MARIJUANA AND MEDICINE

Assessing the Science Base

Janet E. Joy, Stanley J. Watson, Jr., and
John A. Benson, Jr., Editors
Division of Neuroscience and Behavioral Health
INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS Washington, D.C.



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MARIJUANA AND MEDICINE Assessing the Science Base Janet E. Joy, Stanley J. Watson, Jr., and John A. Benson, Jr., Editors Division of Neuroscience and Behavioral Health INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Page ii Disclaimer: The endnotes within this e-book do not perform pop-up devises, due to non-consecutive note numbers within the text. --> NATIONAL ACADEMY PRESS * 2101 Constitution Avenue, N.W. * Washington, D.C. 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 principal investigators responsible for the report were chosen for their special competences and with regard for appropriate balance. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. This study was supported under Contract No. DC7C02 from the Executive Office of the President, Office of National Drug Control Policy. Library of Congress Cataloging-in-Publication Data Marijuana and medicine: assessing the science base / Janet E. Joy, Stanley J. Watson, Jr., and John A. Benson, Jr., editors; Division of Neuroscience and Behavioral Health, Institute of Medicine. p. cm. Includes bibliographical references and index. ISBN 0-309-07155-0 (hardcover) 1. Marijuana—Therapeutic use. 2. Cannabinoids—Therapeutic use. I. Joy, Janet E. (Janet Elizabeth), 1953- II. Watson, Stanley J., 1943- Ill. Benson, John A. IV. Institute of Medicine (U.S.). Division of Neuroscience and Behavioral Health. RM666.C266 M365 1999 615'.32345—dc21                99-6484 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Lock Box 285, Washington, D.C. 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's online bookstore at www.nap.edu. The full text of this report is available online at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www4.nas.edu/IOM/. Copyright 1999 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Cover: Illustration from Marijuana Botany by Robert Connell Clarke, Ronin Publishing, 1981. 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Page iii PRINCIPAL INVESTIGATORS AND ADVISORY PANEL JOHN A. BENSON, JR. (Co-Principal Investigator), Dean and Professor of Medicine, Emeritus, Oregon Health Sciences University School of Medicine STANLEY J. WATSON, JR. (Co-Principal Investigator), Co-Director and Research Scientist, Mental Health Research Institute, University of Michigan STEVEN R. CHILDERS, Professor of Physiology and Pharmacology, Center for Neuroscience, Bowman Gray School of Medicine, Wake Forest University J. RICHARD CROUT, President of Crout Consulting, Drug Development and Regulation, Bethesda, Maryland THOMAS J. CROWLEY, Professor, Department of Psychiatry, and Executive Director, Addiction Research and Treatment Services, University of Colorado Health Sciences Center JUDITH FEINBERG, Professor, Department of Internal Medicine, and Associate Director, Division of Infectious Diseases, University of Cincinnati School of Medicine HOWARD L. FIELDS, Professor of Neurology and Physiology, University of California at San Francisco DOROTHY HATSUKAMI, Professor of Psychiatry, University of Minnesota ERIC B. LARSON, Medical Director, University of Washington Medical Center, and Associate Dean for Clinical Affairs, University of Washington BILLY R. MARTIN, Professor of Pharmacology and Toxicology, and Director of National Institute on Drug Abuse Center on Drug Abuse, Medical College of Virginia, Virginia Commonwealth University TIMOTHY L. VOLLMER, Professor of Medicine, Multiple Sclerosis Research Center, Yale University School of Medicine Study Staff JANET E. JOY, Study Director DEBORAH O. YARNELL, Research Associate AMELIA B. MATHIS, Project Assistant CHERYL MITCHELL, Administrative Assistant (until September 1998) THOMAS J. WETTERHAN, Research Assistant (until September 1998) CONSTANCE M. PECHURA, Division Director (until April 1998) NORMAN GROSSBLATT, Manuscript Editor

