Sources: LeCraw (1996) and 21 U.S.C. 812.

APPENDIX C

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 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 pain).

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.

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APPENDIX D

Recommendations made in Recent Reports on the Medical Use of Marijuana

Recommendations from five recent key reports pertaining to the medical use of marijuana are listed by subject. Recommendations made on issues outside the scope of his report, such as drug law and scheduling clecisions, are not included here. The following reports were reviewed:

Health Council of the Netherlands, Standing Committee on Medicine. 1996. Marihuana as medicine. Rijswikj, the Netherlands: Health Council of the Netherlands.

Report of the Council on Scientific Affairs. 1997. Report to the AMA House of Delegates. Subject: Medical Marijuana.

British Medical Association. 1997. Therapeutic uses of cannabis. Harwood Academic Publishers, United Kingdom.

National Institutes of Health. 1997. Workshop on the medical utility of marijuana. Bethesda, MD: National Institutes of Health.

World Health Organization. 1997. Cannabis: a health perspective and research agenda.

November 1998, the British House of Lords Science and Technology Committee published, Medical Use of Cannabis, in which they reported their conviction that "cannabis almost certainly does have genuine medical applications." The House of Lords report was released too late in the preparation of the IOM report to permit careful analysis, and is not summarized here.

It is available on the internet at: www.parliament uk.

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Appendix D

General recommendations

Health Council of the Netherlands

In order to assess the efficacy of marihuanaand cannabinoids, the committee studied literature published during the past 25 years. Based on their findings, the committee concluded that there was insufficient evidence to justify the medical use of marijuana.

AMA House of Delegates

Adequate and well-controlled studies of smoked marijuana be conducted in patients who have serious conditions for which preclinical, anecdotal, or controlled evidence suggests possible efficacy including AIDS wasting syndrome, severe acute or delayed emesis induced by chemotherapy, multiple sclerosis, spinal cord injury, dystonia, and neuropathic pain.

British Medical Association

Further research is required to establish suitable methods of administration, optimal dosage regimens and routes of administration for the above indications.

National Institutes of Health

For at least some potential indications, marijuana looks promising enough to recommend that there be new controlled studies done for the following indications: appetite stimulation and wasting, chemotherapy-induced nausea and vomiting, neurological and movement disorders, analgesia, glaucoma (but see note below). Until studies are done using scientifically acceptable clinical trial design and subjected to appropriate statistical analysis, the question concerning the therapeutic utility of marijuana will likely remain largely unanswered.

World Health Organization

Therapeutic uses of cannabinoids warrant further basic pharmacological and experimental investigation and clinical research into their effectiveness. More research is needed on the basic neuropharmacology of THC and other cannabinoids so that better therapeutic agents can be found.

Analgesia

Health Council of the Netherlands

No recommendations

AMA House of Delegates

Controlled evidence does not support the view that THC or smoked marijuana offer clinically effective analgesia without causing significant adverse events when used alone Preclinical evidence suggests that cannabinoids can potentiate opioid analgesia and that cannabinoids may be effective in animal models of neuropathic pain. Further research into the use of cannabinoids in neuropathic pain is warranted.

British Medical Association

The prescription of nabilone, THC and other cannabinoids should be permitted for patients with intractable pain. Further research is needed into the potential of cannabidiol as an analgesic in chronic, terminal and post-operative pain.

National Institutes of Health

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Appendix D

Evaluation of cannabinoids in the management of neuropathic pain, including HIV-associated neuropathy, should be undertaken.

World Health Organization

No recommendations, although the report notes that some newly synthesized cannabinoids are extremely potent analgesics, however, separation of the analgesia and side effects remains to be demonstrated.

Nausea and vomiting

Health Council of the Netherlands

No recommendations

AMA House of Delegates

Research involving THC and smoked marijuana should focus on their possible use in treating delayed nausea and vomiting, and their adjunctive use in patients who respond inadequately to 5-HT3 antagonists. The use of an inhaled substance has the potential for benefit in ambulatory patients who are experiencing the onset of nausea, and are thus unable to take oral medications.

British Medical Association

Further research is needed on the use of A8-THC as an anti-emetic, the use of cannabidiol in combination of THC, and the relative effectiveness of cannabinoids compared with 5-HT3 antagonists. Further research is needed in other cases, such as post-operative nausea and vomiting.

National Institutes of Health

Inhaled marijuana merits testing in controlled, double-blind, randomized trials for nausea and vomiting.

World Health Organization

More basic research on the central and peripheral mechanisms of the effects of cannabinoids on gastrointestinal function may improve the ability to alleviate nausea and emesls.

Wasting syndrome and appetite stimulation

Health Council of the Netherlands

No recommendations

AMA House of Delegates

THC is moderately effective in the treatment of AIDS wasting, but its long duration of action and intensity of side effects preclude routine use. The ability of patients who smoke marijuana to titrate their dosage according to need and the lack of highly effective, inexpensive options to treat this debilitating disease create the conditions warrants formal clinical trial of smoked marijuana as an appetite stimulant in patients with AIDS wasting syndrome.

