INTRODUCTION

CHAPTER 1.
INTRODUCTION 1
How This Study Was Conducted 3
Marijuana Today 4
Who Uses Medical Marijuana? 9
Cannabis and the cannabinoids18
Organization of the Report 23
References 24

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Chapter 1. Introduction

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).

Scientific data on controversial subjects are commonly misinterpreted,
over interpreted, and misrepresented, and the medical marijuana debate is no
exception We have tried to present the scientific studies in such a way as
to reveal their strengths and limitations. One of the goals of this report
is to help people to understand the scientific data, including the logic
behind the scientific conclusions, so it goes into greater detail than
previous reports on the subject. In many cases, we have explained why
particular studies are inconclusive and what sort of evidence is needed to
support particular claims about the harms or benefits attributed to
marijuana. Ideally, this report will enable the thoughtful reader to
interpret the new information about marijuana that will continue to emerge
rapidly well after this report is published.

Can marijuana relieve health problems? Is it safe for medical use?
Those straightforward questions are embedded in a web of social concerns,
which lie outside the scope of this report. Controversies concerning non
medical use of marijuana spill over onto the medical marijuana debate and
tend to obscure the real state of scientific knowledge. In contrast with the
many disagreements bearing on the social issues, the study team has found
substantial consensus, among experts in the relevant disciplines, on the
scientific evidence bearing on potential medical use.

This report analyzes science, not the law. As in any policy debate, the
value of scientific analysis is that it can provide a foundation for further
discussion. Distilling scientific evidence does not in itself solve a policy
problem. What it can do is illuminate the common ground, bringing to light
fundamental differences out of the shadows of misunderstanding and
misinformation that currently prevail. Scientific analysis cannot be the end
of the debate, but it should at least provide the basis for an honest and
informed discussion.

Our analysis of the evidence and arguments concerning the medical use
of marijuana focuses on the strength of the supporting evidence, and does
not refer to the motivations of people who put forth the evidence and
arguments. That is, it is not relevant to scientific validity whether an
argument is put forth by someone who believes that all marijuana use should
be legal or by someone who believes that any marijuana use is highly
damaging to individual users and to society as a whole. Nor does this report
comment on the degree to which scientific analysis is compatible with
current regulatory policy. Although many have argued that current drug laws
pertaining to marijuana are inconsistent with scientific data, it is
important to understand that decisions about drug regulation are based on a
variety of moral and social considerations, as well as on medical and
scientific ones.

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Even when a drug is used only for medical purposes, value judgments
affect policy decisions concerning its medical use. For example, the
magnitude of a drug's expected medical benefit affects regulatory judgments
about the acceptability of risks associated with its use. Also, although a
drug is normally approved for medical use only on proof of its "safety and
efficacy," patients with life-threatening conditions are sometimes (under
protocols for "compassionate use") allowed access to unapproved drugs whose
benefits and risks are uncertain. Value judgments play an even more
substantial role in regulatory decisions concerning drugs, such as
marijuana, that are sought and used for non medical purposes. Then
policy-makers must take into account not only the risks and benefits
associated with medical use, but also possible interactions between the
regulatory arrangements governing medical use and the integrity of the legal
controls set up to restrict non medical use.

It should be clear that many elements of drug control policy lie
outside the realm of biology and medicine. Ultimately, the complex moral and
social judgments that underlie drug control policy must be made by the
American people and their elected officials A goal of this report is to
evaluate the biological and medical factors that should be taken into
account in making those judgments.

How This Study Was Conducted

Information was gathered through scientific workshops, site visits,
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, DC -- were open
to the public and included scientific presentations and 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 (listed in appendix A). The selection of the experts was
based on recommendations by their peers, who ranked them among the most
accomplished scientists and the most knowledgeable about marijuana and
cannabinoids in their own fields. In addition, advocates for (John Morgan)
and against (Eric A. Voth) the medical use of marijuana were invited to
present scientific evidence in support of their positions.

Information presented at the scientific workshops was supplemented by
analysis of the scientific literature, and evaluating the methods used in
various studies and the validity of the authors' conclusions. Different
kinds of clinical studies are useful in different ways: results of a
controlled, double-blind study with adequate sample sizes can be expected to
apply to the general population from which study subjects were drawn; an
isolated case report can suggest further studies, but cannot be presumed to
be broadly applicable; and survey data can be highly informative, but are
generally limited by the need to rely on self-reports of drug use and on
unconfirmed medical diagnoses. This report relies mainly on the most

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relevant and methodologically rigorous studies available, and treats the
results of more limited studies cautiously. In addition, study results are
presented in such a way as to allow thoughtful readers to judge the results
themselves.

