Executive Summary
Over the past 18 months there has been wide-ranging public discussion on the
potential
medical uses of marijuana, particularly smoked marijuana. To contribute to the
resolution
of the debate, the National Institutes of Health (NIH) held a 2-day scientific
meeting on February
19-20, 1997, to review the scientific data concerning the potential therapeutic
uses for marijuana
and the need for and feasibility of additional research.
Central to the current debate about the therapeutic uses of marijuana is the
claim that smoked
marijuana offers therapeutic advantages over the currently available oral form
(dronabinol capsules)
of its most active ingredient, delta-9-tetrahydrocannabinol (9-THC), for a wide variety of
conditions. As the therapeutic claims surrounding marijuana are wide-ranging, 10
separate NIH
Institutes (with interest in the relevant areas) selected a group of eight
experts with broad experience
in clinical studies and therapeutics (and none of whom had a predetermined
position on the medical
utility of marijuana) to examine the data from the published scientific
literature presented by
speakers in the various therapeutic fields. The Ad Hoc Group of Experts also
considered public
comments including those of patients and advocacy groups as well as written
material submitted
to the Group after the meeting. The Expert Group was asked to focus on four
questions:
Question 1 - What research has been done previously and what is
currently known about the
possible medical uses of marijuana?
Question 2 - What are the major unanswered scientific questions?
Question 3 - What are the diseases or conditions for which marijuana
might have potential as a
treatment and that merit further study?
Question 4 - What special issues have to be considered in conducting
clinical trials of the
therapeutic uses of marijuana?
Each presentation of data by a speaker was followed by a question-and-answer
session by the Expert Group. There was no requirement that individuals on the Group agree or
express a
consensus view, although they were free to do so if they so desired. A second
day was provided
for public comment and further discussion by the Expert Group.
This report is a compilation of the opinions of the Expert Group. Speakers
reviewed the literature
on the potential efficacy of cannabinoids, including smoked marijuana, in the
areas of analgesia,
neurological and movement disorders, nausea and vomiting associated with cancer
chemotherapy,
glaucoma, and appetite stimulation/cachexia. A review of selected aspects of the
general clinical
pharmacology of marijuana precedes the disorder-specific commentary.
The discovery of receptors in the central nervous system (CNS) for cannabinoid
compounds, and
the presence of an endogenous ligand for these receptors, is of importance to the
debate concerning
the potential therapeutic uses of marijuana. This discovery supports a
recommendation for more
basic research to discover the functional roles of the cannabinoid receptors as a
key underpinning
for possible therapeutic applications. Such an approach allows the bridging of
knowledge from
molecular neurobiology to animal studies to human clinical trials.
The scientific process should be allowed to evaluate the potential therapeutic
effects of marijuana
for certain disorders, dissociated from the societal debate over the potential
harmful effects of
nonmedical marijuana use. All decisions on the ultimate usefulness of a medical
intervention are
based on a benefit/risk calculation, and marijuana should be no exception to this
generally
accepted principle.
The availability of THC in capsule form does not fully satisfy the need to
evaluate the potential
medical utility of marijuana. The Expert Group noted that, although
delta-9-tetrahydrocannabinol
(THC, dronabinol, Marinol®, or 9-THC) is the principal
psychoactive component of the cannabis
leaf, there may be other compounds in the leaf that have useful therapeutic
properties. Furthermore,
the bioavailability and pharmacokinetics of THC from smoked marijuana are
substantially different
than those of the oral dosage form. These are the rationales for studying the
pharmacological
actions of other constituents of the cannabis leaf, as well as determining
whether a differential
benefit occurs with smoked marijuana rather than oral dronabinol.
The Expert Group noted that even for conditions where good therapies are
available, some patients
develop adverse reactions or are nonresponders. The needs of this subset of
nonresponders must be
considered in the deliberations on testing marijuana as a possible therapeutic
agent.
The Expert Group also noted that risks associated with marijuana, especially
smoked marijuana,
must be considered not only in terms of immediate adverse effects on the lung;
e.g., bronchi and
alveoli, but also long-term effects in patients with chronic diseases.
Additionally, age, immune
status, the development of intercurrent illnesses, and concomitant diseases
should be considered
in the determination of the risk calculation. The possibility that frequent and
prolonged marijuana
use might lead to clinically significant impairments of immune system function is
great enough
that relevant studies should be part of any marijuana medication development
research, particularly
when marijuana will be used by patients with compromised immune systems.