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Page iv Consultant MIRIAM DAVIS Section Staff CHARLES H. EVANS, JR., Head, Health Sciences Section LINDA DEPUGH, Administrative Assistant CARLOS GABRIEL, Financial Associate

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Page v 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 Institute of Medicine in making the 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. The committee wishes to thank the following individuals for their participation in the review of this report: JAMES C. ANTHONY, Johns Hopkins University JACK D. BARCHAS, Cornell University Medical College SUMNER H. BURSTEIN, University of Massachusetts Medical School AVRAM GOLDSTEIN, Stanford University LESTER GRINSPOON, Harvard Medical School MILES HERKENHAM, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland HERBERT D. KLEBER, Columbia University GEOFFREY M. LEVITT, Venable Attorneys at Law, Washington, D.C. KENNETH P. MACKIE, University of Washington RAPHAEL MECHOULAM, The Hebrew University of Jerusalem CHARLES P. O'BRIEN, University of Pennsylvania JUDITH G. RABKIN, Columbia University

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Page vi ERIC G. VOTH, International Drug Strategy Institute, Topeka, Kansas VIRGINIA V. WELDON, Washington University While the individuals listed above provided constructive comments and suggestions, it must be emphasized that responsibility for the final content of this report rests entirely with the authoring committee and the Institute of Medicine.

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Page vii PREFACE Public opinion on the medical value of marijuana has been sharply divided. Some dismiss medical marijuana as a hoax that exploits our natural compassion for the sick; others claim it is a uniquely soothing medicine that has been withheld from patients through regulations based on false claims. Proponents of both views cite "scientific evidence" to support their views and have expressed those views at the ballot box in recent state elections. In January 1997, the White House Office of National Drug Control Policy (ONDCP) asked the Institute of Medicine to conduct a review of the scientific evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids. That review began in August 1997 and culminates with this report. The ONDCP request came in the wake of state "medical marijuana" initiatives. In November 1996, voters in California and Arizona passed referenda designed to permit the use of marijuana as medicine. Although Arizona's referendum was invalidated five months later, the referenda galvanized a national response. In November 1998, voters in six states (Alaska, Arizona, Colorado, Nevada, Oregon, and Washington) passed ballot initiatives in support of medical marijuana. (The Colorado vote will not count, however, because after the vote was taken a court ruling determined there had not been enough valid signatures to place the initiative on the ballot.)

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Page viii Information for this study was gathered through scientific workshops, site visits to cannabis buyers' clubs and HIV/AIDS clinics, analysis of the relevant scientific literature, and extensive consultation with biomedical and social scientists. The three 2-day workshops—in Irvine, California; New Orleans, Louisiana; and Washington, D.C.—were open to the public and included scientific presentations and individual reports, mostly from patients and their families, about experiences with and perspectives on the medical use of marijuana. Scientific experts in various fields were selected to talk about the latest research on marijuana, cannabinoids, and related topics. (Cannabinoids are drugs with actions similar to THC, the primary psychoactive ingredient in marijuana.) In addition, advocates for and against the medical use of marijuana were invited to present scientific evidence in support of their positions. Finally, the Institute of Medicine appointed a panel of nine experts to advise the study team on technical issues. Public outreach included setting up a Web site that provided information about the study and asked for input from the public. The Web site was open for comment from November 1997 until November 1998. Some 130 organizations were invited to participate in the public workshops. Many people in the organizations—particularly those opposed to the medical use of marijuana—felt that a public forum was not conducive to expressing their views; they were invited to communicate their opinions (and reasons for holding them) by mail or telephone. As a result, roughly equal numbers of persons and organizations opposed to and in favor of the medical use of marijuana were heard from. Advances in cannabinoid science over the past 16 years have given rise to a wealth of new opportunities for the development of medically useful cannabinoid-based drugs. The accumulated data suggest a variety of indications, particularly for pain relief, antiemesis, and appetite stimulation. For patients who suffer simultaneously from severe pain, nausea, and appetite loss, such as those with AIDS or who are undergoing chemotherapy, cannabinoid drugs might offer broad-spectrum relief not found in any other single medication. Marijuana is not a completely benign substance. It is a powerful drug with a variety of effects. However, the harmful effects to individuals from the perspective of possible medical use of marijuana are not necessarily the same as the harmful physical effects of drug abuse. Although marijuana smoke delivers THC and other cannabinoids to the body, it also delivers harmful substances, including most of those found in tobacco smoke. In addition, plants contain a variable mixture of biologically active compounds and cannot be expected  to provide a pre-