IOM appointed a panel of nine experts to advise the study team on
technical issues. These included neurology and the treatment of pain (Howard
Fields), regulation of prescription drugs (J. Richard Crout), AIDS wasting
and clinical trials (Judith Feinberg), treatment and pathology of multiple
sclerosis (Timothy Vollmer), drug dependence among adolescents (Thomas
Crowley), varieties of drug dependence (Dorothy Hatsukami), internal
medicine, health care delivery, and clinical epidemiology (Eric B. Larson),
cannabinoids and marijuana pharmacology (Billy R. Martin), and cannabinoid
neuroscience (Steven R. Childers).

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.

The study team visited four cannabis buyers' clubs in California (the
Oakland Cannabis Buyers' Cooperative, the San Francisco Cannabis Cultivators
Club, the Los Angeles Cannabis Resource Center, and Californians Helping
Alleviate Medical Problems, or CHAMPS) and two HIV-AIDS clinics (the AIDS
Health Care Foundation in Los Angeles and the Louisiana State University
Medical Center in New Orleans). We listened to many individual stories from
the buyers' clubs about using marijuana to treat a variety of symptoms and
heard clinical observations on the use of Marinol¨ to treat AIDS patients.
Marinol¨ is the brand name for dronabinol, which is
[Image]9-tetrahydrocannabinol (THC) in pill form and is available by
prescription for the treatment of nausea associated with chemotherapy and
AIDS wasting.

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Marijuana, Today

The Changing Legal Landscape

In the 20th century, marijuana has been used more for its euphoric
effects than as a medicine. Its psychological and behavioral effects have
concerned public officials since the drug first appeared in the southwestern
and southern states during the first two decades of the century. By 1931, at
least 29 states had prohibited use of the drug for non medical purposes.3
Marijuana was first regulated at the federal level by the Marijuana Tax Act
of 1937, which required anyone producing, distributing, or using marijuana
for medical purposes to register and pay a tax, and which effectively
prohibited non medical use of the drug. Although the Act did not make
medical use of marijuana illegal, it did make it expensive and inconvenient.
In 1942, marijuana was removed from the U.S. Pharmacopoeia because it was
believed to be a harmful and addictive drug that caused psychoses, mental
deterioration, and violent behavior.

In the late 1960s and early 1970s, there was a sharp increase in
marijuana use among adolescents and young adults. The current legal status
of marijuana was established in 1970 with the passage of the Controlled
Substances Act, which divided drugs into five Schedules and placed marijuana
in Schedule I, the category for drugs with high potential for abuse and no
accepted medical use (see appendix B. scheduling criteria). In 1972, the
National Organization for the Reform of Marijuana Legislation (NORML), an
organization which supports decriminalization of marijuana, unsuccessfully
petitioned the Bureau of Narcotics and Dangerous Drugs to move marijuana
from Schedule I to Schedule II. NORML argued that marijuana is therapeutic
in numerous serious ailments, is less toxic, and in many cases more
effective than conventional medicines.13 Thus, for 25 years, the medical
marijuana movement has been closely linked with the
marijuana-decriminalization movement, which has colored the debate. Many
people criticized that association in their letters to IOM and during the
public workshops of this study. The argument against the medical use of
marijuana presented most often to the IOM study team is that "the medical
marijuana movement is a Trojan horse"; that is, it is a deceptive tactic
used by advocates of marijuana decriminalization who would exploit the
public's sympathy for seriously ill patients.

Since NORML's petition in 1972, there have been a variety of legal
decisions concerning marijuana. From 1973 to 1978, eleven states adopted
statutes that decriminalized use of marijuana, although some of them
recriminalized marijuana use in the 1980s and 1990s. During the 1970s,
reports of the medical value of marijuana began to appear, particularly
claims that marijuana relieved the nausea associated with chemotherapy.
Health departments in six states conducted small studies to investigate the
reports. When the AIDS epidemic spread in the 1980s, patients found that
marijuana sometimes relieved their symptoms, most dramatically those
associated with AIDS wasting. Over this period, a number of defendants

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charged with unlawful possession of marijuana claimed that they were using
the drug to treat medical conditions and that violation of the law was
therefore justified (the so-called "medical necessity" defense). Although
most courts rejected these claims, some accepted them.8

Against that backdrop, voters in California and Arizona in 1996 passed
two referendums that attempted to legalize the medical use of marijuana
under particular conditions. Public support for patient access to marijuana
for medical use appears substantial; public opinion polls taken during 1997
and 1998 generally report 60-70 percent of respondents in favor of allowing
medical uses of marijuana.15 However, those referendums are at odds with
federal laws regulating marijuana, and their implementation raises complex
legal questions.

Despite the current level of interest, referendums and public
discussions have not been well informed by carefully reasoned scientific
debate. Although previous reports have all called for more research, the
nature of the research that will be most helpful depends greatly on the
specific health conditions to be addressed. And while there have been
important recent advances in our understanding of the physiological effects
of marijuana, few of the recent investigators have had the time or resources
to permit detailed analysis. The results those advances, only now beginning
to be explored, have significant implications for the medical marijuana
debate.

