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Appendix E
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 below by subject. Recommendations made on issues outside the scope of this report, such as drug law and scheduling decisions, 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 American Medical Association House of Delegates. Subject: Medical Marijuana. Chicago: AMA.

·      British Medical Association. 1997. Therapeutic Uses of Cannabis. United Kingdom: Harwood Academic Publishers.

·      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. Geneva: WHO.

In November 1998, the British House of Lords Science and Technology Committee published Medical Use of Cannabis, in which the committee reported its conviction that ''cannabis almost certainly does have genuine medical applications.'' The House of Lords report was released too late in the preparation of the present Institute of Medicine report to per-



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Page 244 Appendix E 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 below by subject. Recommendations made on issues outside the scope of this report, such as drug law and scheduling decisions, 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 American Medical Association House of Delegates. Subject: Medical Marijuana. Chicago: AMA. ·      British Medical Association. 1997. Therapeutic Uses of Cannabis. United Kingdom: Harwood Academic Publishers. ·      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. Geneva: WHO. In November 1998, the British House of Lords Science and Technology Committee published Medical Use of Cannabis, in which the committee reported its conviction that ''cannabis almost certainly does have genuine medical applications.'' The House of Lords report was released too late in the preparation of the present Institute of Medicine report to per-

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Page 245 mit careful analysis and is not summarized here. It is available on the Internet at: www.parliament.uk. General Recommendations Health Council of the Netherlands In order to assess the efficacy of marijuana and cannabinoids, the committee studied literature published during the past 25 years. Based on those 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 should 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 Research on the clinical indications for medical prescription of cannabinoids should be undertaken. For all indications listed below (antiemetics, pain, epilepsy, glaucoma, asthma, immunological effects, multiple sclerosis, spinal cord injury, and other spastic disorders) further research is required to establish suitable methods of administration, optimal dosage regimens, and routes of administration. A central registry should be kept of patients prescribed cannabinoids so that the effects can be followed up over the long term. National Institutes of Health For at least some potential indications, marijuana looks promising enough to recommend that new controlled studies be done. The indications in which varying levels of interest were expressed are the following: appetite stimulation and wasting, chemotherapy-induced nausea and vomiting, neurological and movement disorders, analgesia, [and] glaucoma. 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 un-

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Page 246 answered. To the extent that the NIH can facilitate the development of a scientifically rigorous and relevant database, the NIH should do so. 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 made. AMA House of Delegates Controlled evidence does not support the view that THC or smoked marijuana offers 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 postoperative pain. National Institutes of Health Evaluation of cannabinoids in the management of neuropathic pain, including HIV-associated neuropathy, should be undertaken. World Health Organization No recommendations made, although the report notes that some newly synthesized cannabinoids are extremely potent analgesics; how-

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Page 247 ever, separation of the analgesia and side effects remains to be demonstrated. Nausea and Vomiting Health Council of the Netherlands No recommendations made. AMA House of Delegates THC and smoked marijuana are considerably less effective than currently available therapies to treat acute nausea and vomiting caused by chemotherapy, although certain patients still do not respond adequately to conventional therapy. 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 5HT3 antagonists. The use of an inhaled substance has the potential to benefit 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 D8-THC as an antiemetic, the use of cannabidiol in combination with THC, and the relative effectiveness of cannabinoids compared with 5-HT3 antagonists. Further research is needed in other cases, such as postoperative 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 emesis.

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Page 248 Wasting Syndrome and Appetite Stimulation Health Council of the Netherlands No recommendations made. 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 warranting formal clinical trials of smoked marijuana as an appetite stimulant in patients with AIDS wasting syndrome. British Medical Association Allowing the prescription of nabilone and THC for cancer chemotherapy and HIV/AIDS seems justified for preventing weight loss and treating anorexia in HIV/AIDS irrespective of whether the patient is experiencing nausea and/or vomiting. National Institutes of Health 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 recommendations are made, although the report notes that dronabinol is an effective appetite stimulant for patients with AIDS wasting syndrome.

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Page 249 Muscle Spasticity Health Council of the Netherlands No recommendations made. 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 that have not responded to other drugs are indicated. In the meantime, 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 No recommendations are made, although the report notes that marijuana or the use of other cannabinoids as human therapies might be considered for treating spasticity and nocturnal spasms complicating multiple sclerosis and spinal cord injury. World Health Organization The report notes that cannabinoids have not yet been proven useful in treating multiple sclerosis, but therapeutic uses of cannabinoids are being demonstrated by controlled studies as an antispasmodic. Research in this area should continue. Movement Disorders Health Council of the Netherlands No recommendations made.

