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Marijuana
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PREPUBLICATION COPY
UNCORRECTED PROOFS
MARIJUANA AND MEDICINE:
ASSESSING THE SCIENCE BASE
INSTITUTE OF MEDICINE
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. 1999
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 the National Drug Control Policy.
Additional copies of this report are 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 National Academy Press's online bookstore at http://www.nap.edu.
The full text of this report is available on line at http://www.nap.edu
For more information about the Institute of Medicine, visit the IOM
home page at http://www2.nas.edu/iom.
Copyright 1999 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 image adopted as a logotype by the Institute of Medicine
is based on a relief carving from ancient Greece, now held by the Staatliche
Museum in Berlin.
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, Portland, Oregon
STANLEY J. WATSON, JR., co-Principal Investigator,
co-Director and Research Scientist, Mental Health Research Institute,
University of Michigan, Ann Arbor, Michigan
STEVEN R. CHILDERS, Professor, Bowman Gray School of Medicine,
Wake Forest University, Center for Neuroscience, Winston-Salem, North
Carolina
J. RICHARD CROUT, Private Consultant, Bethesda, Maryland
THOMAS J. CROWLEY, Professor, University of Colorado, Health
Sciences Center, Addiction Research and Treatments Services, Denver,
Colorado
JUDITH FEINBERG, Professor, University of Cincinnati Medical
Center, Division of Infectious Diseases, Department of Internal Medicine,
Cincinnati, Ohio
HOWARD L. FIELDS, Professor, University of California in San
Francisco, Neurology and Anesthesiology, San Francisco, California
DOROTHY HATSUKAMI, Professor, University of Minnesota, Department
of Psychiatry,
Minneapolis, Minnesota
ERIC B. LARSON, Medical Director, University of Washington
Medical Center, Seattle, Washington
BILLY R. MARTIN, Professor, Virginia Commonwealth University,
Department of Pharmacology, Richmond, Virginia
TIMOTHY VOLLMER, Professor, Yale School of Medicine, Yale
MS Research Center, New Haven, Connecticut
iii
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, 1988)
CONSTANCE M. PECHURA, Division Director (until April 1998)
NORMAN GROSSBLATT, Manuscript Editor
Consultant
MIRIAM DAVIS
Section Staff
CHARLES H. EVANS, JR., Head, Health Sciences Section
LINDA DEPUGH, Administrative Assistant
CARLOS GABRIEL, Financial Associate
iv
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 ANTHONY, Johns Hopkins University
JACK BARCHAS, Cornell University Medical College
SUMNER 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
HERBERT KLEBER, Columbia University
GEOFFREY LEVITT, Venable Attorneys at Law
KENNETH MACKIE, University of Washington
RAPHAEL MECHOULAM, Hebrew University
CHARLES O'BRIEN, University of Pennsylvania
JUDITH RABKIN, Columbia University
ERIC VOTH, International Drug Strategy Institute
While the individuals listed above have 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.
v
Preface
Why study the medical value of marijuana now? What circumstances provoked
this analysis and report? There have been a variety of influences since
the IOM Report of 1982. First, advocates of personal choice with a growing
distrust of scientific medicine sought alternatives congruent with their
values about health and life. This view was expressed at the ballot
box in recent state referenda. Proponents claimed their own "scientific
evidence" of marijuana's safety and effectiveness. Others, distressed
by the societal ravages of drug abuse, especially among young people,
view legalized medical marijuana as a subterfuge enabling liberalization,
the potential "gateway" to even more harmful substance abuse.
Meanwhile, there have been remarkable and accelerating advances of relevant
knowledge in molecular and behavioral neuroscience, in particular newly
elaborated systems of transmitters, receptors, and antagonists all illuminating
the physiological effects of cannabinoids, both those found in nature
and those normally found in the brain. (Cannabinoids are the group of
compounds related to THC, the primary psychoactive ingredient in marijuana.)
The new science could inform policies responding to the public divide.
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.
Information for this study was gathered through analysis of the relevant
scientific literature, scientific workshops, site visits to cannabis
buyers' clubs and HIV/AIDS clinics, and extensive consultation with
biomedical and social scientists. Three 2-day workshops -- in Irvine,
California; New Orleans, Louisiana; and Washington, DC -- were open
to the public and included scientific presentations and also reports,
mostly from patients and their families, about their 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. 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 comments 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 of the last 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, nausea, and appetite stimulation. For
patients, such as those with AIDS or undergoing chemotherapy, who suffer
simultaneously from severe pain, nausea, and appetite loss, 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 precisely
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., M.D.
Stanley J. Watson, Jr. M.D., Ph.D.