Several months after the passage of the California and Arizona medical
marijuana referendums, the Office of National Drug Control Policy (ONDCP)
asked whether IOM would conduct a scientific review of the medical value of
marijuana and its constituent compounds. In August 1997, IOM formally began
the study and appointed John A. Benson Jr. and Stanley J. Watson Jr. to
serve as principle investigators for the study. The charge to IOM was to
review the medical use of marijuana and the harms and benefits attributed to
it (details are given in appendix C).

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Medical Marijuana Legislation Among the States

The 1996 California referendum known as Proposition 215 allowed
seriously ill Californians to obtain and use marijuana for medical purposes
without criminal prosecution or sanction. A physician's recommendation is
needed. Under the law, physicians cannot be punished or denied any right or
privilege for recommending marijuana to patients who suffer from any illness
for which marijuana will provide relief.

The 1996 Arizona referendum known as Proposition 200 was largely about
prison reform but also gave physicians the option to prescribe controlled
substances, including those in Schedule I (e.g., marijuana), to treat the
disease or relieve the suffering of seriously or terminally ill patients.
Five months after the referendum was passed, it was stalled when Arizona
legislators voted that all prescription medications must be approved by the
Food and Drug Administration, and marijuana is not so approved. In November
1998, Arizona voters passed a second referendum designed to allow
physician's to prescribe marijuana as medicine, but this is still at odds
with federal law.8 .

As of summer 1998, eight states -- California,, Connecticut, Louisiana,
New Hampshire, Ohio, Vermont, Virginia, and Wisconsin -- had laws that
permit physicians to prescribe marijuana for medical purposes or to allow a
medical necessity defense.8 In November 1998, five states -- Arizona,
Alaska, Oregon, Nevada, and Washington -- passed medical marijuana ballot
initiatives. The District of Columbia also voted on a medical marijuana
initiative, but was barred from counting the votes because an amendment
designed to prohibit them from doing so was added to the federal
appropriations bill, however, exit polls suggested that a majority of voters
had approved the measure.

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Marijuana and Medicine

Marijuana plants have been used since antiquity for both herbal
medication and intoxication. The current debate over the medical use of
marijuana is essentially a debate over the value of its medicinal properties
relative to the risk posed by its use.

Marijuana's use as an herbal remedy before the 20th century is well
documented.1, 10, 11 However, modern medicine adheres to different standards
from those used in the past. The question is not whether marijuana can be
used as an herbal remedy, but rather how this remedy meets today's standards
of efficacy and safety. We understand much more than previous generations
about medical risks. Our society generally expects its licensed medications
to be safe, reliable, and of proven efficacy, and contaminants and
inconsistent ingredients in our health treatments are not tolerated. That
refers not only to prescription and over-the-counter drugs, but also to the
vitamin supplements and herbal remedies purchased at the grocery store. For
example, the essential amino acid l-tryptophan was widely sold in health
food stores as a natural remedy for insomnia until early 1990 when it became
linked to an epidemic of a new and potentially fatal illness
(eosinophilia-myalgia syndrome).9, 12 When it was removed from the market
shortly thereafter, there was little protest, despite the fact that it was
safe for the vast majority of the population. The 1536 cases and 27 deaths
were later traced to contaminants in a batch produced by a single Japanese
manufacturer.

Although few herbal medicines meet today's standards, they have
provided the foundation for modern Western pharmaceuticals. Most current
prescriptions have their roots either directly or indirectly in plant
remedies.7 At the same time, most current prescriptions are synthetic
compounds that are only distantly related to the natural compounds that led
to their development. Digitalis was discovered in foxglove, morphine in
poppies, and taxol in the yew tree. Even aspirin (acetylsalicylic acid) has
its counterpart in herbal medicine: for many generations, American Indians
relieved headaches by chewing the bark of the willow tree, which is rich in
a related form of salicylic acid.

Although plants continue to be valuable resources for medical advances,
drug development is likely to be less and less reliant on plants and more
reliant on the tools of modern science. Molecular biology, bioinformatics
software, and DNA array-based analyses of genes and chemistry are all
beginning to yield great advances in drug discovery and development. Until
recently, drugs could only be discovered; now they can be designed. Even the
discovery process has been accelerated through the use of modern drug
screening techniques. It is increasingly possible to identify or isolate the
chemical compounds in a plant, determine which compounds are responsible for
the plant's effects, and select the most effective and safe compounds either
for use as purified substances or as tools to develop even more effective,
safer, or less expensive compounds.

