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Caffeine for the Sustainment of Mental Task Performance Formulations for Military Operations Committee on Military Nutntion Research Food and Nutntion Board INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

NATIONAL ACADEMY PRESS · 2101 Constitution Avenue, NW · Washington, DC 20418 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. Support for this project was provided by the U.S. Department of the Army, Army Medical Research and Materiel Command through grant No. DAMD17- 94-J-4046 and grant No. DAMD17-99-1-9478. The U.S. Anny Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702- 5014, is the awarding and administering acquisition office. The views presented in this publication are those of the Committee on Military Nutrition Research and do not necessarily reflect the position or policy of the government, and no official endorsement should be inferred. International Standard Book Number 0-309-08258-7 Library of Congress Control Number 2001097708 This report is available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055; call (800) 624- 6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's on-line bookstore at http://www.nap.edu. For more information about the Institute of Medicine and the Food and Nutrition Board, visit the IOM and FNB home pages at http://www.iom/ and http://www.iom/fnb/. Copyright 2001 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

Knowing Is not enough; we must apply. Miffing is not enough; we must To. Goethe ,, 11' _ / / INSTITUTE OF MEDICINE Shaping the Future for Health

National Acaclemy Of Sciences National Acaclemy Of Engineering Institute of Medicine National Research Council 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. Bruce M. Alberts 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. Wm. A. Wulf is president of the National Academy of ~ . . cngmeermg. 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. Kenneth I. Shine 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. Me Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

COMMITTEE ON MILITARY NUTRITION RESEARCH JOHN E. VANDERVEEN (Chair), San Antonio, Texas LAWRENCE E. ARMSTRONG, Departments of Physiology and Neurobiol- ogy, and Exercise Science, University of Connecticut, Storrs GAIL E. BUTTERFIELD (deceasedJ, Nutrition Studies, Palo Alto Veterans Affairs Health Care System and Program in Human Biology, Stanford Uni- versity, Palo Alto, California WANDA L. CHENOWETH, Department of Food Science and Human Nutri- tion, Michigan State University, East Lansing JOHANNA T. DWYER, Frances Stern Nutrition Center, New England Medical Center Hospital and Departments of Medicine and Community Health, Tufts Medical School and School of Nutrition Science and Policy, Boston, Massachusetts JOHN D. FERNSTROM, Depa~l~ent of Psychiatry, Pharmacology, and Neu- roscience, University of Pittsburgh School of Medicine, Pennsylvania ROBIN B. KANAREK, Depa~l~ent of Psychology, Tufts University, Boston, Massachusetts ORVILLE A. LEVANDER, Nutrient Requirements and Functions Laboratory, U.S. Depardnent of Agriculture Beltsville Human Nutrition Research Cen- ter, Beltsville, Maryland ESTHER M. STERNBERG, Neuroendocrine Immunology and Behavior Section, National Institute of Mental Health, Bethesda, Maryland U.S. Army Grant Representative LTC KARL E. FRIEDL, U.S. Army, Military Operational Medicine Research Program, U.S. Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland Staff MARY I. POOS, Study Director TAZIMA A. DAVIS, Senior Project Assistant (from September 18, 2000) KARAH NAZOR, Project Assistant (through July 28, 2000) v

FOOD AND NUTRITION BOARD CUTBERTO GARZA (Chair), Division of Nutrition, Cornell University, Ithaca, New York LARRY R. BEUCHAT, Center for Food Safety and Quality Enhancement University of Georgia, Griffin BENJAMIN CABALLERO, Center for Human Nutrition, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland ROBERT J. COUSINS, Center for Nutritional Sciences, University of Florida, Gainesville SHIRIKI KUMANYIKA, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia ALFRED H. MERRILL, JR., Department of Biochemistry, Emory Center for Nutrition and Health Sciences, Emory University, Atlanta, Georgia LYNN PARKER, Child Nutrition Programs and Nutrition Policy, Food Re- search and Action Center, Washington, D.C. ROSS L. PRENTICE, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington A. CATHERINE ROSS, Nutrition Department, The Pennsylvania State Un versity, University Park ROBERT M. RUSSELL, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachu- setts BARBARA O. SCHNEEMAN, Department of Nutrition, University of Cali- fornia at Davis ROBERT E. SMITII, R.E. Smith Consulting, Inc., Newport, Vermont VIRGINIA A. STALLINGS, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Pennsylvania STEVE L. TAYLOR, Department of Food Science and Technology and Food Processing Center, University of Nebraska, Lincoln BARRY L. ZOUMAS, Department of Agricultural Economics and Rural Soci- ology, The Pennsylvania State University, University Park Stay ALLISON A. YATES, Director LINDA MEYERS, Deputy Director GAIL SPEARS, Staff Editor GEORGE YORK, Administrative Assistant GARY WALKER, Financial Associate V1 it_