Principal Investigators
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 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
list), 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, J. Richard Gralla, Howard Fields,
Norbert Kaminski, Paul Kaufman, Thomas Klein, Donald Kotler, Richard
Musty, Clara Sanudo-Pena, 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, Richard
Musty, David Pate, Roger Pertwee, Raphael Mechoulam. Clara Sanudo-Pena,
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 list) provided extensive and constructive
suggestions for improving the report. It was greatly enhanced by their
thoughtful attentions.
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
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).
Jane Sanville, project officer for the study sponsor, was consistently
helpful during the many negotiations and discussion held throughout
study process.
Many IOM 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 Fulco, Carlos 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 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 were 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.
EXECUTIVE SUMMARY
ES.1
EXECUTIVE SUMMARY
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
(see box: Statement of Task). 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.)
Can marijuana relieve health problems? Is it safe for medical use?
Those straightforward questions are embedded in a web of social concerns,
most of which lie outside the scope of this report. Controversies concerning
the nonmedical use of marijuana spill over onto the medical marijuana
debate and obscure the real state of scientific knowledge. In contrast
with the many disagreements bearing on social issues, the study team
found substantial consensus among experts in the relevant disciplines
on the scientific evidence about potential medical uses of marijuana.
This report summarizes and analyzes what is known about the medical
use of marijuana, it emphasizes evidence-based medicine (derived from
knowledge and experience informed by rigorous scientific analysis),
as opposed to belief-based medicine (derived from judgment, intuition,
and beliefs untested by rigorous science).
Throughout this report, marijuana refers to unpurified plant
substances, including leaves or flower tops whether consumed by ingestion
or smoking. References to "the effects of marijuana" should
be understood to include the composite effects of its various components;
that is, the effects of THC, the primary psychoactive ingredient in
marijuana, are included among its effects, but not all the effects of
marijuana are necessarily due to THC. Cannabinoids are the group
of compounds related to THC, whether found in the marijuana plant, in
animals, or synthesized in chemistry laboratories.
ES.2
Three focal concerns in evaluating the medical use of marijuana are:
*Evaluation of the effects of isolated cannabinoids.
*Evaluation of the health risks associated with the medical use
of marijuana.
*Evaluation of the efficacy of marijuana.
EFFECTS OF ISOLATED CANNABINOIDS
Cannabinoid Biology
Much has been learned since a 1982 IOM Marijuana and Health report.
Although it was clear then that most of the effects of marijuana were
due to its actions on the brain, there was little information about
how THC acted on brain cells (neurons), which cells were affected by
THC, or even what general areas of the brain were most affected by THC.
Additionally, too little was known about cannabinoid physiology to offer
any scientific insights into the harmful or therapeutic effects of marijuana.
That all changed with the identification and characterization of cannabinoid
receptors in the 1980s and 1990s. During the last 16 years, science
has advanced greatly and can tell us much more about the potential medical
benefits of cannabinoids.
CONCLUSION: At this point, our knowledge about the biology
of marijuana and cannabinoids allows us to make some general conclusions:
*Cannabinoids likely have a natural role in pain modulation, control
of movement, and memory.
*The natural role of cannabinoids in immune systems is likely multifaceted
and remains unclear.
*The brain develops tolerance to cannabinoids.
*Animal research demonstrates the potential for dependence, but
this potential is observed under a narrower range of conditions
than with benzodiazepines, opiates, cocaine, or nicotine.
*Withdrawal symptoms can be observed in animals, but appear to
be mild compared to opiates or benzodiazepines, such as diazepam
(Valium®).
ES.3
CONCLUSION: The different cannabinoid receptor types found
in the body appear to play different roles in normal human physiology.
In addition, some effects of cannabinoids appear to be independent
of those receptors. The variety of mechanisms through which cannabinoids
can influence human physiology underlies the variety of potential
therapeutic uses for drugs that might act selectively on different
cannabinoid systems.
RECOMMENDATION 1: Research should continue into the physiological
effects of synthetic and plant-derived cannabinoids and the natural
function of cannabinoids found in the body. Because different cannabinoids
appear to have different effects, cannabinoid research should include,
but not be restricted to, effects attributable to THC alone.
Efficacy Of Cannabinoid Drugs
The accumulated data indicate a potential therapeutic value for cannabinoid
drugs, particularly for symptoms such as pain relief, control of nausea
and vomiting, and appetite stimulation. The therapeutic effects of cannabinoids
are best established for THC, which is generally one of the two most
abundant of the cannabinoids in marijuana. (Cannabidiol, the precursor
of THC, is generally the other most abundant cannabinoid.)