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Yet even as the modern pharmacological toolbox becomes more
sophisticated and biotechnology yields an ever greater abundance of
therapeutic drugs, people increasingly seek alternative, low-technology
therapies.4, 5 In 1997, 46 percent of Americans sought nontraditional
medicines and spent over 27 billion unreimbursed dollars; the total number
of visits to alternative medicine practitioners appears to have exceeded the
number of visits to primary care physicians. 5, 6 Recent interest in the
medical use of marijuana coincides with this trend toward self-help and a
search for "natural" therapies. Indeed, several people who spoke at the IOM
public hearings in support of the medical use of marijuana said that they
generally preferred herbal medicines to standard pharmaceuticals. However,
few alternative therapies have been carefully and systematically tested for
safety and efficacy, as is required for FDA-approved medications.2

Who Uses Medical Marijuana?

There have been no comprehensive surveys of the demographics and
medical conditions of medical marijuana users, but a few reports provide
some indication. In each case, survey results should be understood to
reflect the situation in which they were conducted and are not necessarily
characteristic of medical marijuana users as a whole. Respondents to surveys
reported to the IOM study team were all members of "buyers' clubs,"
organizations that provide their members with marijuana, although not
necessarily through direct cash transactions. The atmosphere of the
marijuana buyers' clubs ranges from that of the comparatively formal and
closely regulated Oakland Cannabis Buyers' Cooperative to that of a "country
club for the indigent," as Dennis Peron described the San Francisco Cannabis
Cultivators Club (SFCCC), which he directed.

John Mendelson, an internist and pharmacologist at the University of
California, San Francisco (UCSF) Pain Management Center, surveyed 100
members of the SFCCC who were using marijuana at least weekly. Most of the
respondents were unemployed men in their forties. Subjects were paid $50 to
participate in the survey; this might have encouraged a greater
representation of unemployed subjects. All subjects were tested for drug
use. About half tested positive for marijuana only; the other half tested
positive for drugs in addition to marijuana (23% for cocaine and 13% for
amphetamines). The predominant disorder was AIDS, followed by roughly equal
numbers of members who reported chronic pain, mood disorders, and
musculoskeletal disorders (table 1.1).

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Table 1.1 Self-Reported Disorders Treated with Marijuana by Members of San
Francisco Cannabis Cultivators Club

Disorder Number of
Subjects
HIV 60
Musculoskeletal disorders and arthritis 39
Psychiatric disorders (primarily depression) 27
Neurological disorders and nonmusculoskeletal pain
syndromes 9
Gastrointestinal disorders (most often nausea) 7
Other disorders glaucoma, allergies, nephrolitiasis, and
the skin manifestations of Reiter syndrome 7
Total disorders 149
Total number of respondents 100

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The membership profile of the San Francisco club was similar to that of
the Los Angeles Cannabis Resource Center (LACRC), where 83% of the 739
patients were men, 45% were 36-45 years old, and 71% were HIV-positive.
Table 1.2 shows a distribution of conditions somewhat different from that in
SFCCC respondents, probably because of a different membership profile. For
example, cancer is generally a disease that occurs late in life; 34 (4.7%)
of LACRC members were over 55 years old; only 2% of survey respondents in
the SFCCC study were over 55 years old.

Jeffrey Jones, executive director of the Oakland Cannabis Buyers'
Cooperative, reported that its largest group of patients is HIV-positive men
in their forties. The second largest group is patients with chronic pain.

Among the 42 people who spoke at the public workshops or wrote to the
study team, only six identified themselves as members of marijuana buyers'
clubs. Nonetheless, they presented a similar profile: HIV - AIDS was the
predominant disorder, followed by chronic pain (table 1.3). All HIV-AIDS
patients reported that marijuana relieved nausea and vomiting and improved
their appetite. About half the patients who reported using marijuana for
chronic pain also reported that it reduced nausea and vomiting.

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Table 1.2 Self-Reported Disorders Treated with Marijuana by Members of Los
Angeles Cannabis Resource Center (LACRC) According to Center Staffa

Treated Disorder Number of Percent of
Subjects Subjects
HIVb 528 71

Cancer 40 5.4
Terminal cancer 10 1.4
Mood disorders
(depression) 4 .05
Musculosketetal
(multiple sclerosis, arthritis) 30 4.1
Chronic pain and back pain 33 4.5
Gastrointestinal 17 2.3
Neurological disorders
(epilepsy, Tourette syndrome, brain trauma)7 0.9
Seizures or migrainec 13 1.8

Glaucoma 15 2.0
Miscellaneous 42 5.7
Total number 739 100

a Results are based on review of 739 individual records by LACRC staff
members. In contrast with Mendelson's survey of SFCCC (table 1.1), only the
primary disorder is indicated here. Membership in LACRC is contingent on a
doctor's letter of acknowledgment, but diagnoses are not independently
confirmed.

b HIV patients use marijuana to control nausea, increase appetite (to combat
wasting), and relieve gastrointestinal distress caused by AIDS medications.
These uses are not indicated separately.

c As described by LACRC staff; some of these cases might also be
neurological disorders.

d Because of rounding error, percentages do not add up to 100.