Dectication The Committee on Military Nutrition Research dedicates this report to the late Gail Butterfield, a diligent and enthusiastic member of the committee who made invaluable contributions to this study and numerous other studies during her six years of service. Her unique background in nutrition and physiology was a special asset to the committee's work. She was dedicated to contributing to the health and nutritional well-being of America's military personnel, both active-duty members and veterans. . . V11

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 National Research Council'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, evi- dence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative proc- ess. We wish to thank the following individuals for their review of this report: E. Wayne Askew, University of Utah Fergus M. Clydesdale, University of Massachusetts Joseph T. Coyle, Harvard Medical School David Dinges, University of Pennsylvania School of Medicine Harold Goforth, Point Lorna College Steven R. Hursh, Science Applications International Corporation 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 Catherine E. Woteki, University of Maryland at College Park, appointed by the Institute of Medicine, who was 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. . . . vail

Preface This publication is the latest in a series of reports prepared by the Commit- tee on Military Nutrition Research (CMNR) of the Food and Nutrition Board (FNB), Institute of Medicine, National Academies. Other reports in the series have included such issues as food components to enhance performance; nutri- tional needs in hot, cold, and high-altitude environments; body composition and physical performance; nutrition and physical performance; cognitive testing methodology; fluid replacement and heat stress; and antioxidants and oxidative stress. These reports are part of the response that the CMNR provides to the commander of the U.S. Army Medical Research and Materiel Command (USAMRMC) regarding issues brought to the committee by the Military Opera- tional Medicine Research Program at Fort Detrick, Maryland, and the Military Nutrition Division of the U.S. Army Research Institute of Environmental Medi- cine at Natick, Massachusetts. Typically, reports in this series review the scien- tific background of an issue, and provide direct responses to questions posed by USAMRMC and specific recommendations from CMNR. HISTORY OF THE COMMITTEE The CMNR was established in October 1982, following a request by the as- sistant surgeon general of the Army that the Board on Military Supplies of the National Academy of Sciences set up a special committee. The purpose of this committee was to advise the U.S. Depa~l~ent of Defense on the need for and conduct of nutrition research and related issues. The CMNR was transferred to the FNB in 1983. The CMNR's current tasks are as follows: · to identify nutritional factors that may critically influence the physical and mental performance of military personnel under all environmental extremes; · to identify deficiencies in the existing database; 1X

x CAFFEINE FOR MENTAL TASK PERFORMANCE · to recommend research to remedy these deficiencies as well as approaches for studying the relationship of diet to physical and mental performance; and · to review and advise on standards for military feeding systems. Within this context, the CMNR was asked to focus on nutrient requirements for performance during operational missions rather than requirements for m~li- tary personnel in garrison (the latter were judged to be not significantly different O ~ —~ . . - , ~ hi,= from those of the civilian population). Although the membership of the committee has changed periodically, the disciplines represented consistently have included human nutrition, nutritional biochemistry, performance physiology, food science, and psychology. For issues that require broader expertise than exists within the committee, the CMNR has convened workshops or utilized consultants. The workshops provide additional state-of-the-art scientific information and informed opinion for the consideration of the cornm~ttee. ORGANIZATION OF THIS REPORT Chapter 1 of this report provides background information on the military interest in caffeine and the history of its use, and Chapter 2 briefly reviews caf- feine metabolism and pharmacology. Chapters 3 through 6 review the recent scientific literature organized around the Army's task questions of efficacy, safety, formulations, dosage, ethical considerations, and alternatives. The CMNR's summary responses to questions, conclusions, and recommendations are presented in Chapter 7. The workshop agenda and abstracts are presented in Appendix A. Appendix B contains CMNR recommendations concerning caf- feine from the report, Food Components to Enhance Performance (IOM, 1994~. Biographical sketches of CMNR members and the workshop speakers are given in Appendix C. Speakers invited to the workshop were also requested to submit a brief list of selected background papers. Their recommended readings, relevant citations collected by CMNR staff prior to the workshop, and citations from each chapter are included in the references. ACKNOWLEDGMENTS It is my pleasure as chairman of the CMNR to acknowledge the contribu- tions of the FNB staff. Their dedication in the planning and organization of the workshop and in editing this report made it possible for the committee to pro- vide an in-depth response to the Army's request. In particular, I wish to ac- knowledge the superior efforts of Mary I. Poos, the staff officer for the CMNR. She worked diligently with committee members in securing the expert panel of speakers and organizing the program for the workshop into coherent sessions.

