003). Spontaneously reported data of this nature also have strengths and limitations regarding utility. This is especially true when drawing safety conclusions from aggregated data represented in the database. A significant limitation in reviewing these data is that calls categorized as “adverse reaction” are infrequently reported to poison centers, as compared to incidents involving single, acute exposures to potentially toxic substances. Kingston and Blumenthal (2003) reported that only 2.2 percent of all poison center calls nationwide involved reports of “adverse reaction” and

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APPENDIX B

B-137

only 0.1 percent of calls involved botanicals. The article noted that poison centers are infrequently consulted regarding botanical adverse events, and the relative representation of botanical adverse events in the database is quite small. The authors further concluded that the sensitivity of this database may not be sufficient to identify any significant trends one way or the other. Corporate-Sponsored Adverse Event Monitoring Programs Corporate-sponsored adverse event monitoring systems have typically developed from two different but sometimes related initiatives. The first has been mandatory regulatory reporting whereby manufactures have been required to collect and report to regulatory bodies various levels of incident data involving their products. Noncompliance can result in civil and/or criminal penalties, and a level playing field is established regarding all companies in a particular market segment. The best example here would be the pharmaceutical industry. All companies manufacturing pharmaceuticals are required to document and report any allegations of injury involving their products. This reporting requirement has resulted in full disclosure of negative findings from studies or reports of individual incidents resulting in adverse effects involving pharmaceuticals. These data are simultaneously reviewed by the manufacturer and their regulators for trends and signals regarding product safety. This type of reporting initiative has also been experienced in the EPA-regulated product environment involving pesticides, herbicides, and other registered products. The second initiative supporting adverse event monitoring (without regulatory reporting) has evolved from product stewardship programs. In this instance, manufacturers have accepted the responsibility of being good stewards of the products they manufacture and sell to consumers. National industry trade associations have helped nurture the development of these programs to help their members and their industries manage risk, care for their consumers, and demonstrate commitment to ethical practices regarding consumer safety. Examples of trade associations and industries that have initiated stewardship initiatives include: • American Chemistry Council—Responsible Care Program •

Consumer Specialty Products Association—Product Care Program

•

National Association of Chemical Distributors—Responsible Distribution Program

•

Cosmetic, Toiletry, and Fragrance Association—Consumer Commitment Code

•

National Paint and Coatings Association—Coatings Care Program

A component of stewardship has often included a focus on emergency response. The Consumer Specialty Products Association’s Product Care Program contains a guiding principle dedicated to incident response and management. One component of the principle, “In-Market Support, Incident Evaluation, and Follow-up,” contains the following language: “When product-related incidents occur, we will have systems in place to minimize adverse effects, assist our consumers/customers, and provide needed information.” It is becoming the standard of care for companies in many of these industries to provide emergency information and support in conjunction with their customer service departments. It is also routinely the practice of these companies to secure specific expertise by outsourcing this PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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function to private medical entities such as poison centers or medical practices that provide product-related toxicology support. Contract poison control services are provided by many poison control centers in a limited fashion, and there are other poison centers that specialize in providing this type of service in the industrial sector and have developed specialized data collection tools and services around these corporate stewardship needs. In addition to the provision of specialized medical information regarding product use for consumers, these surveillance programs help manufacturers meet their regulatory reporting mandate and allow for the collection of comprehensive incident data to aid in the monitoring of product-associated adverse effects. AER Challenges and Opportunities for Supplement Manufacturers and Their Customers Monitoring for adverse effects potentially associated with herbs and other natural medicinals poses unique challenges for an industry that has been ill prepared to engage in such an undertaking without the force of legislation. Additionally, those charged with the responsibility to monitor special populations that are likely to use dietary supplements, such as military personnel, will need to understand the new adverse event framework in order to access information and assess risk. As the data collection process mandated by Congress is similar to the same process for drugs, it is likely that adverse event experiences between drugs and supplements will be compared. Although some similarities exist between drug and supplement adverse event monitoring, the dissimilarity is striking. A comparison is provided in Box B-15. BOX B-15 Spontaneous and Other AE Reports Drugs vs. Supplements Drugs ● Majority from clinicians, clinical studies, anecdotal published case reports ● “Learned” professional interface ● Typically single entity ● Codified/standardized reporting format ● National compendium of products ● Toxicity expected and accepted ● Manufacturer has “their” data from patented ingredient

Supplements ● Majority “spontaneously” reported by consumers ● Likely more consumer calls vs. professionals ● Multiple ingredients ● No standardized reporting format ● No national compendium or list of products ● Toxicity unexpected and not tolerated ● Manufacturer inherits risk from others manufacturing/selling same ingredient

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APPENDIX B

B-139

Manufacturers will need to adapt their systems of surveillance to compensate for striking differences in the reporting framework between supplements and drugs. In some instances, manufacturers will need to establish systems from the ground up. An industry task list might include: • design of a database to manage collected reports; •

design of an “intake system” (internal or external) and policies and procedures for triage of calls;

•

training of all company employees regarding AER policies and procedures;

•

implementing the system to manage and document all incoming incidents from all methods of consumer communication (e-mail, mail, phone calls);

•

establishing processes to ensure that all expedited reports are filed within the 15-day reporting period; and

•

data analysis and manipulation for internal/external monitoring in support of •

trend analysis,

•

benchmarking,

•

monitoring for adulteration (before, during, or after leaving the plant),

•

identifying quality issues,

•

safety profile assessment, and

•

assessment of the denominator perspective for data normalization and generating a safety profile.

As systems of surveillance emerge, certain manufacturers and their customers may seize the opportunity to collaborate and work together. An example might include processes where preferred vendors share their adverse event experience with purchasing entities or both groups work together to design collaborative surveillance projects to ensure that unique populations are not put at risk when using products under extreme or nonconventional conditions. This would include use of supplements by military personnel in combat or other extreme conditions. Collaboration may allow for development of better measures to assess adverse events in the context of issues such as product versus ingredient safety, and reviewing of all ingredients within complex proprietary blends to ensure adequate safety. Purchasing authorities may also have the opportunity to assess the quality and integrity of vendor AERS in regards to qualifications of those managing, documenting, categorizing, and reporting adverse events. Those systems meeting the purchasers’ standards of excellence may receive preferred status and enjoy greater access to new markets and consumers. Collaborative efforts of this nature would serve to increase consumer confidence and help ensure the safe and effective use of quality products.

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Final Comments Regarding Supplements, Botanicals, and AERs Despite emerging initiatives to improve the documenting and reporting of supplementassociated adverse events, a few significant issues will likely affect future surveillance efforts. First, the documenting and assessing of spontaneously reported adverse effects, whether they involve drugs or supplements, must be done by competent and well-trained medical practitioners. It has been suggested by some that simply asking a nonmedical customer service representative to fill out a form such as the FDA 3500a adverse event reporting document will result in the collection of useable and quality information for monitoring of sentinel events. Review of adverse events collected by medical professionals that are not trained in the area of adverse event investigation and documentation poses a challenge in and of itself. This is compounded when reports are collected and documented by lay persons. Expecting lay persons to understand pharmacologic principles of drug or supplement action and probe for confounding variables when investigating and documenting allegations of adverse effects is unrealistic. Furthermore, their inability to interpret and describe lay depictions of clinical signs or symptoms, and then code or categorize these descriptors in a consistent manner, will compromise any effort to collect useful information. This was the legacy of the “ephedra era” when the manufacturer’s efforts to document and report useable adverse event information yielded few reports of sufficient quality to allow an informed analysis. Lastly, a major concern that will remain involves confirming both the identity and quality of any supplement suspected of causing an adverse effect. When reviewing published anecdotal reports of botanical adverse effects, the accurate identity as well as quantitative and qualitative integrity of the suspect botanical is rarely confirmed by experts that are competent in both pharmacognosy and botanical analytical methodology. Thus, effects that have been ascribed to a given botanical ingredient or botanical product have rarely been analytically confirmed and benchmarked for comparison with other such reports involving either the same product or active ingredient(s). Analysis of future reports of serious adverse events that are either reported to the FDA or published in the scientific literature will suffer the same deficiencies associated with previously reported events unless this shortcoming in the assessment process is addressed. It is likely that governmental intervention in the form of financial support and policy direction will be required as no other option is universally available to practitioners that are evaluating and attempting to report or publish adverse events involving supplements or botanicals. The assessment of supplement and botanical safety cannot be adequately characterized without addressing this issue.

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APPENDIX B

B-141

REFERENCES Bent, S., T. N. Tiedt, M. C. Odden, and M. G. Shlipak. 2003. The relative safety of ephedra compared with other herbal products. Ann Intern Med 138(6):468-471. Kingston, R., and M. Blumenthal. 2003. A rational perspective on adverse events reports on herbs: Misinterpretation of adverse reactions tabulated in the TESS Annual Report of the American Association of Poison Control Centers as they relate to ephedra dietary supplements. HerbalGram 60:48-53. Kingston, R. L., and S. W. Borron. 2003. The relative safety of ephedra compared with other herbal products. Ann Intern Med 139(5 Pt 1):385. Lai, M. W., W. Klein-Schwartz, G. C. Rodgers, J. Y. Abrams, D. A. Haber, A. C. Bronstein, and K. Wruk. 2006. 2005 Annual Report of the American Association of Poison Control Centers’ national poisoning and exposure database. Clin Toxicol 44(6-7):803-932.

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Appendix C Findings from Recent Surveys on Dietary Supplement Use by Military Personnel and the General Population

PREPUBLICATION COPY: UNCORRECTED PROOFS C-1

Copyright © National Academy of Sciences. All rights reserved.

MILITARY Corum, 2007

Reference

C-2

Response rate not known

2003–2005 Mean age: 25.4 years (n=5,206)

Demographics

Soldiers (ranks: E1– E9)

Group

Copyright © National Academy of Sciences. All rights reserved.

Supplement purchase: (n=2,241) Commissary/PX: 35.6% Nutrition/health food store on post: 25.3% Nutrition/health food store off post: 25.3% Mail order/Internet: 13.2%

Sources of information: (n=2,241) Friends: 36% Magazines: 31.7% Internet: 22.1% Sales associates: 10.4% Doctors: < 10% TV/radio/newspaper: < 5%

Adverse effects: (n=951) Abdominal pain Breathing difficulty Chest pain Dehydration Diarrhea Dizziness Heart attack Heat stroke Loss of consciousness Muscle cramping Nausea/vomiting Numbness in extremities Palpitations Tremors

Herbal supplements: Caffeine: 17.5% Ginseng: 6.7% Garlic: 5% Ginkgo: 3.9% Echinacea: 3.6%

Ergogenic aids: Sports drinks: 42.8% Sports bars: 17.3% Protein: 13.7% Ephedra Free: 10.1%

Ergogenic aids: Performance enhancement Strength

Herbal supplements: Prevent fatigue

Vitamins/minerals: Multivitamin: 33.8% Vitamin C: 24.4% Calcium: 19.3% Iron: 14.4% Potassium: 12.1% Vitamin A: 12.5% Vitamin B6: 11.5%

Other Findings

Vitamins/minerals: Health Prevent illness

Findings: Motivation

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“Estimate how often you use each of the following individual vitamin and mineral supplements (pills, tablets, gel caps, etc). For each supplement listed below: Step 1: Select ONE bubble in the yellow section that best describes how frequently you use a supplement. Step 2: Select ONE or MORE check boxes in the blue section to select the reasons you use that supplement.”

Health Promotion and Prevention Initiative (HPPI), dietary supplements questionnaire

Questions

Limitations: x Surveys not designed to relate adverse effects or benefits to any particular DS. x Response rate not known. x Results might be skewed because it was completed voluntarily. x They do not have dietary pattern surveys of respondents. x Adverse effects are not usually reported to health care providers.

x 16% listed dehydration as an adverse effect (concern). x Females and males tend to use different dietary supplements (DS). x Many of the DS use were associated with palpitations or anxiety, which could be due to caffeine. x Perception that if something is sold in the base, it means it is safe

Authors’ Conclusions Study Limitations

TABLE C-1 Findings from Recent Surveys on Dietary Supplement Use by Military Personnel and the General Population

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

2006 (spring/summer)

Thomasos, 2007

(n=10,985)

Demographics

Reference

APPENDIX C

Air Force enlisted and officers

Group

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Supplement purchase: Commissary/PX: >40% Other on-base stores: approximately 25% Off-base stores: approximately 24% Internet/mail order:<10%

Sources of information: (most to least commonly reported) Magazines Friends/family Books/journals Internet sites Health care providers TV/radio/newspaper Store sales person

Most common supplement used: (1) Senior enlisted: for weight loss (2) Junior enlisted/officers: for strength and lean body mass gains

Primary reasons for use (from most to least commonly reported): Promote health Weight loss Strength Lean muscle mass Stamina Fatigue reduction Cognition/alertness Memory Other

Findings: Motivation Supplement use: Currently using: 38% Past use only: 31% Never used: 31% Most common supplements used1 (5 or more times/wk): Multivitamin Multimineral Creatine Glutamine Vitamin C Caffeine Calcium Protein powders Fish oils Hydroxycut Chondroitin NO2 Adverse effects: (most to least common) Palpitations Anxiety Dehydration Nausea/vomiting Chest pain Dizziness/confusion Abdominal pain Tremors Diarrhea Muscle pain Numbness/tingling Breathing problems Heart attack Blood in urine Heat injury Visual disturbances Fainting

Other Findings

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Have you ever used any type of dietary supplement?

Adapted from the U.S. Army Center for Health Promotion and Prevention Medicine Dietary Supplement Questionnaire.

Questions

C-3

Additional adverse effects (listed in comments): (in no particular order) Acid reflux Acne Addiction Difficulty sleeping Jitters Body aches Cold sweats Constipation Headaches Hyperactivity

Additional information: x Supplements were categorized into “like types.” x Talk also provides information on supplement use by: Occupation Grade (O1–O6 and E1–E9)

Authors’ Conclusions Study Limitations x Most U.S. Air Force members using DS x >60% DS bought on base x Most spend between $11–50/month x Most members do not report having adverse effects on this survey. x Adverse effects are not usually reported to health care providers (% reported vs. not reported to health care provider is given in presentation slides) x Education on DS is needed.

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Jaghab, 2007

(n=1,200)

All four branches and pay grades

Response rate overall: 51.8%

Copyright © National Academy of Sciences. All rights reserved.