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Table 1.3 Summary of Reports to IOM Study Team by 43 Individuals

Symptoms Dominant Disease
AIDS(7)
AIDS and cancer
Cancer
Testicular cancer
Anorexia, nausea, vomitingCancer and multiple sclerosclerosis
Thyroid conditione
Migraine
Wilsons disease
Depression(2)
Depression and anxiety(2)
Mood disorders Manic depression(2)
Posttraumatic stress
Premenstrual syndrome
Migraine
Injury(2)
Epilepsy and Postpolio syndrome
Trauma and epilepsy
Degenerative disk disease
Pain Rheumatoid arthritis
Nail-patella syndrome
Reflex sympathetic dystrophy
Gulf War chemical exposure
Multiple congenital cartilaginous exostosis
Histiocytosis X
spasticitye
Multiple sclerosis(3)
Muscle Spasticity Paralysis
Spinal cord injury
Spasmodic torticollis
Intraocular pressure Glaucoma
Diarrhea Crohn's disease

Table 1.3. This table lists the people who reported to the IOM study team
during the public workshops, or through letters, that they use marijuana as
medicine, it should not be interpreted as a representative sample of the
full spectrum of people who use marijuana as medicine. Each dominant disease
represents an individual report.

e Not specified.

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Table 1.4 Primary Symptoms of 43 Individuals who Reported to IOM Study Team

. Symptom Frequency Multiple Symptoms
Number who
% of those who
Primary Number of % of Total Reported reported
Symptom Reportsf Symptoms (Primary) Primary
Reported Additional
Symptoms Symptoms
Anorexia,
nausea, 21 31 13 62
vomiting
Diarrhea 4 6 3 75
Intraocular
pressure 2 3 1 50
Mood disorders 12 18 7 58
Muscle
spasticity 12 18 7 58
Pain 16 24 13 81
Totals 67 . 44 66

f Forty-three persons reporting; 20 reported relief from more than one
symptom.

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Note that the medical conditions referred to are only those reported to
the study team or to interviewers; they cannot be assumed to represent
complete or accurate diagnoses. Michael Rowbotham, a neurologist at the UCSF
Pain Management Center, noted that many pain patients referred to that
center arrive with incorrect diagnoses or with pain of unknown origin. At
that center, the patients who report medical benefit from marijuana report
that marijuana does not reduce their pain but enables them to cope with it.

Most -- not all -- people who use marijuana to relieve medical
conditions have previously used it recreationally. An estimated 95% of the
LACRC members had used marijuana before joining the club. It is important to
emphasize the absence of comprehensive information on marijuana use before
its use for medical conditions. Frequency of prior use almost certainly
depends on many factors, including membership in a buyers' club, membership
in a population sector that uses marijuana more often than others (for
example, men 20-30 years old), and the medical condition being treated with
marijuana (for example, there are probably relatively fewer recreational
marijuana users among cancer patients than among AIDS patients).

Patients who reported their experience with marijuana at the public
workshops said that marijuana provided them with great relief from symptoms
associated with disparate diseases and ailments, including AIDS wasting,
spasticity from multiple sclerosis, depression, chronic pain, and nausea
associated with chemotherapy. Their circumstances and symptoms were varied,
and the IOM study team was not in a position to make medical evaluations or
confirm diagnoses. Three representative cases presented to the IOM study
team are presented here; the stories have been edited for brevity, but each
case is presented in the patient's words and with the patient's permission.

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Boxes 1.1-1.3: Selected Cases From the Public Sessions

G.S. spoke at the IOM workshop in Louisiana about his use of marijuana first
to combat AIDS wasting syndrome and later for relief from the side effects
of AIDS medications.

Skin rashes, dry mouth, foul metallic aftertaste, numbness of the face,
swelling of the limbs, fever spikes, headaches, dizziness, anemia, clinical
depression, neuropathy so crippling that I could not type, so painful that
the bed sheets felt like sandpaper, nausea so severe that I sometimes had to
leave the dinner table to vomit, and diarrhea so unpredictable that I dared
not leave the house without diapers.

These are some of the horrors that I endured in the last 10 years
during my fight for life against the human immunodeficiency virus. But these
ravages were not caused by HIV itself, or by any of the opportunistic
infections that mark the steady progression of AIDS. Each of these
nightmares was a side effect of one of the hundreds of medications I have
taken to fight one infection after another on my way to a seemingly certain
early grave.

Had you known me three years ago, you would not recognize me now. After
years of final-stage AIDS, I had wasted to 130 lb. The purple Kaposi's
sarcoma lesions were spreading. The dark circles under my eyes told of
sleepless nights and half-waking days. I encountered passages of time marked
by medication schedules, nausea, and diarrhea. I knew that I was dying.
Every reflection shimmered with death, my ghost-like pallor in the mirror,
the contained terror on the face of a bus passenger beside me, and most of
all, the resigned sadness in my mother's eyes.