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Page ix cisely defined drug effect. For those reasons, the report concludes that the future of cannabinoid drugs lies not in smoked marijuana but in chemically defined drugs that act on the cannabinoid systems that are a natural component of human physiology. Until such drugs can be developed and made available for medical use, the report recommends interim solutions. JOHN A. BENSON, JR. STANLEY J. WATSON, JR. CO-PRINCIPAL INVESTIGATORS

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the San Francisco Cannabis Cultivators Club, Scott Imier and staff at the Los Angeles Cannabis Resource Center, Victor Hernandez and members of Californians Helping Alleviate Medical Problems (CHAMPS), Michael Weinstein of the AIDS Health Care Foundation, and Marsha Bennett of the Louisiana State University Medical Center. We also appreciate the many people who spoke at the public workshops or wrote to share their views on the medical use of marijuana (see appendix AA). lane Sanville, project officer for the study sponsor, was consistently helpful during the many negotiations and discussion held throughout study process. Many lOM staff members provided much appreciated administrative, research, and intellectual support during the study. Robert Cook-Deegan, Marilyn Field, Constance Pechura, Daniel Quinn, Michael Stoto provided thoughtful and insightful comments on draft sections of the report. Others provided advice and consultation in many other aspects of the study process: Kathleen Stratton, Susan Fourt, Carolyn FuIco, CarIos Gabriel, Linda Kilroy, Catharyn Liverman, Clyde Behney, Dev Mani. As project assistant throughout the study, Amelia Mathis was tireless, gracious, and reliable. Deborah Yarnell's contribution as Research Associate for this study was outstanding. She organized site visits, researched and drafted technical material for the report, and consulted extensively with relevant experts to ensure the technical accuracy of the text. The quality of her contributions throughout this study was exemplary. Finally, the Principal Investigators on this study wish to personally thank lanes Joy for her deep commitment to the science and shape of this report. In addition, her help in integrating the entire data gathering and information organization of this report were nothing short of essential. Her knowledge of neurobiology, her sense of quality control, and her unflagging spirit over the IS months illuminated the subjects and were indispensable to the study's successful completion.

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Page xi ACKNOWLEDGMENTS This report covers such a broad range of disciplines—neuroscience, pharmacology, immunology, drug abuse, drug laws, and a variety of medical specialties, including neurology, oncology, infectious diseases, and ophthalmology—that it would not have been complete without the generous support of many people. Our goal in preparing this report was to identify the solid ground of scientific consensus and to steer clear of the muddy distractions of opinions that are inconsistent with careful scientific analysis. To this end we consulted extensively with experts in each of the disciplines covered in this report. We are deeply indebted to each of them. Members of the Advisory Panel, selected because each is recognized as among the most accomplished in their respective disciplines (see page iii), provided guidance to the study team throughout the study—from helping to lay the intellectual framework to reviewing early drafts of the report. The following people wrote invaluable background papers for the report: Steven R. Childers, Paul Consroe, Howard Fields, Richard J. Gralla, Norbert Kaminski, Paul Kaufman, Thomas Klein, Donald Kotler, Richard Musty, Clara Sanudo-Peña, C. Robert Schuster, Stephen Sidney, Donald P. Tashkin, and J. Michael Walker. Others provided expert technical commentary on draft sections of the report: Richard Bonnie, Keith Green, Frederick Fraunfelder, Andrea Hohmann, John McAnulty, Craig Nichols, John Nutt, and Robert Pandina. Still others responded to many inquiries, provided expert counsel, or shared their unpublished data: Paul Consroe, Geoffrey Levitt, Raphael Mechoulam, Richard Musty, David Pate, Roger