The effects of cannabinoids on the symptoms studied are generally
modest, and in most cases, there are more effective medications. However,
people vary in their responses to medications and there will likely
always be a subpopulation of patients who do not respond well to other
medications. The combination of cannabinoid drug effects (anxiety reduction,
appetite stimulation, nausea reduction, and pain relief) suggests that
cannabinoids would be moderately well suited for certain conditions,
such as chemotherapy-induced nausea and vomiting and AIDS wasting.
Defined substances, such as purified cannabinoid compounds, are preferable
to plant products which are of variable and uncertain composition. Use
of defined cannabinoids permits a more precise evaluation of their effects,
whether in combination or alone. Medications that can maximize the desired
effects of cannabinoids and minimize the undesired effects can very
likely be identified.
Although most scientists who study cannabinoids agree that the pathways
to cannabinoid drug development are clearly marked, there is no guarantee
that the fruits of scientific research will be made available to the
public for medical use. Cannabinoid-based drugs will only become available
if public investment in cannabinoid drug research is sustained, and
if there is enough incentive for private enterprise to develop and market
such drugs.
ES.4
CONCLUSION: Scientific data indicate the potential therapeutic
value of cannabinoid drugs, primarily THC, for pain relief, control
of nausea and vomiting, and appetite stimulation; smoked marijuana,
however, is a crude THC delivery system that also delivers harmful
substances.
RECOMMENDATION 2: Clinical trials of cannabinoid drugs for symptom
management should be conducted with the goal of developing rapid-onset,
reliable, and safe delivery systems.
Influence Of Psychological Effects On Therapeutic
Effects
The psychological effects of THC and similar cannabinoids pose three
issues for the therapeutic use of cannabinoid drugs. First, for some
patients -- particularly older patients with no previous marijuana experience
-- the psychological effects are disturbing. Those patients report experiencing
unpleasant feelings and disorientation after being treated with THC,
generally more severe for oral THC than for smoked marijuana. Second,
for conditions such as movement disorders or nausea, in which anxiety
exacerbates the symptoms, the anti-anxiety effects of cannabinoid drugs
can influence symptoms indirectly. This can be beneficial or can create
false impressions of the drug effect. Third, in cases where symptoms
are multifaceted, the combination of THC effects might provide a form
of adjunctive therapy; for example, AIDS wasting patients would likely
benefit from a medication that simultaneously reduces anxiety, pain,
and nausea while stimulating appetite.
CONCLUSION: The psychological effects of cannabinoids, such
as anxiety reduction, sedation, and euphoria can influence their
potential therapeutic value Those effects are potentially undesirable
for certain patients and situations, and beneficial for others.
In addition, psychological effects can complicate the interpretation
of other aspects of the drug effect.
RECOMMENDATION 3: Psychological effects of cannabinoids such
as anxiety reduction and sedation, which can influence medical benefits,
should be evaluated in clinical trials.
ES.5
RISKS ASSOCIATED WITH MEDICAL USE OF MARIJUANA
Physiological Risks
Marijuana is not a completely benign substance. It is a powerful drug
with a variety of effects. However, except for the harms associated
with smoking, the adverse effects of marijuana use are within the range
of effects tolerated for other medications. 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. When interpreting
studies purporting to show the harmful effects of marijuana, it is important
to keep in mind that the majority of those studies are based on smoked
marijuana, and cannabinoid effects cannot be separated from the effects
of inhaling smoke of burning plant material and contaminants.
For most people, the primary adverse effect of acute marijuana use
is diminished psychomotor performance. It is, therefore, inadvisable
to operate any vehicle or potentially dangerous equipment while under
the influence of marijuana, THC, or any cannabinoid drug with comparable
effects. In addition, a minority of marijuana users experience dysphoria,
or unpleasant feelings. Finally, the short-term immunosuppressive effects
are not well established but, if they exist, are not likely great enough
to preclude a legitimate medical use.
The chronic effects of marijuana are of greater concern for medical
use and fall into two categories: the effects of chronic smoking, and
the effects of THC. Marijuana smoking is associated with abnormalities
of cells lining the human respiratory tract. Marijuana smoke, like tobacco
smoke, is associated with increased risk of cancer, lung damage, and
poor pregnancy outcomes. Although cellular, genetic, and human studies
all suggest that marijuana smoke is an important risk factor for the
development of respiratory cancer, proof that habitual marijuana smoking
does or does not cause cancer awaits the results of well-designed studies.
CONCLUSION: Numerous studies suggest that marijuana smoke
is an important risk factor in the development of respiratory disease.
RECOMMENDATION 4: Studies to define the individual health risks
of smoking marijuana should be conducted, particularly among populations
in which marijuana use is prevalent.