But still I was fortunate because along the way I rediscovered the
ancient understanding of marijuana's medicinal benefit. So I smoked pot.
Every day. The pot calmed my stomach against handfuls of pills. The pot made
me hungry so that I could eat without a tube. The pot eased the pain of
crippling neural side effects so that I could dial the phone by myself. The
pot calmed my soul and allowed me to accept that I would probably die soon.
Because I smoked pot I lived long enough to see the development of the first
truly effective HIV therapies. I lived to gain 50 lb, regain my vigor, and
celebrate my 35th birthday. I lived to sit on the bus without frightening
the passenger beside me.

Even at this stage of my recovery, I take a handful of pills almost
every day, and will probably continue to do so for the rest of my life.
While I am grateful for the lifesaving pro/ease-inhibitor therapies, they
bring with them a host of adverse reactions and undesirable side effects.
Different patients experience different reactions, of course, but almost all
patients experience some. Smoking marijuana relieves many of these side
effects.

I am not one of the exceptional eight patients in the United States
with legal permission to smoke marijuana. Every day I risk arrest, property
forfeiture, fines, and imprisonment. But I have no choice, you see, just as
I have no choice but to endure the side effects of these toxic medications.
So many patients like me are breaking the law to enjoy relief that no other
therapy provides.

I sit here, I believe, as living proof that marijuana can have a
beneficial effect in staving off wasting. Every pound was a day. I figured
that for every pound of body weight I could maintain, that was another day
that I could live in hopes that some effective therapy would emerge.

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B.D. spoke at the IOM workshop in Louisiana She is one of eight patients who
are legally allowed to smoke marijuana under a Compassionate Use Protocol
She uses marijuana to relieve nausea, muscle spasticity, and pain associated
with multiple sclerosis.

I was diagnosed with multiple sclerosis in 1988. Prior to that, I was
an active person with ballet and swimming. I now have a swimming pool, so I
swim each and every day, and I smoke marijuana. The government has given me
the marijuana to smoke. Each month, I pick up a can filled with the
marijuana cigarettes rolled by the government.

At one time, I weighed 85 lb and I now weigh 105. Twenty pounds is
quite a bit to put on I could not walk. I did not have the appetite. I use a
scooter now for distance. I can get around the house. I have a standard
poodle who is kind of like an assistant dog. She is good at it. She helps
me.

When I found out that there was a program to get marijuana from the
government, I decided that was the answer. I was not a marijuana-smoker
before that. In fact, I used to consider the people I knew who smoked the
marijuana as undesirables. Now, I myself am an undesirable.

But it works. It takes away the backache. With multiple sclerosis, you
can get spasms, and your leg will just go straight out and you cannot stop
that leg. You may have danced all of your life and put the leg where you
wanted it to be, but the MS takes that from you. So I use the swimming pool,
and that helps a lot. The kicks are much less when I have smoked a marijuana
cigarette. Since 1991, I've smoked 10 cigarettes a day. I do not take any
other drugs. Marijuana seems to have been my helper. At one time, I did not
think much of the people who smoke it. But when it comes to your health, it
makes a big difference.

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J.H.spoke at the IOM workshop in Washington, DC. He was was seriously
injured in an accident, suffers from a form of arthritis associated with
abnormal activity of the sympathetic nervous system known as reflex
sympathetic dystrophy, and has hepatitis C. He uses marijuana to relieve
nausea from liver disease, pain, and muscle spasms.

I am 48 years old, married with two children. I am a veteran who served
during the Vietnam War. I was exposed to hepatitis C in 1972 by a blood
transfusion, which I needed because of a motor-vehicle accident that broke
my back, ruined my right shoulder, my left thumb, and hand, and almost
amputated my right leg at the knee. My hepatitis C was not diagnosed until
1997 -- after the disease had destroyed my pancreasg and I had four heart
attacks, one angioplasty, and a minor stroke. In 1989, while at work, I was
involved in an accident with a large soil-survey auger. My pelvis was
crushed, and serious nerve damage was the result. I also have reflex
sympathetic dystrophy, which is a neurological disease that has a tremendous
amount of pain and muscle spasms.

I have reached what the doctors call end-stage liver disease from the
hepatitis C. I have lost 85 lbs due to the severe bouts of nausea and
vomiting. Every time I come home from a hospital stay, my 7-year-old asks if
I got the liver transplant. I am on a transplant list, but I am not a
candidate until I am seven days from death.

In October 1997, after trying four different antinausea medications,
four of the doctors that I see told me to go to Europe and see a doctor and
try medicinal cannabis. My primary-care doctor wrote me a letter to carry
with my medical records asking that the doctor help me in any way that he
can to alleviate the symptoms of the hepatitis C and the reflex sympathetic
dystrophy. Those symptoms are severe nausea and pain from the hepatitis C
and pain and muscle spasms from the neurological disease.