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Page xii Pertwee, Clara Sanudo-Peña, Carl Soderstrom, J. Michael Walker, and Scott Yarnell. Miriam Davis, consultant to the study team, provided excellent written material for the chapter on cannabinoid drug development. The reviewers for the report (see page iv) provided extensive, constructive suggestions for improving the report. It was greatly enhanced by their thoughtful attention. Many of these people assisted us through many iterations of the report. All of them made contributions that were essential to the strength of the report. At the same time, it must be emphasized that responsibility for the final content of report rests entirely with the authors and the Institute of Medicine. We would also like to thank the people who hosted our visits to their organizations. They were unfailingly helpful and generous with their time. Jeffrey Jones and members of the Oakland Cannabis Buyers' Cooperative, Denis Peron of the San Francisco Cannabis Cultivators Club, Scott Imler and staff at the Los Angeles Cannabis Resource Center, Victor Hernandez and members of Californians Helping Alleviate Medical Problems (CHAMPS), Michael Weinstein of the AIDS Health Care Foundation, and Marsha Bennett of the Louisiana State University Medical Center. We also appreciate the many people who spoke at the public workshops or wrote to share their views on the medical use of marijuana (see Appendix A). Jane Sanville, project officer for the study sponsor, was consistently helpful during the many negotiations and discussion held throughout the study process. Many Institute of Medicine staff members provided greatly appreciated administrative, research, and intellectual support during the study. Robert Cook-Deegan, Marilyn Field, Constance Pechura, Daniel Quinn, and Michael Stoto provided thoughtful and insightful comments on draft sections of the report. Others provided advice and consultation on many other aspects of the study process: Clyde Behney, Susan Fourt, Carolyn Fulco, Carlos Gabriel, Linda Kilroy, Catharyn Liverman, Dev Mani, and Kathleen Stratton. As project assistant throughout the study, Amelia Mathis was tireless, gracious, and reliable. Deborah Yarnell's contribution as research associate for this study was outstanding. She organized site visits, researched and drafted technical material for the report, and consulted extensively with relevant experts to ensure the technical accuracy of the text. The quality of her contributions throughout this study was exemplary. Finally, the principal investigators on this study wish to personally thank Janet Joy for her deep commitment to the science and shape of this report. In addition, her help in integrating the entire data gathering and information organization of this report was nothing short of essential. Her knowledge of neurobiology, her sense of quality control, and her unflagging spirit over the 18 months illuminated the subjects and were indispensable to the study's successful completion.

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Page xiii CONTENTS Executive Summary 1 1  Introduction 13 How This Study Was Conducted, 15 Marijuana Today, 16 Marijuana and Medicine, 19 Who Uses Medical Marijuana? 20 Cannabis and the Cannabinoids, 24 Organization of the Report, 30 2  Cannabinoids and Animal Physiology 33 Introduction, 33 Cannabinoid Receptors, 39 The Endogenous Cannabinoid System, 43 Sites of Action, 48 Cannabinoid Receptors and Brain Functions, 51 Chronic Effects of THC, 56 Cannabinoids and the Immune System, 59 Conclusions and Recommendations, 69 3  First, Do No Harm: Consequences of Marijuana Use and Abuse 83 The Marijuana ''High,'' 83 Drug Dynamics, 84