Army

Army (n=3,636) Navy (n=4,626) Marine (n=3,356) Air Force (n=4,627)

Active duty military (worldwide)

April–August 2005 (n=16,146)

Marriott, 2007

Group

Demographics

Reference

C-4

Top 5 reasons took supplements

Information sources: Personal contacts: 47.9% Print media: 29.1% Friends/family: 24.8% Multimedia nonprint: 23% Health professionals: 17.3% Sales store associates: 5.7%

Reasons for use: Supplement diet Improve health Improve mental health Improve cognitive function Improve physical performance Increase muscle mass Lose weight Specific health problems

Findings: Motivation

Top 10 supplements

Reporting to doctor by military branch: Air Force: 49.5% Navy: 32.6% Army: 31.5% Marine: 25.3%

Reporting increases with age

Reporting use to military personnel: To doctor: 36.6% To nurse/physicians assistant: 21.7% Indicated on health record: 12.8% Women: 62.5% Men: 45.2%

Frequency of use: Once a month: 8.3% Once a week: 7.6% Every other day: 7.7% Once a day: 30.7% 2 times or more a day: 12.8%

Supplement use (last 12 months): Any: 60.3% Multivitamin: 45% Individual vitamin/mineral: 26.9% Antioxidants: 20.8% Bodybuilding: 20.5% Herbal: 11.7% Weight loss: 18% Joint health: 8.5% Performance: 8.4% Other types: 9.1%

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

Electronic

DoD Survey of Health-Related Behaviors Among Military Personnel plus added questions on diet, DS, CAM

Questions

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Educational suggestions:

Author suggestions: analysis on specific information on exact supplements used with estimates of nutrient intake from food and supplements

Supplement use overall by gender, military branch

Presentation also includes: Bodybuilding supplements, Performance enhancing, and weight-loss supplements by pay grade, gender, age, education, BMI, activity, smoking, drinking

Authors’ Conclusions Study Limitations x Nutrient supplements provided through military health care x Diet: < 10% eat three or more servings of fruit and vegetables per day x Women in the Navy highest reported fruit (10.7%) and vegetable (12.9%) of three or more servings per day x Military dining services may represent an opportunity for increased communication about healthy diet and dietary supplement use.

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(presented four branches in one presentation)— split here by branches

Lieberman et al., 2007

Reference

APPENDIX C

Response rate: 80%

(ongoing) Males/females (n=484) Average age: 29 years

physicians (n=573) Ancillary (n=614)

Participation rate: 15%

General army

Located in: Iraq >40% Afghanistan >20% Other > 9%

Group

Demographics

Females:

Males: Health Performance Muscle strength Other Energy

Top 5 reasons for supplement use

Supplement purchase: PX: 52% / 59.3% Online: 35.4% / 39.9% GNC: 22% / 15% Given or sent: 13.1% / 14.2% Unknown: 11.7% / 4.9% Local markets: 2.8% / 1.8%

reported to physicians/ancillary: Performance enhancer 52.5% / 48.5% Gain weight: 24.3% / 22.1% Lose weight: 23.9% / 27% Increase muscle mass/ conditioning/strength: 6.1% / 6.5% Cognitive enhancer/stay awake: 3.7% (to physicians only) Supplement diet/health maintenance: 3.6% (to ancillary only)

Findings: Motivation

Top 10 supplements Males: Multivitamins: 30% Sport drink: 20% Vitamin C: 13% Protein powder: 13%

Supplement use at least once per week: Males: 55% Females: 70%

reported to physicians/ ancillary: Creatine: 32.5% / 27% Protein: 16.2% / 26.2% Multivitamin and minerals: 13.4% / 20.2% None: 11.9% / 10.4% Weight loss: 10.5% / 19.1% Metabolism boosters: 8.6% / 8.8% Ephedra: 7.7% / 5.2% Bodybuilders: 6.6% / 7.7% Glucosamine and chondroitin: 3.5% / 3.7% Nitrous oxide: 2.8% / 5.7% Caffeine: 2.8% (to physicians) Herbal preparations: 3.7% (to ancillary)

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

survey on Army Medical Department (AMEDD) Knowledge Management website

Questions

C-5

Also provides information of supplement use by age, education, occupation; supplement

x All army populations surveyed consume high levels of DS. x Different army populations have different patterns of use. x Editorial comment: Scientific justification for this level of supplement use is lack.

Concerns about side effects (from physicians and ancillary): Interaction of supplements with medications or other supplements Dehydration Side effects (general) Renal/kidney functions Heat injury/heat stress Supplements are not regulated by FDA Safety of taking supplements Cardiac issues Overuse of supplements They (DS users) don’t understand the risks and complications of the supplements. Long-term effects

Also provides top 5 brands of supplements used

Authors’ Conclusions Study Limitations Which supplements work and don’t work Better nutrition in general General risks of taking supplements Weight-loss supplement education

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Lieberman et al., 2007

Reference

C-6

Copyright © National Academy of Sciences. All rights reserved.

Response rate not known

April 1999 males (n=768) Average age: 23.6 years

Demographics

U.S. Army Rangers

Group

Top 5 reasons for supplement use: Energy Health Muscle strength Other Physician

Vitamin E: 6% Calcium: 6% Vitamin D: 5% Vitamin A: 5% Creatine: 5% Sport bar: 5%

Health Other Energy Performance/weight loss /not sure Endurance/strength

Supplement use at least once per week: 81% Top 10 supplements: Sport drink: 41% Multivitamins: 23% Creatine: 19% Protein/amino acids: 18% Antioxidants: 14% Herbs (ginseng, garlic, etc): 9%

Number of different supplements used /week Males: 1–2/ week: 30% 3–4/ week: 12% 5+ / week: 14% Females: 1–2/week: 35% 3–4/week: 18% 5+/week: 18%

Females: Multivitamins: 28% Sport drink: 28% Calcium: 15% Folate :13% Vitamin C: 13% Iron: 10% Vitamin B6: 10% Vitamin D: 8% Vitamin E: 8% Protein powder: 8%

Other Findings

Findings: Motivation

PREPUBLICATION COPY: UNCORRECTED PROOFS

Questions

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

x General comments (see above)

Authors’ Conclusions Study Limitations knowledge, and money spent on supplements per week.

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Copyright © National Academy of Sciences. All rights reserved.

Lieberman et al., 2007

Lieberman et al., 2007

Reference

APPENDIX C

Response rate not known

1999–2001 Males / females (n=315) Average age: 44 years

Response rate not known

July 2000 Males (n=152) Average age: 31.3 years

Demographics

Army War College (mid to upper management)

Special forces

Group

Top 5 reasons for supplement use Males: Health Other Performance/energy Poor diet Physician

Top 5 reasons for supplement use: Health Performance Energy Other Physician

Findings: Motivation

Supplement use at least once per week: Males: 71% Females: 81% Top 10 supplements Males: Multivitamins: 39% Vitamin E: 22% Vitamin C: 17%

Number of different supplements used /week: 1–2/week: 41% 3–4/week: 14% 5+/week: 7%

Number of different supplements used /week: 1–2/week: 45% 3–4/week: 19% 5+/week: 15% Supplement use at least once per week: 65% Top 10 supplements: Sport drink: 36% Multivitamins: 32% Protein powder: 16% Creatine: 16% Sport bar: 15% Vitamin C: 11% Meal replacement bev: 9% Vitamin E: 7% Antioxidants: 6% Androstenedione: 6%

Carbohydrate bev: 7% Androstenedione: 7% Sport bar: 6% Sport gel: 3%

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

Questions

C-7

x General comments (see above)

x General comments (see above)

Authors’ Conclusions Study Limitations

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Copyright © National Academy of Sciences. All rights reserved.

2

Response rate: 73.4%

2002 18–30 years of age (n=6,666)

Demographics

National Health Interview Survey (NHIS) In-person interviews

Group

Have you ever used a multivitamin or vitamin?

NHIS

Questions Sport drink: 10% Antioxidants: 7% B-complex: 6% Garlic: 6% Beta-carotene: 5% Ginkgo biloba: 5% Calcium: 5% Females: Multivitamins: 52% Calcium: 32% Vitamin E: 32% Vitamin C: 29% Antioxidants: 23% Beta-carotene: 16% Magnesium: 13% Folate: 13% B-complex: 13% Vitamin B6: 10%

Females: Health Performance/energy Other Poor diet Physician

Of the 17%: Echinacea: 47% Ginseng: 36%

Supplement use Vitamin (ever): 63% Nonvitamin mineral: 17%

Number of different supplements used /week Males: 1–2/week: 29% 3–4/week: 14% 5+/week: 12% Females: 1–2/week: 36% 3–4/week: 6% 5+/week: 23%

Other Findings

Findings: Motivation

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

x Nonvitamin and mineral supplement users were more likely to be: high education, high physical activity, poor selfperceived health status, prescription medication users

Authors’ Conclusions Study Limitations

PREPUBLICATION COPY: UNCORRECTED PROOFS

Some Gardiner information provided by summary tables given to the committee prior to presentation (and may not be included in presentation)

CIVILIAN Gardiner2, 2007

Reference

C-8

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Gardiner, 2007

Reference

APPENDIX C

Copyright © National Academy of Sciences. All rights reserved.

Response rates for NHANES 1999–2000: 82%, 2001–2002: 84%

18–30 years of age (n=3,231)

1999–2002

Demographics

National Health and Nutrition Examination Survey (NHANES) In-person interviews

Group

Findings: Motivation

Prevalence of supplement use

Nonvitamin/mineral: 7% Sport: 2% Weight loss: 3% Herbs: 4 %

Of the 37%: Multivitamin (any): 23% Vitamin C: 7% Vitamin E: 2% Vitamin B: 1.4% Iron: 2.1% Calcium: 2.6%

Supplement use: Any: 37%

Prescription medication users also taking nonvitamin/mineral supplement: 22%

Prevalence of supplement use among (any/nonvitamin) Physical activity level: Sedentary: 34%/9% Moderate: 22%/19% High: 43%/23%

Gingko: 23% Garlic: 16% St.-John’s-wort: 15% Peppermint: 15% Ginger: 11% Chamomile: 9% Kava: 9% (Glucosamine: 4%) Ephedra: 7%

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

“Have you used or taken any vitamins, minerals, or other dietary supplement in the past month?” If Yes, asked to provide dose, frequency, and duration of use and to show supplement container. If

NHANES

“During the past 12 months, did you use natural herbs for your own health or treatment?”

Questions

C-9

Did not ask about sports drinks, teas, or super foods.

Did not record reason for use or health condition associated with use.

x Supplement use more likely to be ages 23–30 years (older for this group), female, non-Hispanic white, high self-perceived health status, high physical activity level. x Limitation: likely underrepresented because it does not include teas, loose herbs etc., or DS without a bottle or label.

Authors’ Conclusions Study Limitations x Limitation: underrepresented because only those that responded positively to the question: “have you ever used a natural herb?” were further surveyed about use of specific DS; “natural herb” may be misleading. x Only 35 listed, thousands are sold. x Herbs have unique common names based on region or cultural background.

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Copyright © National Academy of Sciences. All rights reserved.

(presented data on military and non-military –

MILITARY / CIVILIAN French, 2007

Kaufman, 2007

Reference

C-10

2005 Males and females 18 years and older

Participation rate: 57%

2005 Males and females, all ages Adults (n=2,684) <18 years (n=581) (under 14 years, parents answer)

Demographics

Nationally representativ e group of U.S. adults “currently

Telephone interviews, random digit dialing

National survey

Group

Supplement purchase: (by age, military only): 18–29 years: GNC: 28% Internet: 19%

Findings: Motivation

Supplement use: Any: 69% Multivitamin (only): 23% 2 or more supplements: 46%

Other: Prescription medication users who take one or more herbals: 30%

Most commonly used: Vitamins (any): 40% Multivitamins: 26% Herbal/ natural (any): 23% Lutein: 9.4 % Lycopene: 7.8% Glucosamine: 4.0% Garlic: 2.6% Chondroitin: 2.5% Ginkgo biloba: 1.6% Co-enzyme Q: 1.5%

Supplement use:

Prescription medication users: (any DS/non-vitamin) 45%/7%

among (any DS/nonvitamin) Physical activity level: Sedentary : 30%/5% Moderate: 38%/5% High: 41%/9%

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

The Natural Marketing Institute ESP (E-screener panel)

Slone survey “We are interested in all medicines which you have taken in the past 7 days. These include prescriptions from your doctor or clinic, nonprescription medicines, vitamins, herbs, or alternative medicines.” Asked to retrieve bottle and provide information on container.

container was not available, asked for exact name.

Questions

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

x Supplement use increases with age (over age 45 years more likely), higher income, and higher education in military x Military more likely to use

x Slone data used as an example of survey design (not analyzed specifically for this meeting) age group not the same as military

Authors’ Conclusions Study Limitations

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

French, 2007

(n=376)

split here by military status)

Copyright © National Academy of Sciences. All rights reserved.

Response rate: 60%

2005 Males and females 18 years and older

Response rate: 60%

Demographics

Reference

APPENDIX C

Nationally representativ e group of U.S. adults (nonmilitary)

serving in the military, national guard, or reserve”

Group

45 years and older: Internet: 23% GNC: 13% Nutrition/health food store: 13% Mail order/catalog: 10% Natural food market: 8%

30–44 years: GNC: 19% Internet: 17% Natural food market: 12% Nutrition/health food store: 7% Mail order/catalog: 5%

Nutrition/health food store: 8% Natural food market: 6% Mail order/catalog: 4%

Findings: Motivation

Categories: Protein powders: 4% Weight loss: 7% Herbal: 12% Sports nutrition: 2% Fiber: 8% Children’s: 3%

Supplement use Any: 73% Multivitamin (only): 18% 2 or more supplements: 55%

Specific: Multivitamins: 57% Calcium: 13% Vitamin E: 9% Vitamin B: 8% Glucosamine/ Chondroitin: 7% Creatine: 6% Fish oil: 5% Omega 3: 4% Flaxseed oil: 4% Amino acids: 4% Vitamin D: 3% CLA:3% Lycopene: 2% Arginine: 1%

Categories: Protein powders: 14% Weight loss: 9% Herbal: 8% Sports nutrition: 8% Fiber: 4% Children’s: 3% Homeopathic: 2% Condition specific: 2%

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

The Natural Marketing Institute ESP (E-screener panel) Questionnaire Index Supplement use in past 3 months

Questionnaire Index Supplement use in past 3 months

Questions

C-11

x See above for general comments. x Supplement use increases with age. x Nonmilitary significantly higher in DS use for specific supplements except for creatine, CLA, amino acids

Authors’ Conclusions Study Limitations multivitamins only, significantly more sports-related supplement products x Also gives information on overall use by gender x Provides brand names of sports nutrition and muscle building supplements used

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Reference

C-12

Demographics

Group

Copyright © National Academy of Sciences. All rights reserved.

Findings: Motivation

Specific: Multivitamins: 58% Calcium: 26% Vitamin E: 20% Vitamin B: 14% Glucosamine/ chondroitin: 11% Creatine: 1% Fish oil: 9% Omega 3: 7% Flaxseed oil: 6% Amino acids: 2% Vitamin D: 8% CLA:1% Lycopene: 2% Arginine: 1%

Homeopathic: 4% Condition specific: 3%

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

Questions

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL Authors’ Conclusions Study Limitations

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Sheppard et al., 2000

Arsenault and Kennedy, 1999

Response rate: 40%

n=229 (133 military)

Response rate: 99%

n=2,215 males, Average age: 25 (18–47 years of age)

U.S. civilian and military health clubs

Entering U.S. Army Special Forces and Ranger training schools

Copyright © National Academy of Sciences. All rights reserved.