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Appendix D

National Institutes of Health

There is a need for further research where long term administration of marijuana might be considered for therapeutic purposes. individuals who are HIV-positive or who have tumors or diseases where immune system function may be important in the genesis of the disease.

Areas of study for the potential appetite-stimulating properties of marijuana include the cachexia of cancer, HIV/AIDS symptomatology, and other wasting syndromes. Investigations should be designed to assess long-term effects on immunology status, the rate of viral replication, and clinical outcomes in participants as well as weight gain . In therapeutic trials of cachexia, research should attempt to separate out the effect of marijuana on mood versus appetite. Some questions need to be answered in the studies: (1) Does smoking marijuana increase total energy intake in patients with catabolic illness. (2) Does marijuana use alter energy expenditure? (3) Does marijuana use alter body weight, and to what extent? (4) Does marijuana use alter body composition and to what extent?

World Health Organization

No specific recommendation, although the report notes that dronabinol is an effective appetite stimulant for patients with AIDS wasting syndrome.

Muscle spasticity

Health Council of the Netherlands

No recommendations

AMA House of Delegates

Considerably more research is required to identify patients who may benefit from THC or smoked marijuana, and to establish whether responses are primarily subjective in nature. A therapeutic trial of smoked marijuana or THC may be warranted in patients with spasticity who do not derive adequate benefit from available oral medications, prior to their considering intrathecal baclofen therapy or neuroablative procedures.

British Medical Association

A high priority should be given to carefully controlled trials of cannabinoids in patients with chronic spastic disorders which have not responded to other drugs are indicated. In the mean time, there is a case for the extension of the indications for nabilone and THC for use in chronic spastic disorders unresponsive to standard drugs.

National Institutes of Health

Few available therapies provide even partial relief for the neuropathic pain that complicates many diseases affecting the central nervous system. Cannabinoid drugs are potentially valuable in these areas, especially if deivered by other than the smoked route. More research is needed.

Movement disorders

Health Council of the Netherlands

No recommendations

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Appendix D

AMA House of Delegates

Considerably more research is required to identify dystonic patients who may benefit from THC or smoked marijuana, and to establish whether responses are primarily subjective in nature.

British Medical Association

The potential of (+) 210 for neruodegenerative disorders should be explored through further research

National Institutes of Health

More studies are needed in movement disorders

World Health Organization

No recommendations, although the report notes that cannabinoids have not yet been proven useful in the treatment of convulsant or movement disorder or in treating multiple sclerosis.

Epilepsy

Health Council of the Netherlands

No recommendations

AMA House of Delegates

No recommendations

British Medical Association

Trials with cannabidiol (which is non-psychoactive) used to enhance the activity of other drugs in cases not well controlled by other anticonvulants are needed.

National Institutes of Health

No recommendations

World Health Organization

No recommendations

Glaucoma

Health Council of the Netherlands

No recommendations

AMA House of Delegates

Neither smoked marijuana nor THC are viable approaches in the treatment of glaucoma, but research on their mechanism of action may be important in developing new agents that act in an additive or synergistic manner with currently available therapies

British Medical Association

Cannabinoids do not at present look promising for these indications, but much further basic and clinical research is needed to develop and investigate cannabinoids which lower intraocular pressure, preferably by topical application (ea. eye drops, inhalant aerosols), without producing unacceptable systemic and central nervous system effects.

National Institutes of Health

Further studies to define the mechanism of action and to determine the efficacy of delta9-tetrahydrocannabinol and marijuana in the treatment of glaucoma are justified.

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Appendix D

World Health Organization

No recommendations

Physiological harms

Health Council of the Netherlands

No recommendations

AMA House of Delegates

No recommendations

British Medical Association

Further research is needed to establish the suitability of cannabinoids for immunocompromised patients, such as those undergoing cancer chemotherapy or with HIV/AIDS.

National Institutes of Health

Additional studies of long term marijuana use are needed to determine if there are or are not important adverse pulmonary, central nervous system (CNS), or immune system problems. The suggested design for clinical studies is to add marijuana, oral THC, or placebo to standard therapy under double-blind conditions: (1) Establish dose-response and dose-duration relationships for IOP and CNS effects. (2) Relate IOP and blood pressure measurements longitudinally to evaluate potential tolernce development to cardiovascular effects. (3) Evaluate CNS effects longitudinally for tolerance development.

World Health Organization

Further studies are required of marijuana use on fertility effects, respiratory function and disease, immunological function, and cardiovascular effects.

Psychological harms

Health Council of the Netherlands

No recommendations

AMA House of Delegates

No recommendations

British Medical Association

No recommendations

National Institutes of Health

No recommendations

World Health Organization

There is a need for controlled studies investigating the relationships between cannabis use, schizophrenia and other serious mental disorders. Insufficient research has been undertaken on the 'amotivational' syndrome which may or may not result from heavy cannabis use. It is not clear that the syndrome exists, even though heavy cannabis use is sometimes associated with reduced motivation to succeed in school and work. New research is needed to show whether the reduced motivation seen in some cannabis users is due to other psychoactive substance use and whether it precedes cannabis use. Further

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Appendix D

development of cognitive and psychomotor tests for controlled studies that are sensitive to the performance effects of cannabis use and that reflect the complexity of specific daily functions (e.g., driving, learning, reasoning) also need additional research. More research in examining the relationship between THC concentrations in blood and other fluids and the degree of behavioral impairment produced.