PREFACE X1 She also conducted extensive reviews and summaries of the scientific literature and performed major edits of the report to ensure clarity and accuracy. I also wish to commend the workshop speakers for their excellent contribu- tions in preparing abstracts and participating through their presentations and discussions at the workshop. Their willingness to take time from very busy schedules to prepare and deliver outstanding presentations made it possible for the committee to conduct the review and prepare this report. Their thoughtful responses to CMNR members' and workshop participants' questions also con- tributed immeasurably to the quality of the review. It would be neglectful not to mention the many experts who attended this open meeting at their own initiative and expense. Their questions and comments contributed in no small measure to broadening the exchange of scientific information. I express my deepest appreciation to the members of the CMNR who par- ticipated extensively during the workshop and in discussions and preparation of the summary and recommendations in this report. I continue to be stimulated by the committee's dedication and willing contribution of time and expertise to the activities of the CMNR. I thank all of you for your continuing contributions to this program. JOHN E. VANDERVEEN, Chair Committee on Military Nutrition Research

. . X11 PREFACE I express my deepest appreciation to the members of the CMNR who participated extensively during the workshop and in discussions and preparation of the summary and recommendations in this report. ~ continue to be stimulated by the committee's dedication and willing contribution of time and expertise to the activities of the CMNR. ~ thank all of you for your continuing contributions to this program. JOHN E. VANDERVEEN, Chair Committee on Military Nutrition Research

Contents EXECUTIVE SUMMARY......... Background, 2 The Committee's Task, 2 Methods, 3 Caffeine Use, 4 Caffeine Metabolism, 4 Response to Military Questions, 6 1 1 BASIC CONCEPTS 17 Military Interest in Caffeine, 17 History of Caffeine Use, 19 The Committee's Task, 20 PHARMACOLOGY OF CAFFEINE..................................................... Absorption, Distribution, and Metabolism, 26 Factors Affecting Caffeine Metabolism, 28 Physiological Effects, 29 Summary, 3 1 EFFICACY OF CAFFErNE ................................................................... Physical Performance, 33 Cognitive Function and Alertness, 37 Compensation of Sleep Deprivation Impairments, 40 Summary, 44 SAFETY OF CAFFEINE USAGE .~ Caffeine and Cardiovascular Disease Risk, 49 Caffeine Effects on Reproduction, 52 Caffeine Effects on Bone Mineral Density, 54 Caffeine Effects on Fluid Homeostasis, 55 X111 25 33 47

XIV 6 CAFFEINE FOR MENTAL TASK PERFORMANCE Detrimental Effects of High Doses of Caffeine, 56 Summary, 59 DOSES AND DELIVERY MECHANISMS 61 Optimum Caffeine Dosage, 61 Caffeine Delivery Mechanisms, 63 Summary, 65 SPECIAL CONSIDERATIONS 67 Education and Training Issues, 68 Labeling, 68 Ethical Considerations, 69 Alternatives to Caffeine for Maintenance of Cognitive Performance, 69 Summary, 77 7 RESPONSE TO MILITARY QUESTIONS, CONCLUSIONS, AND RECOMMENDATIONS 79 Additional Research Recommendations, 96 REFERENCES . APPENDIXES 97 A Workshop Agenda and Abstracts, 115 B Previous Recommendations on Caffeine from the Committee on Military Nutrition Research, 143 Biographical Sketches, 147

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This report from the Committee on Military Nutrition Research reviews the history of caffeine usage, the metabolism of caffeine, and its physiological effects. The effects of caffeine on physical performance, cognitive function and alertness, and alleviation of sleep deprivation impairments are discussed in light of recent scientific literature. The impact of caffeine consumption on various aspects of health, including cardiovascular disease, reproduction, bone mineral density, and fluid homeostasis are reviewed. The behavioral effects of caffeine are also discussed, including the effect of caffeine on reaction to stress, withdrawal effects, and detrimental effects of high intakes. The amounts of caffeine found to enhance vigilance and reaction time consistently are reviewed and recommendations are made with respect to amounts of caffeine appropriate for maintaining alertness of military personnel during field operations. Recommendations are also provided on the need for appropriate labeling of caffeine-containing supplements, and education of military personnel on the use of these supplements. A brief review of some alternatives to caffeine is also provided.

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