I went to Europe in November 1997, where I saw a doctor of internal
medicine. He prescribed me cannabis, 1-2 g a day. I got the medicine and a
pipe and tried it. Within two minutes of taking two puffs from the pipe, the
nausea was gone. I don't think that I felt the high, although I was quite
elated. In about 45 min., I was starving. Normally, I have a fear of eating
because I vomit almost always after I eat or take a pill. I forgot about
that, and I think I ate more that night than I had eaten in months. I did
feel a little nauseated after about four hours, but I smoked two more puffs,
and in about two hours I went to bed. The next morning, I felt hungry.
During my nine-day stay in Europe, I was able to stay free of vomiting and
the waves of nausea became less frequent.

I had experienced four years of pain control using Tegretol¨, a drug
used by epileptics to control seizures. Now, I can't use that medication
because of the damage that it causes to my cirrhotic liver. When I smoked
about two grams of marijuana a day, the nausea was gone and I was no longer
losing weight. The pain was at an acceptable level. Sometimes, I still find
it necessary to use an opiate pain-killer, but only when the pain is at its
worst. Surprisingly, I lost an associated high within a few days. I also
think the cannabis has an antidepressant effect on me, as I no longer have
what I call the "poor me" feelings that I experienced after learning about
the hepatitis C.

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g This is an unlikely consequence of hepatitis C; it is more likely that the
patient's liver was
damaged.

1.18
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The variety of stories presented left the study team with a clear view
of people's beliefs about how marijuana had helped them. But this collection
of anecdotal data, although useful, is limited. We heard many positive
stories, but no stories from people who had tried marijuana but found it
ineffective. This is a fraction with an unknown denominator. For the
numerator, we have a sample of positive responses for the denominator, we
have no idea of the total number of people who have tried marijuana for
medical purposes. Hence, it is impossible to estimate the clinical value of
marijuana or cannabinoids in the general population based on anecdotal
reports. Marijuana clearly seems to relieve some symptoms for some people
even if only as a placebo effect. But what is the balance of harmful and
beneficial effects? That is the essential medical question that can be
answered only by careful analysis of data collected under controlled
conditions.

Cannabis and the cannabinoids

Marijuana is the common name for Cannabis saliva, a hemp plant that
grows throughout temperate and tropical climates. The most recent review of
the constituents of marijuana lists 66 cannabinoids (table 1.5).16 But that
does not mean that there are 66 different cannabinoid effects or
interactions. Most of the cannabinoids are closely related; they fall into
only 10 groups of closely related cannabinoids, many of which differ by only
a single chemical moiety and might be midpoints along biochemical pathways
-- that is, degradation products, precursors, or byproducts.16 18
[Image]9-tetrahydrocannabinol ([Image]9-THC) is the primary psychoactive
ingredient; depending on the particular plant, either THC or cannabidiol is
the most abundant cannabinoid in marijuana (figure 1.1) Throughout this
report, THC is used to indicate [Image]9-THC. In the few cases where
variants of THC are discussed, the full names are used. All the cannabinoids
are lipophilic -- they are highly soluble in fatty fluids and tissues but
not in water. Indeed, THC is so lipophilic that it is aptly described as
"greasy".

Throughout this report, marijuana refers to unpurified plant extracts,
including leaves and flower tops, regardless of how they are consumed --
whether by ingestion or by 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 are included among the effects of
marijuana; but not all the effects of marijuana are necessarily due to THC.
Discussions concerning cannabinoids refer only to those particular compounds
and not to the plant extract. This distinction is important; it is often
blurred or exaggerated.

cannabinoids are produced in epidermal glands on the leaves (especially
the upper ones), stems, and the bracts that support the flowers of the
marijuana plant. Although the flower itself has no epidermal glands, it has
the highest cannabinoid content anywhere on the plant, probably because of
the accumulation of resin

1.19
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secreted by the supporting bracteole (the small, leaf-like part below the
flower). The amounts of cannabinoids and their relative abundance in a
marijuana plant vary with growing conditions, including humidity,
temperature, and soil nutrients (reviewed in Pate 199414). The chemical
stability of cannabinoids in harvested plant material is also affected by
moisture, temperature, sunlight, and storage. They degrade under any storage
condition.

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Figure 1.1 Cannabinoid Biosynthesis

Cannabinoid Biosynthesis

Figure legend: Arrows indicate cannabinoid biosynthesis pathway; dark
arrows indicate established pathways, the light gray arrow indicates a
probable, but not well established, pathway (R. Mechoulam, personal
communication, 1999).17 The great majority of studies reporting on effects
of cannabinoids refer to THC; most of the rest are about CBD and CBN. Other
cannabinoids found in marijuana do not appear to play an important role in
effects of marijuana.