ES.6
Marijuana Dependence And Withdrawal
A second concern associated with chronic marijuana use is dependence
on the psychoactive effects of THC Although few marijuana users develop
dependence, some do. Risk factors for marijuana dependence are similar
to those for other forms of substance abuse. In particular, antisocial
personality and conduct disorders are closely associated with substance
abuse.
CONCLUSION: A distinctive marijuana withdrawal syndrome
has been identified, but it is mild and short-lived. The syndrome
includes restlessness, irritability, mild agitation, insomnia, sleep
EEG disturbance, nausea, and cramping.
Marijuana As A "Gateway" Drug
Patterns in progression of drug use from adolescence to adulthood
are strikingly regular. Because it is the most widely used illicit drug,
marijuana is predictably the first illicit drug most people encounter.
Not surprisingly, most users of other illicit drugs have used marijuana
first. In fact, most drug users begin with alcohol and nicotine before
marijuana -- usually before they are of legal age.
In the sense that marijuana use typically precedes rather than follows
initiation of other illicit drug use, it is indeed a "gateway"
drug. But because underage smoking and alcohol use typically precede
marijuana use, marijuana is not the most common, and is rarely the first,
"gateway" to illicit drug use. There is no conclusive evidence
that the drug effects of marijuana are causally linked to the subsequent
abuse of other illicit drugs. An important caution is that data on drug
use progression cannot be assumed to apply to the use of drugs for medical
purposes. It does not follow from those data that if marijuana were
available by prescription for medical use, the pattern of drug use would
remain the same as seen in illicit use.
Finally, there is a broad social concern that sanctioning the medical
use of marijuana might increase its use among the general population.
At this point there are no convincing data to support this concern.
The existing data are consistent with the idea that this would not be
a problem if the medical use of marijuana were as closely regulated
as other medications with abuse potential.
ES.7
CONCLUSION: Present data on drug use progression neither
support nor refute the suggestion that medical availability would
increase drug abuse. However, this question is beyond the issues
normally considered for medical uses of drugs, and should not be
a factor in evaluating the therapeutic potential of marijuana or
cannabinoids.
USE OF SMOKED MARIJUANA
Because of the health risks associated with smoking, smoked marijuana
should generally not be recommended for long-term medical use. Nonetheless,
for certain patients, such as the terminally ill or those with debilitating
symptoms the long-term risks are not of great concern. Further, despite
the legal, social, and health problems associated with smoking marijuana,
it is widely used by certain patient groups.
RECOMMENDATION 5: Clinical trials of marijuana use for
medical purposes should be conducted under the following limited
circumstances: trials should involve only short-term marijuana use
(less than six months); be conducted in patients with conditions
for which there is reasonable expectation of efficacy; be approved
by institutional review boards; and collect data about efficacy.
The goal of clinical trials of smoked marijuana would not be to develop
marijuana as a licensed drug, but rather as a first step towards the
possible development of nonsmoked, rapid-onset cannabinoid delivery
systems. However, it will likely be many years before a safe and effective
cannabinoid delivery system, such as an inhaler, will be available for
patients. In the meantime there are patients with debilitating symptoms
for whom smoked marijuana might provide relief The use of smoked marijuana
for those patients should weigh both the expected efficacy of marijuana
and ethical issues in patient care, including providing information
about the known and suspected risks of smoked marijuana use.
ES.8
RECOMMENDATION 6: Short-term use of smoked marijuana (less than
six months) for patients with debilitating symptoms (such as intractable
pain or vomiting) must meet the following conditions:
*failure of all approved medications to provide relief has been
documented;
*the symptoms can reasonably be expected to be relieved by rapid
onset cannabinoid drugs;
*such treatment is administered under medical supervision in
a manner that allows for assessment of treatment effectiveness;
*and involves an oversight strategy comparable to an institutional
review board process that could provide guidance within 24 hours
of a submission by a physician to provide marijuana to a patient
for a specified use.
Until a non-smoked, rapid-onset cannabinoid drug delivery system becomes
available, we acknowledge that there is no clear alternative for people
suffering from chronic conditions that might be relieved by smoking
marijuana, such as pain or AIDS wasting. One possible approach is to
treat patients as e-of-1 clinical trials, in which patients are fully
informed of their status as experimental subjects using a harmful drug
delivery system, and in which their condition is closely monitored and
documented under medical supervision, thereby increasing the knowledge
base of the risks and benefits of marijuana use under such conditions.