Creatine use: 12.2 g/day for 40 weeks Military supplement use: Vitamin: 65% Mineral: 47% Protein: 45% Creatine: 29% Herbal: 21% Androstenedione: 13% Hydroxy-ȕmethyl butyrate: 10% Anabolicandrogenic esteroids: 3%

Daily use: 35% (any kind) Ergogenics: 14%

Current use: 64% (any kind) Ergogenics: 29% Multivitamin: 37% Vitamin C: 20% Creatine: 18% Ginseng: 9%

Supplement use: Past and/or present: 85% Use for: General health Performance enhancement Interested in: preventing infectious diseases, performance, and wound healing

Findings: Motivation

Other Findings

x Supplement use associated with resistance training goal of strength x Creatine use associated with male gender, goal of strength training, lower freq and duration of aerobic training, use of protein, andro/DHEA, and HMB. x Information on creatine from: Popular media: 69% Physicians: 14% Dieticians: 10%

x Use is higher than in general population of young men (39% use them occasionally). x Supplement use associated with higher army physical fitness tests, daily exercise, weight lifting, and nonsmokers. x Not associated with age, ethnicity, BMI, chewing tobacco, or alcohol use.

C-13

PREPUBLICATION COPY: UNCORRECTED PROOFS

Use of creatine and other supplements

Use of vitamins, minerals, performance or other supplements

TABLE C-2 Surveys on Use of Dietary Supplements in the Military Reference Demographics Group Questions Findings: Usage

APPENDIX C

x Military population is at risk for potential AE of inadequate use of DS, including abrupt cessation when deployed in operations or entering training. x Presence of DS in bases and discontent with food might result in higher use of DS. Recommendations: x Further studies of benefits and risks are necessary. x Routine one-size fits all advise should not be given. x OK to treat deficiencies but questions about performance effects. x Military health care professionals should be well informed about risks and benefits. x Concerns: creatine use with other anabolic supplements x Popular magazines as main source of information. x Education and access to information of users is critical. x 45% of current creatine users reported adverse effects: gastrointestinal, muscle cramping/ spasms, dehydration

Authors Conclusions and Study Limitations

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Bovill et al., 2000

McGraw et al., 2000

n=291 Average age: 39 years (18–83 years of age)

McPherson and Schwenka, 2004

Copyright © National Academy of Sciences. All rights reserved.

Response rate not known

n=152 male Average age: 31 years

Response rate not known

n=367 Average age: 22 years

Response rate: 73%

Demographics

Reference

C-14

U.S. Army Special Forces

U.S. Army Rangers

U.S. soldiers, retirees, spouses in military hospital

Group

Supplement use: 86% occasionally Frequency: Sports drinks: 66% Sports bars: 43% Multivitamins: 42% Vitamin C: 22% Protein powder: 22%

CAM use: Active duty: 72% Retiree: 85% Family: 89% Supplement use: Herbal supplements: 36% Nutritional food supplements: 36% Supplement use: 36% Frequency: Creatine: 19% Multivitamin/min eral: 16% Protein/Amino acids: 14% Vitamin C: 7% Sport bars: 6%

Massage and supplements were most commonly used

Findings: Usage

General health: 63% Performance: 20%

Pain Stress Anxiety Depression Weight loss

Findings: Motivation

x Supplement use associated with frequency of strength training. x Not associated with age or habitual exercise. x Information on nutrition from: Magazines/newspapers/ books: 76% Friends: 54% Radio/TV: 34% Physicians/nurses: 33% Internet: 30%

x Supplement use lower than general male population (42%), elite athletes (59%), or U.S. Army Special Operations candidates (64%) x Supplement use associated with frequency of strength training x Not associated with smoking or aerobic training.

81–98% thought the treatment was effective

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

Surveys asked about nutrition, supplement use, demographics, and health habits.

Use of supplements and associated factors.

Use of complementary and alternative medicine (CAM)

Questions

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Health providers need to become educated in CAM therapies. Further studies needed. x Limitations: Geographical area might have biased the results. Western region (increased CAM, more providers)

Authors Conclusions and Study Limitations

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Copyright © National Academy of Sciences. All rights reserved.

Brasfield, 2004

Deuster et al., 2003

n=157 male (119 SF, 38 non-SF)

Bovill et al., 2003

Response rate: 64%

n=874 750 male 124 female Average age: 24.9 years (ranged from 17– 49 years of age)

Response rate: 100%

n=38 Average age: 25 years (18–40 years of age)

Response rate: 89%

Demographics

Reference

APPENDIX C

Representative sample of soldiers

Enlisted U.S. Army, active duty

U.S. Army Rangers

U.S. Army Special Forces (SF) and support soldiers (nonSF)

Group

Daily supplement use: 81.5% Most common: CHO/electrolyte fluids Protein powder: 24% Creatine: 13% Ephedrine: 13% Also reported use of ginseng, glutamine, vitamins/minerals Supplement use: 60.9% Frequency: Multivitamin: 56% Vitamin C: 28% Creatine: 23% Ephedra: 21% Ginseng: 21% Calcium: 20% Vitamin E: 15%

Supplement use: Current 87% Specific use: Similar to above (Bovill et al., 2000)

Findings: Usage

General health Performance enhancer Prevent illness

A majority of soldiers incorrectly believed that protein is used for energy for short-term athletic events (64%), and vitamins provide energy (58%).

Findings: Motivation

More females than males

Source of information (in order of frequency): Other (friends, family, etc.) Magazines Store salesman Internet Doctors Books TV

x Supplement use more SF (90%) than non-SF (76%) x Supplement use associated with more frequent exercise and greater nutrition knowledge x Not associated with: age, weight, ethnicity x Information on nutrition from: Similar to above (Bovill et al., 2000)

Other Findings

PREPUBLICATION COPY: UNCORRECTED PROOFS

Use of supplements and motivation

Nutrient, alcohol, DS intake, and PA activity level.

Questions

C-15

x Limitations: Self-reporting might result in

x High number of adverse effects that might be attributed to DS use. x Recommendations: Use of some DS should be discontinued prior to undergoing surgery; health care screening; routine assessment; education; further surveys recommended.

x Use of supplements is not necessary based on the dietary intakes of protein by the Rangers.

x Possible trend in increased use of supplements in military.

Authors Conclusions and Study Limitations

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

n=294 Average age: 23 years (survey was conducted in 1999)

U.S. Army Rangers

Use of supplements; potential factors associated: age, participation in competitive or recreational athletics, weight training; sources of nutritional information.

x No difference in age of user compared to nonuser. x Supplement use associated with recreational activities, weight training x Source of information: Other soldiers: 59% Fitness magazines: 46% Internet: 18% Nutritionist: 8% Unit surgeon: 6%

No association with aerobic exercise frequency.

DS users consumed: 3 or more DS: 53% 2 DS: 22% 1 DS: 25%

Supplement use: 56% Frequency: Whole protein: 62% Creatine: 46% Thermogenics: 44% Anabolic steroids: <2%

consumed a DS; however, more men consumed creatine, ginseng, and garlic.

Vitamin A: 13% Iron: 13% Garlic: 12%

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

x Stores on military bases specifically to sell DS. In 2004, 92 stores worldwide on military installations.

x Adverse events: 18% Palpitations: 46% Dizziness/confusion: 30% Tremors: 26% Abdominal pain: 24% Numbness/tingling extremities: 16% Loss of consciousness: 4%

misunderstanding and misreporting Generalizations to general population are not possible. Categorization of DS

Copyright © National Academy of Sciences. All rights reserved.

PREPUBLICATION COPY: UNCORRECTED PROOFS

x Soldiers consume ergogenics at the same rate as other athletic populations. x Supplement use is inversely correlated to nutritional knowledge. x Recommendation: further education of unit surgeons Response rate: x Limitations: 40% Self-exclusion of soldiers with higher usage might result in low response and apparently lower supplement use level. BMI=Body mass index; CAM=Complementary Alternative Medicine; DoD=U. S. Department of Defense; DS=dietary supplement; PA=physical activity

Johnson et al., submitted

C-16

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

APPENDIX C

C-17

REFERENCES Arsenault, J., and J. Kennedy. 1999. Dietary supplement use in U.S. Army Special Operations candidates. Mil Med 164(7):495-501. Bovill, M. E., S. M. McGraw, W. J. Tharion, and H. R. Lieberman. 2000. Supplement use and nutrition knowledge in a special forces unit. FASEB Journal 15(5):A999. Bovill, M. E., W. J. Tharion, and H. R. Lieberman. 2003. Nutrition knowledge and supplement use among elite U.S. army soldiers. Mil Med 168(12):997-1000. Brasfield, K. 2004. Dietary supplement intake in the active duty enlisted population. U.S. Army Medical Department Journal 44-56. Corum, S. J. C. 2007. Dietary supplements questionnaire. Presentation at the Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Deuster, P. A., A. Sridhar, W. J. Becker, R. Coll, K. K. O'Brien, and G. Bathalon. 2003. Health assessment of U.S. Army Rangers. Mil Med 168(1):57-62. French, S. 2007. Insights into dietary supplement usage by U.S. active military personnel. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Gardiner, P. 2007. Prevalence of dietary supplements in the U.S. young adult population. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Jaghab, D. 2007. Survey of army health care providers concerning dietary supplements. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Johnson, A. E., C. A. Haley, and J. A. Ward. Submitted. Hazards of dietary supplement use. Kaufman, D. W. 2007. Design and conduct of surveys on dietary supplement use. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 12. Lieberman, H. R., T. Stavinoha, S. McGraw, and L. Sigrist. 2007. Use of dietary supplements in U.S. Army populations. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Marriott, B. M. 2007. Dietary supplement use by active duty military personnel: A world wide sample. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. McGraw, S. M., W. J. Tharion, and H. R. Lieberman. 2000. Use of nutritional supplements by U.S. Army Rangers. FASEB J 14(4):A742. McPherson, F., and M. A. Schwenka. 2004. Use of complementary and alternative therapies among active duty soldiers, military retirees, and family members at a military hospital. Mil Med 169(5):354-357. Schneider, K., L. Hervig, W. Y. Ensign Jr., W. K. Prusaczyk, and H. W. Goforth Jr. 1998. Use of supplements by U.S. Navy SEALS. Med Sci Sports Exerc 30:S60. Sheppard, H. L., S. M. Raichada, K. M. Kouri, L. Stenson Bar Maor, and J. D. Branch. 2000. Use of creatine and other supplements by members of civilian and military health clubs: A cross-sectional survey. Int J Sport Nutr Exerc Metab 10(3):245-259.

PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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C-18

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Thomasos, C. 2007. Assessment of Air Force dietary supplement usage by major commands. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13.

PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

n=91

(Schneider et al., 1998) Naval Sea, Air, Land (SEAL) personnel

Group

Questions

Findings: Usage

Findings: Motivation

C-19

Other Findings

Copyright © National Academy of Sciences. All rights reserved.

PREPUBLICATION COPY: UNCORRECTED PROOFS

Supplement use: Increase muscle 78% mass, strength, Response rate More than one and power, not known supplement Provide energy concurrently: Improve general 4–9 DS: 32% health 3 DS: 34% 2 DS: 18% 1 DS: 16% *Some of the findings from Bovill et al., 2000, and Bovill et al., 2003, are virtually the same and might come from the same study CAM=complementary and alternative medicine; BMI=body mass index; DS=dietary supplement; PA=physical activity.

Demographics

Reference

Additional studies (Military)

APPENDIX C

Notes: navy, concurrent sups

Authors Conclusions and Study limitations

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Copyright © National Academy of Sciences. All rights reserved.

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Appendix D Case Studies

THE CASE OF DEHYDROEPIANDROSTERONE: DECISIONS FOR ACTION Dehydroepiandrosterone (DHEA) was selected for a review of safety and efficacy because, as the committee compiled data about the use of dietary supplements by military personnel, anabolic supplements or bodybuilding supplements were highlighted as one of the categories of dietary suplements that were most popular. DHEA is a steroid compound that is also popular in the civilian population that drives on its alleged increase in muscle mass and enhancement of physical performance. It is not a surprise then that, performance enhancement being one of the main reasons for military personnel taking dietary supplements, DHEA has become popular among military members. DHEA was among the top 10 dietary supplements used at least once a week by Rangers (7 percent) and Special Forces (6 percent) in surveys conducted in 1999 and 2000, respectively (Lieberman et al., 2007). In another survey comparing civilian and military use of dietary supplements among members of health clubs, as many as 13 percent of military personnel were using DHEA (Sheppard et al., 2000). When asked about “bodybuilder supplement use” 6.6 percent of military members reported their use to health care providers (Jaghab, 2007); some of these may have been DHEA. In addition, the most recent U.S. Department of Defense (DoD) Survey of Health-Related Behaviors Among Military Personnel (Marriott, 2007) found that as many as 20.5 percent of military personnel used bodybuilder supplements within the last 12 months. As a variety of sources suggested a high level of use, the committee initiated a review of DHEA safety and efficacy. The committee searched for literature reviews (Figures 4-1 and 4-2) over the last 10 years and also more recent original studies, not included in reviews. In addition, a search for articles specifically designed to signal safety or performance effects of critical importance to the military was conducted. Suprisingly, the popular view that DHEA increases muscle mass and therefore might improve performance appears to be largely based on the findings of a 1998 paper that had significant methodological limitations (Morales et al., 1998). The various reviews of the literature addressing efficacy indicate that there is little substantiation for such a claim. There is a gender-specific effect on blood testosterone that perhaps merits further research to determine effects of DHEA on lean tissue and bone density gain in women during resistance training. Various reviews found the use of DHEA by women increases testosterone concentration. Other reviews evaluated suspected benefits on cognition, mood, and bone strength from consuming DHEA. A search for original articles of studies that include situations or conditions of unique relevance for the military yielded no result. Based on Table 4-2 and the findings from literature reviews, the committee agrees that there is a low level of benefit to be gained from using DHEA by military personnel. Reviews highlighted androgenizing adverse effects experienced by PREPUBLICATION COPY: UNCORRECTED PROOFS D-1

Copyright © National Academy of Sciences. All rights reserved.