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Page xiv Marijuana Use and Dependence, 92 Link Between Medical Use and Drug Abuse, 101 Psychological Harms, 104 Physiological Harms: Tissue and Organ Damage, 109 Summary and Conclusions, 125 4  The Medical Value Of Marijuana and Related Substances 137 Standards for Evaluating Clinical Trials, 138 Analgesia, 139 Nausea and Vomiting, 145 Wasting Syndrome and Appetite Stimulation, 154 Neurological Disorders, 159 Glaucoma, 173 Summary, 177 Other Reports on Marijuana as Medicine, 180 5  Development of Cannabinoid Drugs 193 Federal Drug Development Policy, 194 Development and Marketing of Marinol, 202 Market Outlook for Cannabinoids, 208 Regulation of and Market Outlook for Marijuana, 213 Conclusions, 218 Appendixes   A Individuals and Organizations That Spoke or Wrote to the Institute of Medicine About Marijuana and Medicine 225 B Workshop Agendas 232 C Scheduling Definitions 240 D Statement of Task 242 E Recommendations Made in Recent Reports on the Medical Use of Marijuana 244 F  Rescheduling Criteria 256 Index 259

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Page xv LIST OF TABLES AND FIGURES Tables 1.1 Self-Reported Disorders Treated with Marijuana by Members of San Francisco Cannabis Cultivators Club, 21 1.2 Self-Reported Disorders Treated with Marijuana by Members of Los Angeles Cannabis Resource Center (LACRC), According to Center Staff, 22 1.3  Summary of Reports to IOM Study Team by 43 Individuals, 23 1.4 Primary Symptoms of 43 Individuals Who Reported to IOM Study Team, 24 1.5 Cannabinoids Identified in Marijuana, 25 2.1 Landmark Discoveries Since the 1982 IOM Report, 34 2.2 Compounds That Bind to Cannabinoid Receptors, 44 2.3 Comparison of Cannabinoid Receptor Agonists, 46 2.4 Cellular Processes That Can Be Targeted for Drug Development, 48 2.5 Brain Regions in Which Cannabinoid Receptors Are Abundant, 49 2.6 Cannabinoid Receptors, 51 2.7 Effects of Cannabinoids on the Immune System, 60 2.8 Historical Comparisons Between Cannabinoids and Opiates, 69 3.1 Psychoactive Doses of THC in Humans, 85 3.2 Drug Withdrawal Symptoms, 90 3.3 Factors That Are Correlated with Drug Dependence, 94

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Page xvi 3.4 Prevalence of Drug Use and Dependence in the General Population, 95 3.5 Relative Prevalence of Diagnoses of Psychiatric Disorders Associated with Drug Use Among Children, 96 3.6 Effect of Decriminalization on Marijuana Use in Emergency Room (ER) Cases, 103 4.1 Studies on the Effects of Marijuana and Cannabinoids in Multiple Sclerosis, 163 4.2 Classes of Antispasticity Drugs, 164 4.3  Drugs Used to Treat Movement Disorders, 168 4.4 Clinical Trials of Cannabidiol (CBD) in Epileptics, 171 4.5 Anticonvulsant Drugs for Various Types of Seizures, 172 4.6 Classes of Drugs Used to Treat Glaucoma, 176 5.1 Cannabinoids and Related Compounds Commonly Used in Research, 201 5.2 Cannabinoids Under Development for Human Use, 209 Figures 1.1 Cannabinoid biosynthesis, 26 2.1  Diagram of neuron with synapse, 38 2.2 Cannabinoid receptors, 40 2.3 Cannabinoid agonists trigger a series of reactions within cells, 41 2.4 Chemical structures of selected cannabinoid agonists, 45 2.5 Locations of brain regions in which cannabinoid receptors are abundant, 50 2.6  Diagrams showing motor regions of the brain, 52 3.1 Age distribution of marijuana users among the general population, 93 4.1 Emesis-stimulating pathways, 146 4.2 Effect of nabilone on multiple sclerosis symptoms, 162 5.1  Stages of clinical testing, 196

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MARIJUANA AND MEDICINE

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