ES.9
Statement of Task
The study will assess what is currently known, and not known about
the medical use of marijuana. It will include a review of the science
base regarding the mechanism of action of marijuana, an examination
of the peer-reviewed scientific literature on the efficacy of therapeutic
uses of marijuana, and the costs of using various forms of marijuana
versus approved drugs for specific medical conditions (e.g., glaucoma,
multiple sclerosis, wasting diseases, nausea, and palm).
The study will also include an evaluation of the acute and chronic
effects of marijuana on health and behavior; a consideration of the
adverse effects of marijuana use compared with approved drugs; an evaluation
of the efficacy of different delivery systems for marijuana (e.g., inhalation
vs. oral); and an analysis of the data concerning marijuana as a gateway
drug; and an examination of the possible differences in the effects
of marijuana due to age and type of medical condition.
Specific Issues
Specific issues to be addressed fall under three broad categories:
the science base, therapeutic use, and economics.
Science Base
*Review of neuroscience related to marijuana, particularly relevance
of new studies on addiction and craving
*Review of behavioral and social science base of marijuana use,
particularly assessment of the relative risk of progression to other
drugs following marijuana use
*Review of the literature determining which chemical components
of crude marijuana are responsible of possible therapeutic effects
and for side effects
Therapeutic Use
*Evaluation of any conclusions on the medical use of marijuana drawn
by other groups
*Efficacy and side-effects of various delivery systems for marijuana
compared to existing medications for glaucoma, wasting syndrome,
pain, nausea, or other symptoms
*Differential effects of various forms of marijuana that relate
to age or type of disease.
Economics
*Costs of various forms of marijuana compared with costs of existing
medications for glaucoma, wasting syndrome, pain, nausea, or other
symptoms
*Assessment of differences between marijuana and existing medications
in terms of access and availability
These specific areas, along with the assessments described above will
be integrated into a broad description and assessment of the available
literature relevant to the medical use of marijuana.
ES.10
Recommendations
Recommendation 1: Research should continue into the physiological
effects of synthetic and plant-derived cannabinoids and the natural
function of cannabinoids found in the body. Because different cannabinoids
appear to have different effects, cannabinoid research should include,
but not be restricted to effects attributable to THC alone
Scientific data indicate the potential therapeutic value of cannabinoid
drugs for pain relief, control of nausea and vomiting, and appetite
stimulation. This value would be enhanced by a rapid onset of drug effect.
Recommendation 2: Clinical trials of cannabinoid drugs for symptom
management should be conducted with the goal of developing rapid-onset,
reliable, and safe delivery systems.
The psychological effects of cannabinoids are probably important determinants
of their potential therapeutic value. They can influence symptoms indirectly
which could create false impressions of the drug effect or be beneficial
as a form of adjunctive therapy.
Recommendation 3: Psychological effects of cannabinoids such
as anxiety reduction and sedation, which can influence perceived
medical benefits, should be evaluated in clinical trials.
Numerous studies suggest that marijuana smoke is an important risk
factor in the development of respiratory diseases, but the data that
could conclusively establish or refute this suspected link have not
been collected.
ES.11
Recommendation 4: Studies to define the individual health risks
of smoking marijuana should be conducted, particularly among populations
in which marijuana use is prevalent.
Because marijuana is a crude THC delivery system that also delivers
harmful substances, smoked marijuana should generally not be recommended
for medical use. Nonetheless, marijuana is widely used by certain patient
groups, which raises both safety and efficacy issues.
Recommendation 5: Clinical trials of marijuana use for medical
purposes should be conducted under the following limited circumstances:
trials should involve only short-term marijuana use (less than six
months); be conducted in patients with conditions for which there
is reasonable expectation of efficacy; be approved y institutional
review boards; and collect data about efficacy.
If there is any future for marijuana as a medicine, it lies in its
isolated components, the cannabinoids and their synthetic derivatives.
Isolated cannabinoids will provide more reliable effects than crude
plant mixtures. Therefore, the purpose of clinical trials of smoked
marijuana would not be to develop marijuana as a licensed drug, but
such trials could be a first step towards the development of rapid-onset,
nonsmoked cannabinoid delivery systems.
Recommendation 6: Short term use of smoked marijuana (less than
six months) for patients with debilitating symptoms (such as intractable
pain or vomiting) must meet the following conditions:
*failure of all approved medications to provide relief has been
documented;
*the symptoms can reasonably be expected to be relieved by rapid-onset
cannabinoid drugs;
*such treatment is administered under medical supervision in
a manner that allows for assessment of treatment effectiveness;
*and involves an oversight strategy comparable to an institutional
review board process that could provide guidance within 24 hours
of a submission by a physician to provide marijuana to a patient
for a specified use.
ES.12
Chapter 1
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