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

D-2

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

women and other minor effects, such as facial acne or increase sebum production; no adverse effect was identified that would decrease the readiness of military personnel. There were also some theoretical increased risk cardiovascular disease (CVD) in women due to the reduction in high-density lipoprotein (HDL) noted in some studies. Although some drugs are known to either increase or decrease blood DHEA, there were not reports that supplementary DHEA affected action of most drugs. An exception could be for those individuals who are prescribed other steroid hormones (e.g., testosterone analogs, estrogen). It is possible that DHEA consumption could affect the metabolism of those drugs. One long-term theoretical but critical adverse effect that was uncovered during the safety reviews is the potential association of DHEA levels in blood with a higher breast cancer risk seen in various epidemiological studies. The potential for hepatic neoplasia was also suggested by results from a review of animal studies. This potential adverse effect is serious enough that, although a cause and effect could not be established from those studies, a high level of concern was determined for DHEA (Box 4-1). The military should decide on the course of action based on the high level of concern and low benefit derived from its use. A course of action might be: x To follow up with the research community to determine whether the equivocal animal data related to neoplasia is translated to humans and to monitor future research on either safety or benefits to determine if it need so be reclassified in the future that would likely lead to different management actions. Research on these compounds should be monitored to determine if the compound should be reclassified as future research unfolds. x To develop an outreach strategy to educate military members about the high risks and low benefits of using DHEA by o Including DHEA in a list of dietary supplements to avoid. Recommend the use of alternative products (e.g., creatine, HMB) or strategies (modification of resistance training regime, increase energy intake) that might provide similar desired effects. o To inform military health care providers, fitness trainers and therapists, registered dietitians, nutritionists, commanders, and other educators about the risks and benefits of using DHEA and recommend alternative products or foods. o To monitor the use and adverse effects among military personnel. THE CASE OF EPHEDRA: DECISIONS FOR ACTION Ephedra, Ephedra sinica Stapf, and other ephedrine-containing Ephedra species, was selected by the committee for a review of safety for various reasons. First, due to the severe adverse effects reported, the sale of Ephedra in dietary supplements has been banned in the United States since 2004 (Rados, 2004); it is therefore the first and only dietary supplement that has been banned since the Dietary Supplement Health and Education Act (DSHEA) was implemented (the ephedra alkaloids, ephedrine, and pseudoephedrine, however, are allowed to be sold as over-the-counter medications in the United States). A study by Deuster et al. (2003) reported that 13 percent of the U.S. Army Rangers surveyed use ephedrine. Similarly, a high percentage of ephedra users were calculated (21 percent) from a self-reporting questionnaire distributed among active U.S. Army personnel (Brasfield, 2004). These surveys, however, were conducted prior to the ephedra ban in the United States; the impact of the ban on the use of ephedra and its alkaloids is not known. Recently, a survey distributed among army health care

PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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APPENDIX D

D-3

providers that focus on supplement usage revealed that 5.2 percent and 7.7 of soldiers reported use of ephedra to their physicians or other health care personnel, respectively (Jaghab, 2007). Although the numbers might not be representative of the military population, it raises safety concerns about the use of ephedra. The odds of adverse events from its misuse of over-thecounter medications might be small but continues to be of concern. Also, botanicals that are chemically similar to ephedra and might mimic its effects are available in the market. Although initially the military had considered ephedra among the dietary supplements likely to be efficacious and of interest, defense applications for ephedra use were never developed by the The Technical Cooperation Program (TTCP1) panel because of safety concerns (Lieberman et al., 2007). Owing to these safety concerns and use among military personnel, ephedra’s safety was evaluated. The committee initiated a safety review by applying Figure 4-1 and 4-2 (see Chapter 4). An initial search for review on ephedra was carried out in appropriate databases such as PubMed, Napralert, Toxline, Sci Finder, UIC, and Company Digital Libraries. Among the terms used in the search were: ephedra and Latin binomials, healthy, performance, ergogenic, memory, interactions, adverse, toxicity, and infection. The review was focused on perceived benefits such as weight-loss aid and performance enhancer only, as relevant benefits for military personnel. A few studies demonstrate a statistically significant weight loss using ephedra versus placebo. Most studies, however, show only 0.6–0.8 kg weight loss per month using ephedra or 1.0 kg with ephedra-caffeine combinations. The committee concluded that these effects are not clinically relevant. Moreover, there are no clinical studies with long-term data. Likewise, clinical studies with ephedra alkaloids have not shown to result in significant improvements in performance for the specific modalities tested. On the contrary, combinations of ephedrine HCl (synthetic ephedrine) and caffeine seem to enhance various measurements of performance. During clinical trials it was noted that the risk of adverse events increased two to four fold and that the adverse effect profile of ephedra was primarily related to serious cardiovascular effects, from palpitations to tachicardias and strokes. Although most adverse effects are relevant to the general population, some of them, such as psychosis, vision impairment, dehydration, or muscle failure, would specifically present heightened risks for military personnel. Interaction with sympathomimetic drugs should be of concern as well as the occurrence of palpitations. Some of the adverse events (e.g., psychosis, increased heart rate and blood pressure, myocardial infarction, arrhythmias) were also seen in studies when ephedra and caffeine were provided in combination. The committee concluded that the use of ephedra (and related alkaloids) present a high level of concern. Owing to the moderate potential for benefits and high level of concern, this committee supports the current ban on ephedra use. Military leadership might decide to take the following actions on ephedra and its alkaloids, particularly directed towards populations that might use performance enhancers such as Rangers or Special Operations forces: x To develop an outreach strategy to educate soldiers about the high risks and low benefits of using ephedra and its alkaloids by o Including ephedra and its alkaloids in outreach materials as a list of dietary supplements to avoid. Recommend the use of alternative products (e.g., creatine, HMB) or strategies (modification of resistance training regime, increase energy intake) that might provide similar desired effects. 1

The TTCP panel is an international panel of military scientists with the mission of conducting research, sharing information, and writing papers on performing-enhancing treatments for potential operational use.

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D-4

USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

o To inform military health care providers, fitness trainers and therapists, registered dietitians, nutritionists, commanders, and other educators about the risks and benefits of using ephedra and its alkaloids and recommend alternative products or foods. o To monitor the use and potential associated adverse effects among military personnel. THE CASE OF MELATONIN: DECISIONS FOR ACTION The interest of the committee in melatonin originated from the potential value for use by military personnel as a sleep enhancer and for reentrainment following rapid deployment across multiple time zones (Lieberman et al., 2007). Although melatonin use was not reported as being used in any of the military surveys reviewed, melatonin is being used at a high rate as a dietary supplement in the general population. This committee foresees that in the future, military services might be taking melatonin to overcome circadian reentrainment or to improve sleep; therefore, the committee selects melatonin as being of interest to the military and supports a review of safety and efficacy before decisions about its value for military personnel are made. Melatonin is a hormone secreted by the pineal gland in the brain and it is reportedly found in a number of plant foods. It has widespread effects in the body, many of them poorly understood.. Endogenous secretion of melatonin is believed to help maintain internal circadian synchrony among organ systems throughout the body. Exogenous melatonin is available over the counter in the United States. Literature searches conducted by the committee were focused on ingestion of melatonin for inducing daytime sleep in healthy adults, for improving nocturnal sleep in persons with insomnia, and for circadian reentrainment (e.g., jet lag, night shift work). The searches were conducted in Thomson ISI and PubMed. There are numerous published clinical studies and experiments. This committee reviewed the findings from three recent reviews (Arendt and Skene, 2005; Morin et al., 2007; Wagner et al., 1998) and three meta-analyses (Brzezinski et al., 2004; Buscemi et al., 2005, 2006). The committee concluded that there is moderate potential for benefits (very modest evidence of improvement of sleep, but moderate to good evidence of circadian reentrainment under controlled conditions). Mild adverse events have been identified such as drowsiness, core body heat loss, and gastrointestinal distress (e.g., nausea) that might affect military performance; serious adverse were not found. Exogenous melatonin’s putative synergistic effects with sedative hypnotics were not found. Given the moderate concern and moderate potential for benefits of exogenous melatonin, the military leadership could initiate the following activities: x Follow up with the scientific community conducting research on the effects of melatonin for sleep and circadian reentrainment during operations in environments unconducive to sleep, to determine if melatonin has advantages over sedativehypnotics that have carryover effects on performance. x Develop an outreach strategy to educate military members, military health care providers, fitness trainers and therapists, registered dietitians, nutritionists, and commanders about the potential interactions of melatonin with sedative-hypnotic medications and the potential for increased heat loss.

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APPENDIX D

D-5

REFERENCES Arendt, J., and D. J. Skene. 2005. Melatonin as a chronobiotic. Sleep Med Rev 9(1):25-39. Brasfield, K. 2004. Dietary supplement intake in the active duty enlisted population. US Army Med Dept J 44-56. Brzezinski, A., M. G. Vangel, R. J. Wurtman, G. Norrie, I. Zhdanova, A. Ben-Shushan, and I. Ford. 2005. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 9(1):41-50. Buscemi, N., B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, G. Baker, T. P. Klassen, and S. Vohra. 2005. The efficacy and safety of exogenous melatonin for primary sleep disorders - A meta-analysis. J Gen Intern Med 20(12):1151-1158. Buscemi, N., B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, S. Vohra, T. P. Klassen, and G. Baker. 2006. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep-restriction: Meta-analysis. BMJ 332(7538):385-393. Deuster, P. A., A. Sridhar, W. J. Becker, R. Coll, K. K. O'Brien, and G. Bathalon. 2003. Health assessment of U.S. Army Rangers. Mil Med 168(1):57-62. Jaghab, D. 2007. Survey of army health care providers concerning dietary supplements. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Lieberman, H. R., T. Stavinoha, S. McGraw, and L. Sigrist. 2007. Use of dietary supplements in U.S. Army populations. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Marriott, B. M. 2007. Dietary supplement use by active duty military personnel: A worldwide sample. Institute of Medicine Committee on Dietary Supplement Use by Military Personnel meeting, Washington, DC, February 13. Morales, A. J., R. H. Haubrich, J. Y. Hwang, H. Asakura, and S. S. Yen. 1998. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf) 49(4):421-432. Morin, A. K., C. I. Jarvis, and A. M. Lynch. 2007. Therapeutic options for sleep-maintenance and sleeponset insomnia. Pharmacotherapy 27(1):89-110. Rados, C. 2004. Ephedra ban: No shortage of reasons. FDA Consum 38(2):6-7. Sheppard, H. L., S. M. Raichada, K. M. Kouri, L. Stenson Bar Maor, and J. D. Branch. 2000. Use of creatine and other supplements by members of civilian and military health clubs: A cross-sectional survey. Int J Sport Nutr Exerc Metab 10(3):245-259. Wagner, J., M. L. Wagner, and W. A. Hening. 1998. Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother 32(6):680-686.

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Copyright © National Academy of Sciences. All rights reserved.

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Appendix E Adverse Event Reporting Forms

PREPUBLICATION COPY: UNCORRECTED PROOFS E-1

Copyright © National Academy of Sciences. All rights reserved.

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MEDMARXSM Adverse Drug Reaction Data Entry Form *Required Information *Date of reaction:________________________(mm/dd/yyyy)

*Source of reaction:

Inpatient

Outpatient

*Description of reaction: ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ ____________________________________________________________________________________________________________ *Body system(s) involved: Allergy & Immune System Blood/Bone Marrow/Lymphatic System Body as a Whole, General/Constitutional Bones/Joints, Muscles & Connective Tissue Brain, Neurologic, & Nervous System

Cardiac/Heart Circulation/Vascular & Coagulation Ears/Auditory, Nose & Throat Endocrine System (Hormones) Eyes/Ocular & Vision

Gastrointestinal/Digestive System Liver/Hepatobiliary & Pancreas Mental Health & Behavior Metabolism & Nutrition

Renal & Urinary System Reproduction & Pregnancy Respiratory/Pulmonary, & Thoracic Skin/Subcutaneous Tissues, Hair & Nails

Mouth & Teeth

*Reaction summary terms: Abnormal, Diagnostic test Abnormal, Laboratory value Acidosis Adult respiratory distress syndrome (ARDS) Alkalosis Allergic reaction/hypersensitivity Anemias Angina

Dry skin Dysphagia (difficulty swallowing) Dyspnea (shortness of breath) Edema

Irregular menses Ischemia

Rash Red-man syndrome

Keratitis Lethargy

Renal failure Respiratory arrest

Erectile dysfunction Extrapyramidal/movement disorder Fatigue Feminization of male

Leukopenias Libido alteration

Respiratory distress/depression Rhabdomyolysis

Liver dysfunction/failure Loss of consciousness/syncope Malignancy Masculinization of female Melena Memory impairment

Anorexia Apnea Arthritis Ascites

Fever Fistula Flatulence Flushing

Ataxia Autoimmune disorder Bruising Cardiac arrhythmia

Gastritis Glaucoma Glucose metabolism disorder Gynecomastia

Mucositis/stomatitis Multi-organ failure Muscle weakness Nail changes

Cardiac conduction abnormality Cardiac failure Cardiac infarction Cardiac ischemia Cardiac rate abnormal Cardiomyopathy Cataract Cerebral ischemia Coagulopathy Colitis Confusion Conjunctivitis Constipation Cough Cushing’s syndrome/appearance Dehydration Depression/mood alteration Diarrhea Dizziness Dry eye syndrome

Hair loss/alopecia Headache Hearing changes Heartburn/dyspepsia Hematemesis Hematuria Hemolysis Hemoptysis Hemorrhage Hiccups Hives Hot flashes/flushes Hypertension Hypotension Hypoxia

Nausea Neuropathy Nystagmus Obstruction Otitis Pain Palpitations Pancreatitis Pericardial effusion Petechiae/purpura Pharyngitis Phlebitis Photosensitivity Pigmentation changes Pleural effusion

Dry mouth/salivary gland

Ileus Incontinence Infection Infertility/sterility Injection site reaction/extravasation Insomnia

Rhinitis Rigors/chills Salivary gland changes Seizure Serum sickness Somnolence/depressed consciousness level Speech impairment Stevens-Johnson syndrome Sweating Syndrome inappropriate antidiuretic hormone Syndrome, Other Taste alteration Thombocytopenia Thrombosis/embolism Thyroid dysfunction Tremor Tumor lysis syndrome Ulcer Urinary electrolyte wasting Urinary frequency/urgency Urinary retention Urine color change Vaginal dryness Vaginitis Vascular leak syndrome

Pneumonitis/pneumonia Pneumothorax Proctitis Pruritus/itching Psychosis

Vasculitis Vision Changes Voice changes Vomiting Watery eye

Pulmonary fibrosis

Weight change

©2004 The United States Pharmacopeial Convention, Inc. All Rights Reserved. MEDMARXSM (9/04) Copyright © National Academy of Sciences. All rights reserved.

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*Suspected medication (generic name):___________________________*Patient age:_________(days, weeks, months, years) Circle one *Seriousness Criteria Intervention to prevent incapacity Is a congenital anomaly or birth defect

Is life-threatening

Other medically important condition

Results in death

Not serious (none of the above apply)

Requires initial/prolonged hospitalization

Results in persistent/significant incapacity

*Patient location: Admitting Department

Emergency Transport Vehicle

Intensive Care Unit, Coronary Intensive Care Unit, General Intensive Care Unit, Medical Intensive Care Unit, Neonatal Intensive Care Unit, Pediatric Intensive Care Unit, Surgical Labor / Delivery

Endoscopy / GI Lab Hospice Hospital, another

Long-Term Care Facility Maternity Nursery

Cardiac Catheterization Laboratory Cardiovascular / Pulmonary Services Clinic, Outpatient Dialysis Unit Emergency Department

Nursing (Patient Care) Unit Obstetrical Recovery Room Occupational Therapy

Physical Therapy Post-anesthesia Care Unit Pre-Op holding

Operating Room

Psychiatric, Inpatient

Oncology Department

Psychiatric, Outpatient

Outpatient Surgery Department Patient home / Residence Pediatrics Pharmacy, Inpatient Pharmacy, Outpatient

Radiology Rehabilitation Care Unit Transplant Unit

*Outcome of reaction: Fatal Not recovered/not resolved

Recovered/resolved Recovered/resolved with sequelae

Recovering/resolving Unknown

*Result of reaction on patient level of care: A level of care not determined Airway established / patient ventilated Antidote administered Cardiac defibrillation performed CPR administered

Dialysis Drug therapy initiated / changed Hospitalization, initial Hospitalization, prolonged 1-5 days Hospitalization, prolonged 6-10 days

Hospitalization, prolonged >10 days Laboratory tests performed

Oxygen administered

Narcotic antagonist administered None

Transferred to higher level of care

Observation initiated / increased

Surgery performed

Vital signs / monitoring initiated / increased X-ray / MRI / other diagnostic test performed

*Preventability assessment: Considered preventable, Other Documented drug interaction involved Dose/route/frequency inappropriate

Drug inappropriate for clinical condition History of allergy/previous reaction Not considered preventable

Poor compliance involved Required monitoring/tests not performed Unknown/Unable to assess

*Action(s) taken: Documented ADR-other

Informed patient/caregiver

Policy/Procedure instituted

Suspected Medication(s) Dose Increased

Documented ADR-patient chart

Informed patient's physician

Provided Supportive/Palliative Care

Suspected Medication(s) Dose Reduced

Documented ADRprescription entry system

Other Medication(s) Dose changed/withdrawn

Submitted FDA MedWatch Form

Suspected Medication(s) Dose Unchanged

Policy/Procedure changed

Suspected Medication(s) Discontinued

Unknown

Formulary changed

©2004 The United States Pharmacopeial Convention, Inc. All Rights Reserved. MEDMARXSM (9/04) Copyright © National Academy of Sciences. All rights reserved.