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Table 1.5 cannabinoids Identified in Marijuana

66 Cannabinoids Identified in Marijuana
Number of cannabinoid
Cannabinoid Group Common Variants known in each
Abbreviation
group
[Image]9-tetrahydrocannabinol[Image]9-THC 9

[Image]8-Tetrahydrocannabinol[Image]8-THC 2

Cannabichromene CBC 5
Cannabicyclol CBL 3
Cannabidiol CBD 7
Cannabielsoin CBE 5
Cannabigerol CBG 6
Cannabinidiol CBND 2
Cannabinol CBN 7
Cannabitriol CBT 9
Miscellaneous types . 11

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Organization of the Report

Throughout the report, steps that might be taken to fill the gaps in
understanding both the potential harms and benefits of marijuana and
cannabinoid use will be identified. Those steps include identifying
knowledge gaps, promising research directions, and potential therapies based
on scientific advances in cannabinoid biology.

Chapter 2 reviews basic cannabinoid biology and provides a foundation
to understand the medical value of marijuana or its constituent
cannabinoids. In consideration of the physician's first rule, "first, do no
harm," the potential harms attributed to the medical use of marijuana are
reviewed before the potential medical benefits, chapter 3 reviews the risks
posed by marijuana use, with emphasis on medical use.

Chapter 4 analyzes the most credible clinical data relevant to the
medical use of marijuana. It reviews what is known about the physiological
mechanisms underlying particular conditions (for example, chronic pain,
vomiting, anorexia, and muscle spasticity), what is known about the cellular
actions of cannabinoids, and the levels of proof needed to show that
marijuana is an effective treatment for specific symptoms. It does not
analyze the historical literature; history is informative in enumerating
uses of marijuana, but it does not provide the sort of information needed
for a scientifically sound evaluation of the efficacy and safety of
marijuana for clinical use. Because marijuana is advocated primarily as
affording relief from the symptoms of disease rather than as a cure, this
chapter is organized largely by symptoms as opposed to disease categories.
Finally, chapter 4 compares the conclusions of this report with those of
other recent reports on the medical use of marijuana.

Chapter 5 describes the process of and analyzes the prospects for
cannabinoid drug development.

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References

1. Abel EL. 1980 Marijuana: the first twelve thousand years. New York:
Plenum Press.

2. Angell M, Kassirer JP. 1998. Alternative Medicine - The Risks of Untested
and Unregulated Remedies. The New England Journal of Medicine 339:839-841.

3. Bonnie RJ, Whitebread II CH. 1974. The marihuana conviction: A history of
marihuana prohibition in the United States. Charlottesville, VA: University
Press of Virginia.

4. Eisenberg DM. 1997. Advising patients who seek alternative medical
therapies. Annals of Internal Medicine 127:61-69.

5. Eisenberg DM, Davis RB, Ettner SL, Appel S. Wilkey S. Van Rompay M,
Kessler RC. 1998. Trends in Alternative Medicine Use in the United States,
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6. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL.
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7. Grifo F. Newman D, Fairfield A, Bhattacharya B. Grupenhoff JT 1997. The
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8. Herstek J. 1998. Behavioral Health Issue Briefs. Medical Marijuana
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9. Kilbourne EM, Philen R M, Kamb M L, Falk H. 1996. Tryptophan produced by
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10. Mathre ML, Editor. 1997. Cannabis in Medical Practice. Jefferson, North
Carolina: MacFarland and Company, Inc.

11. Mechoulam R. 1986. The pharmacohistory of Cannabis Sativa. In: Mechoulam
R Editor cannabinoids as therapeutic agents. Boca Raton, FL: CRC Press, Inc.
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12. Milburn DS,, Myers CW. 1991. Tryptophan toxicity: a
pharmacoepidemiologic review of eosinophilia-myalgia syndrome. DICP 25:
1259- 1262.

13. NORML. The Medical Use of http://norml.org/medical/index.html (accessed
July 9, 1998). Marijuana [WWW Document].URL

14. Pate DW.. 1994. Chemical ecology of cannabis. Journal of the
International Hemp Association 1 :29,32-37.

15. Peterson K. 15 January 1997. Notes: Weighing in on a medical
controversy; USA Today's Baby Boomer Panel. USA Today, sec. Life, p. 121).

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16. Ross SA, Elsohly MA. 1995. Constituents of Cannabis Sativa L. XXVIII a
review of the natural constituents: 1980-1994. Zagazig Journal for
Pharmaceutical Sciences 4:1-10.

17. Taura F. Morimoto S. Shoyama Y. 1995. First direct evidence for the
mechanism of delta1-tetrahydrocannabinolic acid biosysnthesis. Journal of
the American Chemical Society 117:9766-9767.

18. Turner CE, Elsohly MA, Boeren E.G. 1980. Constituents of Cannabis Sativa
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review of the natural constituents. Journal of Natural Products 43: 169-234.

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Chapter 2