Physiological harms

Health Council of the Netherlands

No recommendations

AMA House of Delegates

No recommendations

British Medical Association

No recommendations

National Institutes of Health

There significant health risks associated with smoked marijuana that must be considered not only in terms of immediate adverse effects, but also long-term effects in patients with chronic diseases. 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.

World Health Organization

Research on chronic and residual cannabis effects is also needed. The lack of knowledge restricts the ability of researchers to relate drug concentrations in blood or other fluids and observed effects.

More studies are needed on the fertility effects in cannabis users, in view of the high rate of use during the early reproductive years.

More research is required on the effects of cannabis on respiratory function and respiratory diseases. More studies on whether cannabis affects the risk of lung malignancies and what level of use that may occur. More studies are needed to clarify the rather different results of pulmonary histopathological studies in animals and man.

More clinical and experimental research is needed on the effects of cannabis on the immunological function. More clarity should be sought concerning the molecular mechanisms responsible for immune effects, including both cannabinoid receptor and non-receptor events.

The possibility that chronic cannabis use has adverse effects on the cardiovascular system.

Smoked marijuana and use of plants as medicine

Health Council of the Netherlands

Not recommended. The committee believes that physicians cannot accept responsibility for a product of unknown composition that has not been subjected to quality control

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Appendix D

AMA House of Delegates

NIH should use its resources to support the development of a smoke-free inhaled delivery system for marijuana or THC to reduce the health hazards associated with the combustion and inhalation of marijuana.

British Medical Association

Prescription formulations of cannabinoids or substances acting on the cannabinoid receptors should not include either cigarettes or herbal preparations with unknown concentrations of cannabinoids or other chemicals.

National Institutes of Health

NIH should use its resources and influence to rapidly develop a smoke-free inhaled delivery system for marijuana or THC. This will also bring this research effort in line with other Government initiatives to curtail cigarette smoking. "Taking the smoke" out of an inhaled dosage form of marijuana or THC would remove an important obstacle to the accurate determination of inhaled marijuana's beneficial and deleterious effects.

World Health

Not discussed in the context of medical use, although many health hazards associated with chronic marijuana smoking are noted.

Drug development

Health Council of the Netherlands

Not discussed

AMA House of Delegates

NIH should use its resources to support the development of a smoke-free inhaled delivery system for marijuana or THC to reduce the health hazards associated with the combustion and inhalation of marijuana.

British Medical Association

Pharmaceutical companies should undertake basic laboratory investigations and develop novel cannabinoid analogues which may lead to new clinical uses.

National Institutes of Health

NIH should use its resources and influence to rapidly develop a smoke-free inhaled delivery system for marijuana or THC. This will also bring this research effort in line with other Government initiatives to curtail cigarette smoking. "Taking the smoke" out of an inhaled dosage form of marijuana or THC. would remove an important obstacle to the accurate determination of inhaled marijuana's beneficial and deleterious effects.

World Health Organization

Not discussed.

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APPENDIX E

Rescheduling Criteria

DEA's Five Factor Test for Rescheduling
(Formulated in 1992 in Response to Court Challenge to Scheduling)

(1) The Drug's Chemistry Must Be Known and Reproducible

The substance's chemistry must be scientifically established to permit it to be reproduced in dosages which can be standardized. The listing of the substance in a current edition of one of the official as defined by section 201 (I) of the Food, Drug and Cosmetic Act, 21 USC 321(f), is sufficient generally to meet this requirement.

(2) There Must be Adequate Safety Studies

There must be adequate pharmacological and toxicological studies done by all methods reasonably applicable on the basis of which it could be fairly and responsibly concluded, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that the substance is safe for treating a specific, recognized disorder.

(3) There Must Be Adequate and Well-Controlled Studies Proving Efficacy

There must be adequate, well-controlled, well-designed, well-conducted, and well documented studies, including clinical investigations, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs on the basis of which it could fairly and responsibly be concluded by such experts, that the substance will have its intended effect in treating a specific, recognized disorder.

(4) The Drug Must Be Accepted by Qualified Experts

The drug must have a New Drug Application (NDA) approved by the Food and Drug Administration...Or, a consensus of the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, c, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus.

(5) The Scientific Evidence Must Be Widely Available

In the absence of NDA approval, information concerning the chemistry, pharmacology, toxicology and effectiveness of the substance must be reported, published, or otherwise widely available in sufficient detail to permit experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, to fairly and responsibly conclude the substance is safe and effective for use in treating a specific, recognized disorder.

Sources: LeCraw (1996) and 57 Fed. Reg. 10499- (1992).

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