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*Naranjo Scale Probability/Causality Assessment Question

Yes

No

Do Not Know

1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction appear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction appear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Brand Name:_________________________ Dosage form:_________________________ Batch Lot number:_____________________ Strength/Concentration:________________ Dosage Interval:_______________________ Medication Start Date:__________________

Manufacturer:________________________ Intended route of administration:________ Investigational drug name:_____________ Indication:___________________________ Dosage Information Detail:_____________ Medication End Date:__________________

Therapeutic Classification:______________ Labeler:_____________________________ Compounded ingredients:______________ Dosage:_____________________________ Reaction Latency:_____________________

Detection Method: Patient-Objective Evidence Triggers-Medication Orders/Lab Values Patient Sex:

Patient-Subjective Complaint Spontaneous report

Male

Chart Review Other

ICD-9 Code Review

Female

Patient weight:________________________

Unavailable

Location detail:________________________

Duration of reaction:_________________

Pertinent medication history; medical history, including relevant pre-existing conditions; concomitant drug therapy, with dates: ______________________________________________________________________________________________________________________ ______________________________________________________________________________________________________________________ Results of relevant tests/procedures to the reaction: ______________________________________________________________________________________________________________________ ______________________________________________________________________________________________________________________

Reporter level of staff: Anesthesiologist Emergency Medical Services Nurse Anesthetist Nurse, Registered Optometrist Pharmacy Technician Physician Assistant Radiology Technician Unlicensed Assistive Personnel

Dentist and related specialties Laboratory Personnel Nurse Practitioner/Advanced Practice Nurse Nurse, Travel

Dialysis Technician Management Personnel Nurse, Graduate

Patient/Family Member/Caregiver Phlebotomist Physician, Intern

Pharmacist

Respiratory Therapist

Student

Nursing Assistant/Aide

Physical Therapist Physician, Resident

Dietary Personnel Nuclear Medicine Technician Nurse, Licensed Practical/Vocational Nursing Personnel, nonspecific Pharmacy Personnel, nonspecific Physician Psych Tech/Mental Health Technician Unit Secretary/Clerk

Action taken and recommendations to avoid future reactions: ________________________________________________________________________________________________________________________ ________________________________________________________________________________________________________________________ Internal control:___________________________________________ Physician Service detail:________________

Serum Creatinine:_____________ milligrams per deciliter

Patient detail:__________________________

Reporter detail:_____________________

Patient Name:______________________________________________

Medical Record #:__________________________________________ This document is part of a quality improvement process CONFIDENTIAL-Not to be included as part of the patient medical record

Signature of Unit Manager:__________________________________

©2004 The United States Pharmacopeial Convention, Inc. All Rights Reserved. MEDMARXSM (9/04) Copyright © National Academy of Sciences. All rights reserved.

U.S.of Department of Health and Human Services Use Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

MEDWATCH

For VOLUNTARY reporting of adverse events, product problems and product use errors

The FDA Safety Information and Adverse Event Reporting Program

Page ____ of ____

A. PATIENT INFORMATION 1. Patient Identifier

4. Weight

3. Sex

1. Name, Strength, Manufacturer (from product label) lb

Female Male

or

Check all that apply: Adverse Event

Product Problem (e.g., defects/malfunctions)

Product Use Error

Problem with Different Manufacturer of Same Medicine

2. Outcomes Attributed to Adverse Event (Check all that apply) Death:

Disability or Permanent Damage (mm/dd/yyyy)

Life-threatening

Congenital Anomaly/Birth Defect

Hospitalization - initial or prolonged

Other Serious (Important Medical Events)

Required Intervention to Prevent Permanent Impairment/Damage (Devices) 4. Date of this Report (mm/dd/yyyy)

#1

kg

B. ADVERSE EVENT, PRODUCT PROBLEM OR ERROR

3. Date of Event (mm/dd/yyyy)

FDA USE ONLY Triage unit sequence #

D. SUSPECT PRODUCT(S)

2. Age at Time of Event, or Date of Birth:

In confidence

1.

Form Approved: OMB No. 0910-0291, Expires: 10/31/08 See OMB statement on reverse.

#2 2.

Dose or Amount

Frequency

#1 #2 3. Dates of Use (If unknown, give duration) from/to (or best estimate) #1

5. Event Abated After Use Stopped or Dose Reduced? Doesn't #1 Yes No Apply

#2

#2

Yes

No

4. Diagnosis or Reason for Use (Indication)

Doesn't Apply

8. Event Reappeared After Reintroduction?

#1

#1

Yes

No

Doesn't Apply

7. Expiration Date

#2

Yes

No

Doesn't Apply

#1

#1

9. NDC # or Unique ID

#2

#2

#2 5. Describe Event, Problem or Product Use Error

Route

6. Lot #

PLEASE TYPE OR USE BLACK INK

E. SUSPECT MEDICAL DEVICE 1. Brand Name 2. Common Device Name 3. Manufacturer Name, City and State

4. Model #

5. Operator of Device

Lot #

Health Professional Catalog #

Expiration Date (mm/dd/yyyy)

Serial #

Other #

6. If Implanted, Give Date (mm/dd/yyyy)

Lay User/Patient Other:

7. If Explanted, Give Date (mm/dd/yyyy)

8. Is this a Single-use Device that was Reprocessed and Reused on a Patient? Yes

No

9. If Yes to Item No. 8, Enter Name and Address of Reprocessor 6. Relevant Tests/Laboratory Data, Including Dates

F. OTHER (CONCOMITANT) MEDICAL PRODUCTS Product names and therapy dates (exclude treatment of event)

7. Other Relevant History, Including Preexisting Medical Conditions (e.g., allergies, race, pregnancy, smoking and alcohol use, liver/kidney problems, etc.)

G. REPORTER (See confidentiality section on back) 1. Name and Address

E-mail

Phone # 2. Health Professional? 3. Occupation

C. PRODUCT AVAILABILITY

Yes

Product Available for Evaluation? (Do not send product to FDA) Yes

No

Returned to Manufacturer on: (mm/dd/yyyy)

FORM FDA 3500 (10/05)

No

5. If you do NOT want your identity disclosed to the manufacturer, place an "X" in this box:

4. Also Reported to: Manufacturer User Facility Distributor/Importer

Submission of a report does not constitute an admission that medical personnel or the product caused or contributed to the event.

Copyright © National Academy of Sciences. All rights reserved.

ADVICE ABOUT VOLUNTARY REPORTING

Use of Dietary Supplements by Military Personnel http://www.nap.edu/catalog/12095.html

Detailed instructions available at: http://www.fda.gov/medwatch/report/consumer/instruct.htm

Report adverse events, product problems or product use errors with:

.. .. . .

Medications (drugs or biologics) Medical devices (including in-vitro diagnostics) Combination products (medication & medical devices) Human cells, tissues, and cellular and tissue-based products Special nutritional products (dietary supplements, medical foods, infant formulas) Cosmetics

-Fold Here-

.. .

Suspected counterfeit product Suspected contamination Questionable stability Defective components Poor packaging or labeling Therapeutic failures (product didn't work)

Report SERIOUS adverse events. An event is serious when the patient outcome is:

.. .. .. .

How to report: Just fill in the sections that apply to your report Use section D for all products except medical devices Attach additional pages if needed Use a separate form for each patient Report either to FDA or the manufacturer (or both) Other methods of reporting:

Report product problems - quality, performance or safety concerns such as:

.. .. ..

.. .. .. .

Report even if: You're not certain the product caused the event You don't have all the details

Death Life-threatening Hospitalization - initial or prolonged Disability or permanent damage Congenital anomaly/birth defect Required intervention to prevent permanent impairment or damage Other serious (important medical events)

1-800-FDA-0178 -- To FAX report 1-800-FDA-1088 -- To report by phone www.fda.gov/medwatch/report.htm -- To report online

If your report involves a serious adverse event with a device and it occurred in a facility outside a doctor's office, that facility may be legally required to report to FDA and/or the manufacturer. Please notify the person in that facility who would handle such reporting.

-Fold Here-

If your report involves a serious adverse event with a vaccine call 1-800-822-7967 to report. Confidentiality: The patient's identity is held in strict confidence by FDA and protected to the fullest extent of the law. FDA will not disclose the reporter's identity in response to a request from the public, pursuant to the Freedom of Information Act. The reporter's identity, including the identity of a self-reporter, may be shared with the manufacturer unless requested otherwise.

The public reporting burden for this collection of information has been estimated to average 36 minutes per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Department of Health and Human Services Food and Drug Administration - MedWatch 10903 New Hampshire Avenue Building 22, Mail Stop 4447 Silver Spring, MD 20993-0002

Please DO NOT RETURN this form to this address.

OMB statement: "An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number."

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

FORM FDA 3500 (10/05) (Back)

Please Use Address Provided Below -- Fold in Thirds, Tape and Mail

DEPARTMENT OF HEALTH & HUMAN SERVICES

NO POSTAGE NECESSARY IF MAILED IN THE UNITED STATES OR APO/FPO

Public Health Service Food and Drug Administration Rockville, MD 20857 Official Business Penalty for Private Use $300

BUSINESS REPLY MAIL FIRST CLASS MAIL

PERMIT NO. 946

ROCKVILLE MD

MEDWATCH The FDA Safety Information and Adverse Event Reporting Program Food and Drug Administration 5600 Fishers Lane Rockville, MD 20852-9787

Copyright © National Academy of Sciences. All rights reserved.

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Form Approved: OMB No. 0910-0291, Expires: 10/31/08 See OMB statement on reverse.

U.S. Department of Health and Human Services Food and Drug Administration

For use by user-facilities, importers, distributors and manufacturers for MANDATORY reporting

MEDWATCH A. PATIENT INFORMATION

FDA Use Only

C. SUSPECT PRODUCT(S)

2. Age at Time of Event:

4. Weight

3. Sex

lbs

Female

or In confidence

UF/Importer Report #

Page ____ of ____

FORM FDA 3500A (10/05) 1. Patient Identifier

Mfr Report #

or

Date of Birth:

Male

1. Name (Give labeled strength & mfr/labeler) #1 #2

kgs

3. Therapy Dates (If unknown, give duration) from/to (or best estimate)

2. Dose, Frequency & Route Used

B. ADVERSE EVENT OR PRODUCT PROBLEM 1.

Adverse Event

and/or

2. Outcomes Attributed to Adverse Event (Check all that apply) Death:

#1

#1

#2

#2

Product Problem (e.g., defects/malfunctions) 5. Event Abated After Use Stopped or Dose Reduced? Doesn't #1 Yes No Apply

4. Diagnosis for Use (Indication) Disability or Permanent Damage

(mm/dd/yyyy) Life-threatening

Congenital Anomaly/Birth Defect

Hospitalization - initial or prolonged

Other Serious (Important Medical Events)

#1 #2

#2

#1

#1

8. Event Reappeared After Reintroduction?

#2

#2

#1

Yes

No

Doesn't Apply

#2

Yes

No

Doesn't Apply

Required Intervention to Prevent Permanent Impairment/Damage (Devices) 3. Date of Event (mm/dd/yyyy)

4. Date of This Report (mm/dd/yyyy)

Yes

No

9. NDC# or Unique ID

5. Describe Event or Problem

Doesn't Apply

7. Exp. Date

6. Lot #

PLEASE TYPE OR USE BLACK INK

10. Concomitant Medical Products and Therapy Dates (Exclude treatment of event)

D. SUSPECT MEDICAL DEVICE 1. Brand Name 2. Common Device Name 3. Manufacturer Name, City and State

Lot #

4. Model #

5. Operator of Device Health Professional

Catalog #

Expiration Date (mm/dd/yyyy)

Serial #

Other #

6. If Implanted, Give Date (mm/dd/yyyy) 6. Relevant Tests/Laboratory Data, Including Dates

Lay User/Patient Other:

7. If Explanted, Give Date (mm/dd/yyyy)

8. Is this a Single-use Device that was Reprocessed and Reused on a Patient? Yes

No

9. If Yes to Item No. 8, Enter Name and Address of Reprocessor

10. Device Available for Evaluation? (Do not send to FDA) Yes

No

Returned to Manufacturer on: (mm/dd/yyyy)

11. Concomitant Medical Products and Therapy Dates (Exclude treatment of event) 7. Other Relevant History, Including Preexisting Medical Conditions (e.g., allergies, race, pregnancy, smoking and alcohol use, hepatic/renal dysfunction, etc.)

E. INITIAL REPORTER 1. Name and Address

Submission of a report does not constitute an admission that medical personnel, user facility, importer, distributor, manufacturer or product caused or contributed to the event.

Phone #

2. Health Professional? 3. Occupation Yes

No

Copyright © National Academy of Sciences. All rights reserved.

4. Initial Reporter Also Sent Report to FDA Yes No Unk.

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MEDWATCH FORM FDA 3500A (10/05) (continued)

Page ____ of ____

F. FOR USE BY USER FACILITY/IMPORTER (Devices Only) 1. Check One

2. UF/Importer Report Number

H. DEVICE MANUFACTURERS ONLY 1. Type of Reportable Event

Importer

User Facility

3. User Facility or Importer Name/Address

2. If Follow-up, What Type?

Death

Correction

Serious Injury

Additional Information

Malfunction

Response to FDA Request

Other:

Device Evaluation

3. Device Evaluated by Manufacturer?

4. Device Manufacture Date (mm/yyyy)

Not Returned to Manufacturer 4. Contact Person

5. Phone Number

6. Date User Facility or Importer Became Aware of Event (mm/dd/yyyy)

Yes

8. Date of This Report (mm/dd/yyyy)

7. Type of Report

Evaluation Summary Attached 5. Labeled for Single Use?