Concerns were
expressed by members of the Expert Group on the use of smoked marijuana because
of the
combustion byproducts, particularly when marijuana would be used for conditions
requiring
chronic therapy. Hence, a recommendation was made for the development of
insufflation/inhalation
devices or dosage forms capable of delivering purer THC or cannabinoids to the
lungs free of
dangerous combustion byproducts.
The major conclusions in each therapeutic area are summarized below.
No clinical trials involving smoked marijuana have been performed in patients
with naturally
occurring pain. Two adequate and well-controlled studies in cancer pain compared
graded doses
of oral 9-THC to placebo,
and one of these included graded doses of codeine as a control.
Although there was evidence of analgesic efficacy, the studies indicate there is
a narrow
therapeutic margin between the doses that produce useful analgesia and those
producing
unacceptable adverse CNS effects.
Neurological and Movement Disorders
Numerous preclinical and clinical studies of the use of cannabinoids in
neurological and movement
disorders have been reported as accounts of animal experiments, clinical
anecdotes, surveys, and
clinical studies.
Evidence that marijuana relieves spasticity produced by multiple sclerosis
(MS) and partial
spinal cord injury is largely anecdotal. Large-scale trials or controlled
studies to compare
marijuana or THC with currently available therapies have not been performed.
There is no
published evidence that cannabinoids are superior or equivalent to available
therapies.
Preclinical evidence suggests a possible role for cannabinoids in the
treatment of the epilepsies,
particularly generalized and partial tonic-clonic seizures. There is scant
information on the use
of marijuana or other cannabinoids for the actual treatment of epilepsy.
Individual case studies have reported some benefit of smoked marijuana in
treatment of dystonic
states. Smoked marijuana or oral THC administrations for Parkinson's disease or
Huntington's
chorea have not been effective.
Cannabinoids have shown efficacy as immune modulators in animal models of
neurological
conditions such as experimental allergic encephalomyelitis (EAE) and neuritis.
These data
suggest that cannabinoids might modify the presumed autoimmune cause of a disease
such as
MS. However, long-term risks of smoked marijuana need to be quantified when
considering
chronic therapy for neurological conditions.
Nausea and Vomiting Associated With Cancer Chemotherapy
There is a large body of literature on the effects of cannabinoids on
chemotherapy-induced
nausea and vomiting. Most of the clinical trials used oral dronabinol rather
than smoked
marijuana. The oral THC studies showed this dosage form to be superior to
placebo and
generally equivalent or superior to prochlorperazine, but inferior to
metoclopramide. Only one
study compared smoked marijuana and dronabinol in a crossover design. Of the 20
patients
studied, 9 had no preference, 7 preferred dronabinol, and 4 preferred smoked
marijuana.
Since the approval of dronabinol in the mid 1980s for the relief of nausea and
vomiting associated
with cancer chemotherapy, more effective antiemetics have been developed, such as
ondansetron,
granisetron, and dolasetron, each combined with dexamethasone. The relative
efficacy of
cannabinoids versus these newer antiemetics has not been evaluated. Smoked
marijuana was
tested in one trial in patients who previously had no benefit from older
antiemetic agents. Nearly
one-quarter of patients who initially agreed to participate later declined citing
bias against smoking,
the harshness of smoke, and preference for dronabinol. Among the remaining 56
patients,
78 percent rated smoked marijuana very effective or moderately effective.
Sedation was seen in
88 percent and dry mouth in 77 percent. It is not known whether smoked marijuana
would
benefit patients refractory to the current generation of antiemetic therapy.
Smoked marijuana has been shown to lower intraocular pressure (IOP) in
subjects with normal
IOP and patients with glaucoma. The duration of the pressure-lowering effect is
3 to 4 hours.
Single-administration studies have reported blood pressure falls concurrently
with the IOP
lowering, raising concern that blood flow to the optic nerve could be
compromised. Mitigating
this concern are data suggesting that tolerance may develop to cardiovascular
effects. Efforts to
avoid or reduce side effects led to the development of a topical dosage form of
THC. Topically
applied THC did not lower IOP.
The mechanism of all IOP-lowering drugs currently used to treat glaucoma is
known with the
exception of marijuana. The interactive effect of marijuana with currently
available IOP-lowering
agents is not known but is evaluable. Elucidation of the mechanism of action of
marijuana's
IOP-lowering effect is crucial to its potential utilization for treatment of
glaucoma; a unique
mechanism of action might provide additive benefit whereas a mechanism identical
to an
available medication would suggest an unfavorable benefit/risk ratio.
Clinical studies and survey data in healthy populations have shown a strong
relationship between
marijuana use and increased eating. Marijuana is reported to increase food
enjoyment and the
number of times individuals eat per day. Mechanistic studies of marijuana on
taste and satiety
have shown that it does not affect taste or produce a collapse of normal satiety
mechanisms.