No (Attach page to explain why not) or provide code:

Yes

No

Initial 6. Evaluation Codes (Refer to coding manual) Follow-up #

9. Approximate Age of Device

10. Event Problem Codes (Refer to coding manual)

Method

Patient Code

Results

Device Code 11. Report Sent to FDA?

Conclusions 12. Location Where Event Occurred

No

(mm/dd/yyyy)

Home Nursing Home

13. Report Sent to Manufacturer?

Ambulatory Surgical Facility

Outpatient Treatment Facility

Yes No

Outpatient Diagnostic Facility

Hospital

Yes

7. If Remedial Action Initiated, Check Type

(mm/dd/yyyy)

Recall

Notification

Initial Use of Device

Repair

Inspection

Reuse

Replace

Patient Monitoring

Relabeling

Other:

8. Usage of Device

Modification/ Adjustment

Unknown 9. If action reported to FDA under 21 USC 360i(f), list correction/ removal reporting number:

Other:

(Specify) 14. Manufacturer Name/Address 10.

Additional Manufacturer Narrative

and / or

11.

Corrected Data

G. ALL MANUFACTURERS 1. Contact Office - Name/Address (and Manufacturing Site for Devices)

2. Phone Number

3. Report Source (Check all that apply) Foreign Study Literature Consumer Health Professional 4. Date Received by Manufacturer (mm/dd/yyyy)

User Facility

5.

Company Representative Distributor

(A)NDA # IND #

6. If IND, Give Protocol #

Other:

STN # 7. Type of Report (Check all that apply) 5-day

30-day

7-day

Periodic

10-day

Initial

15-day

Follow-up # ____

9. Manufacturer Report Number

PMA/ 510(k) # Combination Product

Yes

Pre-1938

Yes

OTC Product

Yes

8. Adverse Event Term(s)

The public reporting burden for this collection of information has been estimated to average 66 minutes per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to:

Department of Health and Human Services Food and Drug Administration - MedWatch 10903 New Hampshire Avenue Building 22, Mail Stop 4447 Silver Spring, MD 20993-0002 Please DO NOT RETURN this form to this address.

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Appendix F Biographical Sketches of Workshop Speakers

Lt. Col. Sonya Corum is currently serving as the Director of Experimentation and Analysis Element at the U.S. Army Training Center—Fort Jackson, South Carolina. She graduated with a B.S. degree in Food and Nutrition from Appalachian State University in Boone, North Carolina, in 1988. Her first assignment after completing the Dietetic Internship at Brooke Army Medical Center was at Ireland Army Community Hospital, Fort Knox, Kentucky, as the Chief, Clinical Dietetics. Since that time, Lieutenant Colonel Corum has held a number of positions in medical treatment facilities including Chief, Production and Service at William Beaumont Army Medical Center, and Chief, Nutrition Care at Fort Campbell. She also deployed with the 86th Combat Support Hospital in support of Hurricane Mitch relief. She has served as the Executive Fellow to the Chief, Medical Specialist Corps. Lieutenant Colonel Corum was the Nutrition Staff Officer at the U.S. Army Center for Health Promotion and Preventive Medicine where she spearheaded the Army’s Dietary Supplement Education Campaign. She also deployed with the 31st Combat Support Hospital in support of Operation Iraqi Freedom. Lieutenant Colonel Corum’s education includes a Masters in Business Administration from the University of Texas–El Paso and is a Command and General Staff College graduate. Gerald J. Dal Pan, M.D., M.H.S., is the Director of the Office of Surveillance and Epidemiology in the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (FDA/CDER). Prior to that, he was the Director of the Division of Surveillance, Research, and Communication Support in CDER's Office of Drug Safety, a position he held since December 2003. He received his medical degree from Columbia University, and his master's degree in clinical epidemiology from Johns Hopkins University. He trained in internal medicine at the Hospital of the University of Pennsylvania, and in neurology at the Johns Hopkins Hospital. He is board certified in Internal Medicine and Neurology. Dr. Dal Pan was an instructor in the Neurology Department at Johns Hopkins. He next worked for Guilford Pharmaceuticals in Baltimore, and then for HHI Clinical Research and Statistical Services in Hunt Valley, Maryland. He joined the FDA in July 2000 as a medical officer in the Division of Anesthetic, Critical Care, and Addiction Drug Products. Vasilios Frankos, Ph.D., serves as the Director, Division of Dietary Supplement Programs (DDSP) and the lead scientist for dietary supplements for the FDA and is responsible for the full implementation of the DSHEA Act of 1994. He directs and coordinates policy and administrative activities within the division. He advises on policy PREPUBLICATION COPY: UNCORRECTED PROOFS F-1

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

and management issues on dietary supplement programs, new dietary ingredient safety assessments, good manufacturing practice, and adverse reaction monitoring, and related activities pertaining to dietary supplements. Before becoming the Director of DDSP, Dr. Frankos also served as Special Assistant for Dietary Supplement Science Review providing toxicological and pharmacological evaluation of data used to assess the risks posed by dietary supplement products, Staff Science Advisor in the Office of the Commissioner, and as a Senior Toxicologist in the Center for Food Safety and Applied Nutrition. Dr. Frankos received his M.S. in molecular biology from the University of Maryland, and his Ph.D. in Pharmacology and Toxicology from the University of Maryland Pharmacy School. He has over 30 years experience in the toxicological and pharmacological evaluation of data used to assess the safety of FDA-regulated products. In addition to his FDA activities, he spent 18 years as a principal in the consulting firm ENVIRON International Corp. Steve French, M.B.A., is the Managing Partner of the Natural Marketing Institute with over 25 years of strategic marketing, business development, market research, and management experience. Complementing a B.S. and MBA in marketing, Mr. French has accumulated extensive insight and knowledge into health, wellness, environmentalism, and social responsibility. He has unparalleled experience across a wide range of corporate business functions and has pioneered a range of consumer research databases. Mr. French is a frequent speaker at many industry events and conferences, and is regularly utilized by television, radio, magazine, newspaper, Internet, and other media sources. He is also an author of numerous published articles and written research reports used across many industries. Paula Gardiner, M.D. M.P.H., is an assistant professor in the department of Family Medicine at Boston University Medical School. She is a former research fellow at the Division for Research and Education in Complementary and Integrative Medical Therapies, Osher Institute, Harvard Medical School. Her research focuses on use of dietary supplements by adults and adolescents in the U.S. population. Additionally, her research has focused on the safety issues surrounding dietary supplements such as: prescription medication/dietary supplement interactions and adverse event reporting. She is a member of the USP’s Dietary Supplements Expert Committee where she has focused on improving adverse event reporting in the United States. Mary Hardy, M.D., is board certified in internal medicine and a specialist in botanical and integrative medicine, has actively combined complementary and alternative therapies with traditional Western medicine for many years. A graduate of Louisiana State University School of Medicine in New Orleans, Dr. Hardy completed her internal medicine residency at the Tufts New England Medical Center before studying medical ethics at Harvard Divinity School and Loma Linda University. She completed advanced training in botanical medicine at the Institute for Medical Herbalism and has studied with practitioners in Peru, Kenya, South Africa, and China. She is the complementary and alternative medicine expert for a number of research projects conducted by the Southern California Evidence-Based Practice Center at the RAND Corporation. In addition, she has expanded her interest in botanical research by serving for two and half years as the

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APPENDIX F

F-3

Associate Director of the UCLA Botanical Research Center, funded by the National Institutes of Health. Dr. Hardy also serves on the scientific advisory board of the American Botanical Council and the editorial boards of Alternative Medicine Altert, Alternative Therapies in Women’s Health, Evidence-Based Complementary and Alternative Medicine, FACT as well as Phytomedicine. Dr. Hardy is recognized as an authority on integrative medicine and natural products by organizations such as the Office of Dietary Supplements, the California Medical Board, the American Medical Association, the American Pharmaceutical Association, CBS, NBC, Discovery Channel, and the Los Angeles Times. She is a founding member of the Advisory Council for the newly established Naturopathic Medicine Board of California and has been recently appointed to the External Advisory Council for the Natural Product Directorate for the Canadian government. The multidisciplinary clinic she founded at Cedars-Sinai in the department of Medicine in 1998 allowed her to explore the practical and philosophical issues that both facilitate and impede the development of integrative medicine as a discipline. Contributing to the national development of integrative medicine, she serves as the co-chairperson of the Clinical Practice Committee of the Academic Consortium of Integrative Medicine (an organization of the leading medical schools practicing and teaching in this area). Most recently she is serving as the co-director of the Integrative Medicine Health and Wellness Program at the Venice Family Clinic, the largest free clinic in the United States. Her clinical practice now involves educating cancer patients in integrative therapies at the Ted Mann Family Integrative Oncology Program at UCLA. Her current research interests include reviewing the evidence for the safety and efficacy of natural therapies, especially botanicals. Dr. Hardy’s recently completed a book for Reader’s Digest, Best Remedies, that focuses on integrative medicine. She is also conducting a review of the quality of research trials in herbal medicine and is finishing a systematic review on the effects of dietary supplements on coagulation for the Office of Dietary Supplements. Lt. Col. Paul J. Hoerner is currently the Deputy Director of the U.S. Department of Defense (DoD) Patient Safety Center (PSC). He directs the daily operations of the PSC, with a budget of $1.5 million serving more than 576 DoD medical treatment facilities and 9.2 million beneficiaries worldwide. This includes quarterly, annual, bi-monthly publications, safety alerts and focused analysis for use by the DoD, Army, Navy, and Air Force facilities to improve patient safety. A new arrival to the PSC in September 2006, he recently completed a 1-year fellowship at a medial malpractice insurance company. Prior to that assignment, he was the Chief of Pharmacy Operations at David Grant Medical Center. The pharmacy processed over 3,500 outpatient prescriptions daily and prepared over 1,600 inpatient orders daily. He provided oversight of all aspects of the pharmacy’s various elements (clinical, support, inpatient, and outpatient). Colonel Hoerner’s career goals are to advance his leadership capabilities and expertise in the fields of pharmacy and patient safety. Lt. Col. Danny B. N. Jaghab is a Lieutenant Colonel in the U.S. Army. Since 2004 he has been the Nutrition Staff Officer for the U.S. Army Center for Health Promotion and Preventive Medicine at Aberdeen Proven Grounds, Maryland. His work includes analyzing and assessing current policies and developing and implementing new health

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

promotion and nutrition policies and regulations that better meet the needs of the DoD. He collaborates with federal and national agencies on projects and initiatives as the sole subject matter expert on nutrition for the U.S. Army. From July 2002–July 2004, he directed the U.S. Military Dietetic Internship Consortium at the Brooke Army Medical Center in San Antonio, Texas. He was also previously the Chief of the Nutrition Care Division at the DeWitt Army Community Hospital in Fort Belvoir, Virginia. His honors include the Bronze Star Medal Recipient during Operation Desert Shield/Storm; recipient of the 2004 American Dietetic Association’s Media Excellence Award; recipient of the 2004 Department of Defense Patient Safety Award in the category of Technology; and was elected the 2006 Career Guidance Chair, American Dietetic Association’s National Organization of Men in Nutrition (N.O.M.I.N). He received his B.S. in Nutrition and Dietetics from Drexel University in Philadelphia, Pennsylvania, and his M.S. in Education and Counseling from the Long Island University in West Point, New York. David Kaufman, Sc.D., is Professor of Epidemiology at the Boston University School of Public Health. He obtained his B.A. (1973) from Bethel College, North Newton, Kansas, and his M.S. (1979) and Sc.D. (1983) in Epidemiology from Harvard School of Public Health. In 1975 he joined the newly created Drug Epidemiology Unit (subsequently renamed Slone Epidemiology Unit, and since 2001 the Slone Epidemiology Center) as a Research Associate. His early career as an epidemiologist at the DEU was primarily spent in studies of drugs and other factors in relation to cancer, heart disease, and various other conditions. Together with Drs. Slone, Shapiro, and Lynn Rosenberg, he participated in the development of Case-Control Surveillance. In the 1980s, Dr. Kaufman was coinvestigator of the International Agranulocytosis and Aplastic Anemia Study, a pioneering effort in the evaluation of these extremely rare but often drug-induced blood dyscrasias that was conducted in seven countries with several hundred cases enrolled; he co-authored a book describing the results. He has since directed studies of aplastic anemia in Thailand and the United States and served as an adviser to a study of that disease in Brazil. The Thai study is the largest epidemiological investigation of aplastic anemia that has been conducted, with over 500 cases and 2,200 controls. Dr. Kaufman pursued his interest in rare drug-induced diseases as principal investigator of an international study of Stevens-Johnson syndrome and toxic epidermal necrolysis conducted in four countries in Europe, and a study of anaphylaxis conducted in Spain, Hungary, India, and Sweden. Other major activities have included an international study of analgesics in relation to upper gastrointestinal bleeding, and more recently, the National Analgesic Nephropathy Study, a multicenter study of end-stage renal disease patients in three regions of the United States. Dr. Kaufman worked closely with Allen Mitchell in the development of the Slone Survey, a U.S. population-based survey of medication and dietary supplement use that was initiated in 1998; he is principally responsible for the implementation of that project. Another current study is exploring the relationship of Oxalobacter formigenes, an oxalate-metabolizing bacterium found in the colons of about 70% of the normal population, and calcium oxalate kidney stones. Dr. Kaufman is also the Principal Investigator of recently launched national patient registries of multiple myeloma and myelodysplastic syndromes (Patient Registries at Slone: Myeloma and MDS). Dr. Kaufman was Assistant Director of the Slone Epidemiology Unit from 1986 to 1997, and has been Associate Director since 1998.

PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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APPENDIX F

F-5

Rick Kingston, PharmD., is President, Regulatory and Scientific Affairs for SafetyCall International, a multidisciplinary medical practice and poison center focused on corporate postmarket surveillance and product safety for drugs, dietary supplements and consumer products. He has a 28-year academic career having attained the rank of full Professor in the Department of Experimental and Clinical Pharmacology and currently serving as Clinical Professor of Pharmacy in the College of Pharmacy at the University of Minnesota. At the University of Minnesota, he is course director for the didactic course “Therapeutics of Herbs and Other Natural Medicinals” taught in College of Pharmacy and has previously served as a member of the University’s Center for Plants and Human Health and the NCCAM-funded integrative medicine Center for Spirituality and Healing. Previously, Dr. Kingston was co-founder and former Director of the Minnesota Regional Poison Center and its affiliated industry toxicology and product safety surveillance service programs at St. Paul Ramsey Medical Center, in St. Paul, Minnesota. Dr. Kingston completed his Bachelor of Sciences in Pharmacy degree at the University of New Mexico, his Doctorate in Clinical Pharmacy at the University of Minnesota, and a Post-Doctoral Fellowship in clinical toxicology and pharmacokinetics at St. Paul-Ramsey Medical Center and the University of Minnesota. His 28-year professional experience has been centered in the areas of clinical toxicology and pharmacology, poison control, product postmarket surveillance, and drug and dietary supplement safety. His research and practice interests coincide with SafetyCall International initiatives for corporate clients and include a focus on injury prevention, the epidemiology of toxicology-related incident data, product safety and related regulatory affairs, and specific advances in the clinical management or triage of patients being treated or evaluated for drug, toxin, or consumer product exposures. Harris R. Lieberman, Ph.D., is a Research Psychologist in the Military Nutrition Division of the U.S. Army Research Institute of Environmental Medicine (USARIEM) in Natick, Massachusetts. He is an internationally recognized expert in the area of nutrition and behavior and has published over 125 original, full-length papers in scientific journals and edited books. Dr. Lieberman received his Ph.D. in Physiological Psychology in 1977 from the University of Florida and then conducted postdoctoral research at the Department of Psychology and Brain Science at the Massachusetts Institute of Technology (MIT). From 1980–1990 he was on the staff at MIT where he examined the effects of food constituents and drugs on human behavior and brain function. In 1990 he joined the civilian research staff of USARIEM where he continued his work in nutrition, behavior, and stress. From 1994 to 2000 he was Chief or Deputy Chief of the Military Nutrition program at USARIEM. His recent research has addressed the effects of various nutritional factors, diets, and environmental stress on cognitive performance and brain function. He holds two patents for novel technologies to assess and enhance cognitive performance. He currently chairs his institute’s scientific research committee, serves on the DoD Dietary Supplements Committee, and several other national and international committees. Bernadette M. Marriott, Ph.D., is Principal Associate and Senior Scientist at Abt Associates, and has 38 years of experience in the fields of nutrition, psychology, and

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

comparative medicine with expertise in diet, nutrition and chronic disease. Dr. Marriott has worked in scientific settings in the federal government, universities, and foundations. Her research has focused on nutrition and related behavioral studies, specifically diet and health research, and food labeling. She currently holds an adjunct full professor position in the Department of Nutritional Sciences, University of North Carolina School of Medicine, and has held previous academic positions of assistant through full professorships. Other positions include Vice President for Science Integration, RTI International, Founding Director of the National Institutes of Health (NIH) Office of Dietary Supplements, Deputy Director of the Food and Nutrition Board (Institute of Medicine [IOM]), Vice Provost for Research and Dean of Graduate Studies at Northern Arizona University, Vice President for Programs and Communications for the Burroughs Wellcome Fund, and Associate Director of the Caribbean Primate Research Center, University of Puerto Rico. While at IOM, for eight years she oversaw the activities of the Committee on Military Nutrition Research and is very familiar with nutrient requirements of active duty personnel, nutrient composition of ration packages, exercise, and weight management in the military services. At IOM she edited, helped write and/or oversaw the production of 24 reports, two of particular relevance to this study are Food Components to Enhance Performance (DoD) and Guiding Principles for Nutrition Labeling and Food Fortification, for which she was a special consultant and which addresses foods and dietary supplements. Dr. Marriott has extensive experience managing complex programs, building consensus, and working with scientific data. She currently is principal investigator on two NIH-funded projects on adult and child intake, a corporate-funded project on infant feeding, an obesity study supported by OSTP, and was the scientific lead for diet, exercise, weight management, and related health indicators on the 2005 Department of Defense (DoD) Survey of Health-Related Behaviors Among Military Personnel with Bob Bray. Prior to leaving RTI she was principal investigator on the TMA-funded Weight Management Demonstration Project: Healthy Eating and Active Living in TRICARE Households (HEALTH). Bernadette Marriott has a B.Sc. in biology/immunology from Bucknell University, a Ph.D. in psychology from King’s College, Aberdeen, Scotland, and postgraduate training in trace mineral nutrition, comparative medicine, and advanced statistics. She has published extensively, is on a number of national committees, and is a frequent speaker on diet, dietary supplements and health. Scott J. Montain, Ph.D., is a Research Physiologist working in the Military Nutrition Division at USARIEM, Natick, Massachusetts. Dr. Montain received a M.S (1984) from Ball State University and Ph.D. (1991) from the University of Texas at Austin, before completing postdoctoral training at USARIEM. He is author or coauthor of over 95 peerreviewed journal articles, book chapters, and reports. Dr. Montain currently serves as Councilor for the Exercise and Environmental Physiology section of the American Physiological Society and is a Fellow of the American College of Sports Medicine. Lt. Col. Charity Thomasos is currently stationed at Eglin Air Force Base, Florida, as the director of Nutritional Medicine Flight. She earned her B.S. degree from West Virginia Wesleyan College, Buckhannon, West Virginia, in Clinical Nutrition/Dietetics and M.S. from the Ohio State University, Columbus, in Human Nutrition/Biochemistry. She is a

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APPENDIX F

F-7

member of the American Dietetic Association and the Nutrition and Complementary Medicine practice group. Lt. Col. Thomasos is the Air Force Dietetics Representative to the DoD Dietary Supplement Committee and a member of the Special Operations Forces subcommittee. Andrew J. Young, Ph.D., is a research physiologist and Chief of the Military Nutrition Division at USARIEM in Natick, Massachusetts. He obtained a B.S. in Biology at Virginia Military Institute, and a Ph.D. in Physiology at North Carolina State University, and then served in the U.S. Army with assignments at USARIEM (1977–1981) and at the Walter Reed Army Institute of Research (1981–1983). After leaving the Army, Dr. Young continued as a civilian scientist at USARIEM. His research has concerned the biological basis for, and strategies to mitigate, performance degradations in people experiencing intense physical exertion, sleep restriction, nutritional deprivation, and exposure to extremes of heat, cold and high altitude, all of which are characteristics of sustained combat operations. Dr. Young is a member of the American Physiological Society, a Fellow of the American College of Sports Medicine. He is also Editor-in-Chief of the American College of Sports Medicine’s flagship scientific journal, Medicine and Science in Sports and Exercise.

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Appendix G Biographical Sketches of Committee Members

M.R.C. Greenwood, Ph.D., is Professor of Nutrition and Internal Medicine, chair of the graduate group in Nutritional Biology, Director of the Foods for Health Initiative at the University of California, Davis, and Chancellor Emerita, University of California - Santa Cruz. Previous positions include Chancellor of University of California in Santa Cruz from 1996–2004 and University of California Provost and Senior Vice President of Academic Affairs. Previous to her Santa Cruz appointments she was Dean of Graduate Studies and, Vice Provost for Academic Outreach and Professor of Biology and Internal Medicine at UC Davis. Prior to that, she taught at Vassar College, where she was Chair of the Department of Biology and Director of the Undergraduate Research Summer Institute and was on the adjunct faculty of Columbia University's medical school. From November 1993 to May 1995, while on leave from UC Davis, Greenwood served as Associate Director for Science at the Office of Science and Technology Policy in the executive office of the president of the United States. She has been a member of the Institute of Medicine (IOM) of the National Academies (NAS) since 1992. She is currently the Chair of the NAS Policy and Global Affairs Committee. She was a member of the Food and Nutrition Board from 1985–1990 where she also served as chair from 1990–1993. She is also a fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science, where she served as president in 1998 and chair in 1999. She has been President of the American Society for Clinical Nutrition and NAASO, the Obesity Society. Dr. Greenwood received her A.B., summa cum laude, from Vassar College, and received her Ph.D. from Rockefeller University. Her research areas include obesity, diabetes, and women’s health. Cheryl Anderson, Ph.D., M.P.H., is an Assistant Professor in the department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. Previously, she was an Instructor of Epidemiology at the University of Pennsylvania School of Medicine, Center for Clinical Epidemiology and Biostatistics. Dr. Anderson's research centers on diet and the prevention of chronic diseases in minority and underserved populations. Her current research projects address diet and the prevention of cardiovascular disease (CVD) in the context of chronic kidney disease and the optimal macronutrient intake in CVD prevention. Dr. Anderson is a member of the American Heart Association Committee on Nutrition and Physical Activity. She is also a Dannon Institute Nutrition Leadership Institute (NLI) Scholar and the current president of the NLI Alumni Association. She recently served on the National Institutes of Health (NIH) National Institute of PREPUBLICATION COPY: UNCORRECTED PROOFS G-1

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USE OF DIETARY SUPPLEMENTS BY MILITARY PERSONNEL

Neurologic Disorders and Stroke (NINDS) Writing Group on Primary Prevention of Stroke. She has a bachelor degree from Brown University, M.P.H. from the University of North Carolina at Chapel Hill, and M.S. in epidemiology and Ph.D. in nutritional sciences from the department of epidemiology at the University of Washington School of Public Health and Community Medicine. Bruce R. Bistrian, M.D., Ph.D., is Professor of Medicine at Harvard Medical School and Chief of Clinical Nutrition, Beth Israel Deaconess Medical Center. Formerly he was Co-Director of Hyperalimentation Services, New England Deaconess Hospital, and a lecturer in the Department of Nutrition and Food Science, Massachusetts Institute of Technology (MIT). Dr. Bistrian’s primary research interests include nutritional assessment, metabolic effects of acute infections, nutritional support of hospitalized patients, and the pathophysiology of protein–calorie malnutrition. He is a fellow of the American College of Physicians, and has received an honorary M.A. from Harvard University. Dr. Bistrian is the 2004 recipient of the Goldberger Award of the American Medical Association. Dr. Bistrian has been President of the American Society for Parenteral and Enteral Nutrition, President of the American Society of Clinical Nutrition and President of the Federation of American Societies of Experimental Biology. He current serves on the IOM Committee on Military Nutrition Research. Dr. Bistrian has served on the editorial boards of numerous nutrition and medical journals, and is the author or coauthor of over 400 articles in scientific publications. He earned his M.D. from Cornell University, his M.P.H. from Johns Hopkins University, and his Ph.D. in nutritional biochemistry and metabolism from MIT. Dr. Bistrian is board certified in Internal Medicine and was certified in Critical Care Medicine from 1987–2007 John W. Erdman, Jr., Ph.D., is Professor of Nutrition and Food Science in the Department of Food Science and Human Nutrition and a Professor in the Department of Internal Medicine at the University of Illinois at Urbana-Champaign. His research interests include the effects of food processing nutrient retention, the metabolic roles of vitamin A and beta-carotene, and the effects of tomato and broccoli and their bioactive components on risk of prostate cancer. His research regarding soy protein has extended into studies on the impact of nonnutrient components of foods such as phytoestrogens on chronic disease. Dr. Erdman has published over 160 peer-reviewed research papers. He chaired the 1988 Gordon Conference on Carotenoids, and has served as a Burroughs Wellcome Visiting Professor in Basic Medical Sciences at the University of Georgia, and the G. Malcolm Trout Visiting Scholar at Michigan State University. His awards include the Borden Award from the American Society for Nutritional Sciences and the BabcockHart Award from the Institute of Food Technologists. Dr. Erdman has served on many editorial boards, and on many program and planning committees for the American Society of Nutritional Sciences, the Institute of Food Technologists, and the NAS. In 1992, he was elected a fellow of the Institute of Food Technologists, and in 2003 he was elected Fellow of the American Heart Association. Dr Erdman was elected to the IOM in 2003. He received his M.S. and Ph.D. in food science from Rutgers University. William C. Franke, Ph.D., is an associate director of the Center for Advanced Food Technology at Rutgers University. He provides technical expertise in the area of product

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APPENDIX G

G-3

development and food regulations, especially as related to functional foods and nutraceuticals, and develops new opportunities for technology transfer to small and large companies. He also contributes to administration, marketing, and strategic planning. He is a co-principal investigator for a U.S. Department of Defense Contract to develop combat rations to improve the physical and mental performance of soldiers under stress. Previously, he spent 28 years at Lipton/Unilever and served in a number of senior management positions in product development, quality assurance, and regulatory affairs. Most recently he was Vice President for Scientific and Regulatory Affairs with Unilever United States before he retired. He is a former member of the NAS/IOM Food Forum and served on the IOM expert Committee on Evaluation of the Addition of Ingredients New to Infant Formula. He also served as a member of the board of the Cancer Institute of New Jersey and was recently elected a Fellow of the Institute of Food Technologists. Heart Blend Foods LLC, an R&D company that specializes in the development of heart healthy foods, was founded by Dr. Franke in 2005. The company’s objective is to license technology and/or bring products to market that improve public health. Elizabeth Jeffery, Ph.D., is Professor of Nutritional Toxicology and Professor, Nutritional Sciences at the University of Illinois. Dr. Jeffery teaches and performs research in the area of safety and efficacy of functional foods and dietary supplements, with emphasis on biochemical mechanisms of cancer prevention by broccoli and related crucifers. A toxicologist by training, Dr. Jeffery has held elected positions on the Education and Nominating Committees of the Society of Toxicology. She is past President of the Midwest Regional Chapter of the Society of Toxicology and past Chair of the Toxicology specialty section in the American Society for Pharmacology and Experimental Therapeutics. She is past Director of Research Interest Sections and past Chair of the Dietary Bioactive Components Research Interest Section of the American Nutrition Society. She served on the NAS Committee on the Framework for Evaluating the Safety of Dietary Supplements. She has served as an Associate Editor for the Journal of Toxicology and Applied Pharmacology and as guest Field Editor for the Journal of Pharmacology and Experimental Therapeutics, and is involved in the review of research grant proposals for both the NIH and the U.S. Department of Agriculture (USDA). Dr. Jeffery has a Ph.D. in Biochemistry from the University of London, England. Robin B. Kanarek, Ph.D., is Professor of Psychology at Tufts University in Medford, Massachusetts. Her prior experience includes Research Fellow, Division of Endocrinology, University of California, Los Angeles (UCLA) School of Medicine, Research Fellow in Nutrition at Harvard University, and Professor of Nutrition, Chair of the Psychology Department and Dean of the Graduate School of Arts and Sciences at Tufts University. She is a member of the editorial boards of Physiology and Behavior, Nutritional Neuroscience, and the Tufts Diet and Nutrition Newsletter and is a past Editor-in-Chief of Nutrition and Behavior. Dr. Kanarek has served on ad hoc review committees for the National Science Foundation, NIH, and USDA nutrition research, as well as the Member Program Committee of the Eastern Psychological Association. She is a fellow of the American College of Nutrition and the North American Society for the Study of Obesity; other professional memberships include the American Institute of Nutrition, New York Academy of Sciences, Society for the Study of Ingestive Behavior,

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and Society for Neurosciences. Dr. Kanarek received a B.A. in biology from Antioch College in Yellow Springs, Ohio, and an M.S. and a Ph.D. in psychology from Rutgers University in New Brunswick, New Jersey. Carl L. Keen, Ph.D., is Chairman of the Department of Nutrition at the University of California, Davis, and a Professor of Nutrition and Internal Medicine. Dr. Keen’s research focuses on the influence of diet on embryonic and fetal development; the study of gene-nutrient interactions (emphasizing how subtle changes in cell mineral concentrations influence the expression of select genes), dietary influences on oxidant defense systems and as a consequence the occurrence of cellular oxidative damage, and the influence of dietary flavonoids on vascular health. He has served on numerous government boards including California’s Scientific Advisory Board for the Office of Environmental Health Hazard Assessment, numerous EPA Environmental Health Grant Review Panels, the USDA Human Nutrient Requirements Study Section, and several NIH study sections. He has served on a number of editorial boards and is a member of the American Society for Nutrition, the Teratology Society, the Society for Experimental Biology and Medicine (SEBM), and the American Association for the Advancement of Science. Gail B. Mahady, Ph.D., is Associate Professor of Pharmacy Practice, and Director of the Clinical Pharmacognosy Laboratory at the University of Illinois at Chicago. Dr. Mahady’s research interests include the discovery of novel natural agents for treatment/prevention of infectious disease, specifically plant-based antimicrobial drugs for the prevention and treatment of Helicobacter pylori and Chlamydia infections in humans; the assessment of clinical safety and efficacy of herbal supplements globally for the symptomatic treatment of menopause, premenstrual syndrome, and chronic urinary tract infections; and assessment of quality, safety, and efficacy of botanicals for the World Health Organization's (WHO) Traditional Medicines Programme. She is research faculty within the Pan American Health Organization/WHO Collaborating Center for Traditional Medicine at the College of Pharmacy, University of Illinois at Chicago. She is an Elected Member of the United States Pharmacopoeia Dietary Supplements Information Expert Panel and an NCCAM/NIH review panel member for Annual Bibliography of Significant Advances in Dietary Supplement Research, among many NIH review panels. Dr. Mahady received her Ph.D. in Pharmacognosy from the University of Illinois at Chicago. Sanford A. Miller, Ph.D., is a Senior Fellow at the Center for Food and Nutrition Policy at the University of Maryland, College Park. He was named Professor and Dean Emeritus of the Graduate School of Biomedical Sciences at the University of Texas Health Science Center at San Antonio in December 2000 where he was the Dean of the Graduate School of Biomedical Sciences and Professor in the Departments of Biochemistry and Medicine from 1987–2000. He is the former Director of the Center for Food Safety and Applied Nutrition at the U.S. Food and Drug Administration (FDA). Previously, he was a Professor of Nutritional Biochemistry at MIT. Dr. Miller has served on many national and international government and professional society advisory committees, including as chair of the Joint FAO/WHO Expert Consultation on the Application of Risk Analysis to

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APPENDIX G

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Food Standards Issues. Honors include; the Atwater Memorial Lectureship Award from the USDA Agricultural Research Service, the Babcock-Hart Award from International Life Sciences Institute and the Institute of Food Technologists, the Conrad A. Elvehjem Award of the American Institute of Nutrition, the Esther Peterson Consumer Service Award from the Food Marketing Institute, the Sterling B. Hendricks Award from the USDA, and election to Fellow of the American Society for Nutrition. In June 2000, he was the recipient of the FDA’s Distinguished Alumni Award. He has been a member of many NAS committees, including the Food and Nutrition Board’s Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, and Subcommittee on Upper Reference Levels of Nutrients and Panel on Macronutrients. He was named a National Associate of NAS in 2002. He is author or coauthor of more than 200 original scientific publications. Dr. Miller received a B.S. in Chemistry from the City College of New York, and a M.S. and Ph.D. from Rutgers University in Physiology and Biochemistry. Esther F. Myers, Ph.D., R.D, is Director of Research and Scientific Affairs at the American Dietetic Association (ADA), a position she has held since October 2000, after retiring from the Air Force and serving as Chief Consultant to the Air Force Surgeon General. Dr. Myers currently focuses efforts on research activities needed for the dietetics profession and the association as well as the ADA strategic leadership initiative in obesity and the ADA Foundation initiative, Healthy Weight for Kids. She has been actively involved in the development of ADA’s evidence analysis process and in research projects focusing on evaluating impact of nutrition services in Medicare Demonstration projects and in collaboration with Blue Cross Blue Shield of North Carolina. She is the ADA staff liaison with the Nutrition Care Process and Standardized Language Committee, which is developing and validating terminology to reflect the nutrition care for standardized language systems and electronic health records. Prior to joining ADA, she served as a site visitor for the Commission on Accreditation for Dietetics Education, a peer reviewer for the Journal of the American Dietetic Association, and a member of the Health Services Research Task Force overseeing dietetic outcomes research. She was a member of the IOM Committee on Nutrition Services for Medicare Beneficiaries. Dr Myers received her undergraduate degree from North Dakota State University, master’s degree from the Ohio State University, and doctorate from Kansas State University. Janet Walberg Rankin, Ph.D., is a Professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Polytechnic Institute and State University. She has also served as Chair of its Food, Nutrition, and Health Initiative and acting Department Head, as well as Associate Director, and then Interim Director of the University’s new Institute for Biomedical and Public Health Sciences. Dr. Rankin’s research is related to sports nutrition or interventions for obesity, with specific areas of interest including the effects of dietary macronutrient mix, energy balance, and dietary supplements on performance, body composition, and immunity. Her current research focuses on dietary manipulations that may alter inflammation and oxidative stress in athletes and obese individuals. Dr. Rankin’s involvement with professional organizations has included membership on the Executive Board and later as President of the Southeast Chapter of the American College of Sports Medicine. She is a Fellow of the American College of Sports Medicine, served as Vice President for American College of Sports Medicine, and has been a member or

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chair on many national committees for this organization. Dr. Rankin received her bachelor's degree in zoology from Duke University and her doctorate in nutrition with a minor in exercise physiology from the University of California-Davis.

Consultant David F. Dinges, Ph.D., is Professor and Chief of the Division of Sleep and Chronobiology, and Director of the Unit for Experimental Psychiatry in the Department of Psychiatry at the University of Pennsylvania School of Medicine. His research focuses on physiological, neurobehavioral, and psychological effects of sleep loss, disturbances of circadian biology, and stress, and the implications of these unmitigated effects on health and safety. He has performed extensive scientific work on development and validation of behavioral, technological, and pharmacological countermeasures for these effects. His research has been supported by grants from NIH, NASA, DoD, Department of Transportation, and the Department of Homeland Security. He currently leads the Neurobehavioral and Psychosocial Factors Team for the NASA-funded National Space Biomedical Research Institute. He is a member of the NIH NINR Council. He has been President of the U.S. Sleep Research Society and of the World Federation of Sleep Research and Sleep Medicine Societies, and served on the Board of Directors of the American Academy of Sleep Medicine and the National Sleep Foundation. He is currently Editor-in-Chief of SLEEP. He has received numerous awards, including the 2004 Decade of Behavior Research Award from the American Psychological Association, and the 2007 NASA Distinguished Public Service Medal.

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Appendix H Acronyms and Abbreviations

AAFES ADC ADL AI ALS AMDR AMEDD AMS ANS APFT ATP AUC BMD BMI BP CAM CDR CFF CGI cGMP CHPPM CK CNS CRT CSFII CVD CYP2D6 DEXA DFE DHEA DHEA-S DSHEA DoD DRIs DS

Army and Air Force Exchange Service Average daily consumption Activities of daily living Adequate Intake Amyotrophic lateral sclerosis Acceptable Macronutrient Distribution Ranges Army Medical Department Acute mountain sickness Autonomic nervous system Army Physical Fitness Test Adenosine 5'-triphosphate Area under the curve Bone mineral density Body mass index Blood pressure Complementary and Alternative Medicine Cognitive drug research Critical flicker fusion Clinical global impression scale Current good manufacturing practices Center for Health Promotion and Preventive Medicine Creatine kinase Central nervous system Choice reaction time Continuing Survey of Food Intakes by Individuals Cardiovascular disease Cytochrome P450 2D6 Dual-energy X-ray absorptiometry Dietary Folate Equivalents Dehydroepiandrosterone the sulfated form of DHEA circulating in the body Dietary Supplement Health and Education Act Department of Defense Dietary Reference Intakes Dietary supplement PREPUBLICATION COPY: UNCORRECTED PROOFS H-1

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DSHEA DSID DSNDCPA DSI EC DSVP EAR ECG EEG EMG EOG ER ERGO ESP FDA FFDCA GABA GAS GI GRAS HAS HDL HFA HMB HMG-CoA HPPI HR IARC ICW IMQ IGF-1 INR IOM LLS MAJCOM MAOD MAOI MAP MDRIs MRCA MRI MV/MM NAS ND NE NEX NF

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Dietary Supplement Health and Education Act Dietary Supplement Ingredient Database Dietary Supplement and Nonprescription Drug Consumer Protection Act Dietary supplement information executive committee Dietary supplement verification program Estimated Average Requirement Electrocardiogram Electroencephalography Electromyography Electrooculography Emergency room Energy rich, glucose optimized E-screener panel U.S. Food and Drug Administration Federal Food, Drug, and Cosmetic Act Gamma aminobutyric acid Ginseng abuse syndrome Gastrointestinal Generally recognized as safe High altitude sickness High-density lipoprotein Health and Fitness Assessment ȕ-hydroxy-ȕ-methylbutyrate 3-hydroxy-3-methylglutaryl coenzyme A Health Promotion and Prevention Initiative Heart rate International Agency for Research on Cancer Intracellular water Index of Memory Quality Insulin-like growth factor International normalized ratio Institute of Medicine Lake Louis Score Major Command (USAF) Maximal accumulated oxygen deficit Monoamine oxidase inhibitor Maximal aerobic power Military Dietary Reference Intakes Market Research Corporation of America Magnetic resonance imaging Multivitamins/Multiminerals supplements National Academy of Science Not determined Niacin Equivalents Navy Exchange Service National Formulary PREPUBLICATION COPY: UNCORRECTED PROOFS Copyright © National Academy of Sciences. All rights reserved.

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APPENDIX H

NFCS NHANES NHIS NSORs OASD(HA) OGTT OIG ODS PA PCCs PGE2 PIF PKC PSA PSG PUFA RAE RDA RE REE RMs RMG RVIP SBP SF sIgA SJS SRT TBW tHcy TNFĮ TTCP UL URTI USACHPPM USAF USARIEM USDA USP USUHS VO2 VCO2 VE WAIS WHO WMS

H-3

Nationwide Food Consumption Survey National Health and Nutrition Examination Survey National Health Interview Survey Nutritional Standards for Operational Rations Office of the Assistant Secretary of Defense (Health Affairs) Oral glucose tolerance test Office of the Inspector General Office of Dietary Supplements, National Institutes of Health Physical activity Poison control centers Prostaglandin E2 Proteolysis-inducing factor Protein kinase C Prostate-specific antigen Polysomnography Polyunsaturated fatty acids Retinol Activity Equivalents Recommended Dietary Allowance Retinol Equivalents Resting energy expenditure Reference materials Random movement generation test Rapid visual information processing Systolic blood pressure Special Forces Secretory immunoglobulin A Stevens-Johnson syndrome Selective reminding test Total body water Total plasma homocysteine Tumor necrosis factor alpha The Technical Corporation Program Tolerable Upper Intake Level Upper respiratory tract infections U.S. Army Center for Health Promotion and Preventive Medicine U.S. Air Force U.S. Army Research Institute of Environmental Medicine U.S. Department of Agriculture United States Pharmacopeia Uniformed Services University of the Health Sciences Oxygen uptake Rate of elimination of carbon dioxide Pulmonary ventilation during exercise Wechsler Adult Intelligence Scale World Health Organization Wechsler Memory Scale

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Walter Reed Army Institute of Research

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Appendix I Glossary

Antioxidant

A substance that inhibits the destructive effects of oxidation

Antihyperglycemic

An agent that counteracts high levels of glucose in the blood

Beta blockers

A class of drugs used for various indications, but particularly for the management of cardiac arrhythmias and cardioprotection after myocardial infarction. They block the action of endogenous catecholamines (epinephrine [adrenaline] and norepinephrine [noradrenaline] in particular), on ȕadrenergic receptors, part of the sympathetic nervous system that mediates the fight-or-flight response.

Botanicals

Drug, medicinal preparation, or similar substance obtained from a plant or plants

Codex Ebers

A famous Egyptian papyrus recording over 800 medical formulas

CYP2D6

Enzymes involved in the metabolism of xenobiotics in the body

Drug

The term drug means (A) articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of PREPUBLICATION COPY: UNCORRECTED PROOFS I-1

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any articles specified in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to sections 403(r)(1)(B) and 403(r)(3) or sections 403(r)(1)(B) and 403(r)(5)(D), is made in accordance with the requirements of section 403(r) is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 403(r)(6) is not a drug under clause (C) solely because the label or the labeling contains such a statement (FDA, 2004b). Dietary supplement

A product (other than tobacco) that is intended to supplement the diet; contains one or more dietary ingredients (including vitamins, minerals, herbs or other botanicals, amino acids, and other substances) or their constituents; is intended to be taken by mouth as a pill, capsule, tablet, or liquid; and is labeled in the front panel as being a dietary supplement.1

Ergogenic aids

Any external influences that can positively affect physical or mental performance. These include mechanical aids, pharmacological aids, physiological aids, nutritional aids, and psychological aids. They may directly influence the physiological capacity of a particular body system thereby improving performance, remove psychological constraints that impact performance, or increase the speed of recovery from training and competition.

Food

The term food means (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article (FDA, 2004b).

Food additive

Any substance the intended use of which results or may reasonably be expected to result—directly or indirectly—in its becoming a component or otherwise affecting the characteristics of any food. This definition includes any substance used in the

1

In the Dietary Supplement Health and Education Act, 1994.

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APPENDIX I

I-3

production, processing, treatment, packaging, transportation, or storage of food (FDA, 2004a).2 GLUT-4

An important factor in the regulation of blood glucose, and the primary glucose transporter in skeletal muscle

Hyperinsulinemic

A condition in which the level of insulin in the blood is higher than normal. Caused by overproduction of insulin by the body. Related to insulin resistance.

Hypocaloric

A diet characterized by a low number of dietary calories, usually 1,000–1,200 kcal/day

MedWatch

The Food and Drug Administration (FDA) Medical Products Reporting Program, is an initiative designed both to educate all health professionals about the critical importance of being aware of, monitoring for, and reporting adverse events and problems to the FDA and/or the manufacturer and to ensure that new safety information is rapidly communicated to the medical community, thereby improving patient care. The purpose of the MedWatch program is to enhance the effectiveness of postmarketing surveillance of medical products as they are used in clinical practice and to rapidly identify significant health hazards associated with these products.

Obese

An individual with a body mass index (BMI) greater than or equal to 30.0 kg/m2.

Overweight

An individual with a body mass index (BMI) of 25.0 to 29.9 kg/m2.

Pharmacovigilance

The pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long-term and short-

2

The purpose of the legal definition, however, is to impose a premarket approval requirement. Therefore, this definition excludes ingredients whose use is generally recognized as safe (where government approval is not needed), those ingredients approved for use by the FDA or the U.S. Department of Agriculture prior to the food additives provisions of law, and color additives and pesticides where other legal premarket approval requirements apply (FDA, 2004a).

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term side effects of medicines. Generally speaking, pharmacovigilance is the science of collecting, monitoring, researching, assessing, and evaluating information from health care providers and patients on the adverse effects of medications, biological products, herbalism, and traditional medicines with a view to identifying new information about hazards associated with medicines and preventing harm to patients. Phytates

Compounds present in plant foods that bind iron and may prevent its absorption

Rangers

A specially trained elite unit of the United States Army

Special Forces

Special forces are highly trained and organized elite groups of soldiers, who take part in covert warfare, reconnaissance, counterterrorism, and other specialized and dangerous missions.

Thermogenics

Supplements that induce the production of heat

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