Food intake associated with marijuana use is influenced by the social setting.
There are no controlled studies of marijuana in the AIDS-wasting syndrome, nor
have there been
any systematic studies of the effects of smoked marijuana on immunological status
in HIV-infected
patients. Smoking (tobacco, marijuana, or crack cocaine) has been shown to
increase the risk of
developing bacterial pneumonia in HIV-positive immune-compromised patients.
Dronabinol has
been shown to increase appetite and produce weight gain in AIDS and cancer
patients, although
the weight gain is not in lean body mass. Dronabinol is approved for the
treatment of anorexia in
patients with AIDS-associated weight loss.
Question 3: Which Diseases or Conditions Merit Further
Study?
Concerning Question 3, there were varying degrees of enthusiasm to pursue
smoked marijuana
for several indications. This enthusiasm was tempered by the fact that, for many
of these
disorders, effective alternative treatments are already available. Given the
general consensus
among the experts that the number, design and documentation of studies performed
to date with
smoked marijuana did not provide definitive answers, it was difficult to compare
marijuana with
products that had received regulatory approval under more rigorous experimental
conditions.
This does not mean, however, that the issue should be foreclosed. It simply
means that in order
to evaluate various hypotheses concerning the potential utility of marijuana in
various therapeutic
areas, more and better studies would be needed. In the words of Dr. William
Beaver, Professor
of Pharmacology and Anesthesia, Georgetown University School of Medicine, who
chaired the
workshop, "For at least some potential indications, marijuana looks promising
enough to
recommend that there be new controlled studies done." The indications in which
varying levels
of interest was expressed are the following:
Accordingly, the NIH should consider relevant administrative mechanisms to
facilitate grant
applications in each of these areas. Whether or not the NIH is the primary
source of grant
support for a proposed bona fide clinical research study, if that study meets
U.S. regulatory
standards (U.S. Food and Drug Administration (FDA) protocol approval and Drug
Enforcement
Administration (DEA) controlled substances registration) the study should receive
marijuana
and/or matching placebo supplied by the National Institute on Drug Abuse (NIDA).
In this way,
a new body of studies may emerge to test the various hypotheses concerning
marijuana.
The last question, Question 4, concerning the special issues involved in
conducting clinical trials
with marijuana, was particularly difficult. There was considerable discussion
and debate as to
whether smoked marijuana (with the inherent health risks of smoking) would need
to demonstrate
clear superiority or some unique benefit compared with other medications
currently available for
these conditions. The Expert Group concluded that smoked marijuana should be
held to standards
equivalent to other medications for efficacy and safety considerations.
Moreover, there might
be some patient populations; e.g., cancer patients experiencing nausea and
vomiting during
chemotherapy, for whom the inhalation route might offer
advantages over the currently available
capsule formulation. This raises many issues concerning the best mode of
administration. Generally
accepted pharmacotherapy development schema would favor finding routes of
administration
under which dosing could be more tightly controlled and easily titrated. Smoking
plant material
poses difficulties in standardizing testing paradigms, and components of the
smoke are hazardous,
especially in the immunocompromised patient. Additionally, practical problems
exist. Given the
no-smoking policy of hospitals and public facilities, it would be difficult to
imagine the utility of
smoked marijuana in these settings. Therefore, the experts generally favored the
development of
alternative dosage forms, including an inhaler dosage form into which a
controlled unit dose of
THC could be placed and volatilized. Other problems noted were the difficulty in
attempting to
match placebo control against smoked marijuana (especially for those with
previous marijuana
experience), and the fact that under U.S. law, researchers will need to obtain
DEA registration to
handle marijuana, which is currently a Schedule I controlled substance (see
Appendix).
In summary, the testing of smoked marijuana to evaluate its therapeutic effects is a difficult, but not impossible, task. Until studies are done using scientifically acceptable clinical trial design and subjected to appropriate statistical analysis, the questions concerning the therapeutic utility of marijuana will likely remain much as they have to date--largely unanswered. To the extent that the NIH can facilitate the development of a scientifically rigorous and relevant database, the NIH should do so.
1. Dronabinol is currently marketed in the United States for the stimulation of appetite in AIDS patients. The effects of smoked marijuana on cachexia associated with AIDS or cancer would need to be determined.
2. Dronabinol is currently marketed in the United States for the control of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. The effects of smoked marijuana for this indication merit consideration for further research.
Go to the Medical Marijuana Menu
Go to the HIV & Nutrition Menu
Go to the HIVpositive.us Main Menu