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Page 250 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 (+)-HU-210 for neruodegenerative disorders should be explored through further research. National Institutes of Health No recommendations made, although the report notes that marijuana or the use of other cannabinoids as human therapies might be considered for treating for some forms of dystonia. World Health Organization No recommendations made, although the report notes that cannabinoids have not yet been proven useful in the treatment of movement disorders. Epilepsy Health Council of the Netherlands No recommendations made. AMA House of Delegates No recommendations made. British Medical Association Trials with cannabidiol (which is nonpsychoactive), used to enhance the activity of other drugs in cases not well controlled by other anticonvulants, are needed. National Institutes of Health No recommendations made, although the report notes that marijuana

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Page 251 or the use of other cannabinoids as human therapies might be considered for treating various active epilepsy states. World Health Organization No recommendations made, although the report notes that cannabinoids have not yet been proven useful in the treatment of convulsant disorders, but therapeutic uses of cannabinoids are being demonstrated by controlled studies as an anticonvulsant. Glaucoma Health Council of the Netherlands No recommendations made. AMA House of Delegates Neither smoked marijuana nor THC is a viable approach 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 this indication, but much further basic and clinical research is needed to develop and investigate cannabinoids that lower intraocular pressure, preferably by topical application (e.g., 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 D9-tetrahydrocannabinol and marijuana in the treatment of glaucoma are justified. There does not appear to be any obvious reason to use smoked marijuana as a primary "stand-alone" investigational therapy, as there are many available agents for treatment, and these topical preparations seem to be potentially ideal. An approach that may be useful is to study smoked marijuana in incomplete responders to standard therapies. 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 intraocular pressure

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Page 252 (IOP) and central nervous system effects. (2) Relate IOP and blood pressure measurements longitudinally to evaluate potential tolerance development to cardiovascular effects. (3) Evaluate central nervous system effects longitudinally for tolerance development. World Health Organization No recommendations made, although the report notes that, while THC has long been known to reduce the increased intraocular pressure of glaucoma, it has not been fully studied therapeutically. The report also notes that therapeutic uses of cannabinoids are being demonstrated by controlled studies in the treatment of glaucoma. Physiological Harms Health Council of the Netherlands No recommendations made. AMA House of Delegates No recommendations made. British Medical Association Further research is needed to establish the suitability of cannabinoids for immunocompromised patients, such as those undergoing cancer chemotherapy or those with HIV/AIDS. National Institutes of Health Risks associated with smoked marijuana 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. Additional studies of long-term marijuana use are needed to determine if there are or are not important adverse pulmonary, central nervous system, or immune system problems.

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Page 253 World Health Organization Further studies are needed on the fertility effects in cannabis users in view of the high rate of use during the early reproductive years. Further clinical and experimental research is required on the effects of cannabis on respiratory function and respiratory diseases. More studies are needed to show whether cannabis affects the risk of lung malignancies and at what level of use that may occur. In addition, 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 immunological function. More clarity should be sought concerning the molecular mechanisms responsible for immune effects, including both cannabinoid receptor and nonreceptor events. The possibility that chronic cannabis use has adverse effects on the cardiovascular system should have a priority in epidemiological research. Research on chronic and residual cannabis effects is also needed. The pharmacokinetics of chronic cannabis use in humans are poorly described, and this lack of knowledge restricts the ability of researchers to relate drug concentrations in blood or other fluids and observed effects. Psychological Harms Health Council of the Netherlands No recommendations made. AMA House of Delegates No recommendations made. British Medical Association No recommendations made. National Institutes of Health No recommendations made. World Health Organization There is a need for controlled studies investigating the relationships between cannabis use, schizophrenia, and other serious mental disorders.

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Page 254 There is also a need for case-controlled studies comparing those experiencing cannabis problems with people who have, and do not have, alcohol and other psychoactive substance use problems. There is a need for better delineation of the clinical features of cannabis dependence and for studies of its responsiveness to interventions aimed at assisting users to stop. 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 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 is needed to examine the relationship between THC concentrations in blood and other fluids and the degree of behavioral impairment produced. Smoked Marijuana and Use Of Plants As Medicine Health Council of the Netherlands The committee believes that physicians cannot accept responsibility for a product of unknown composition that has not been subjected to quality control. AMA House of Delegates No specific recommendations made, but related issues are discussed in the general recommendation and drug development sections. 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 Smoked marijuana should be held to standards equivalent to other

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Page 255 medications for efficacy and safety considerations. There might be some patient populations for whom the inhalation route might offer advantages over the currently available capsule formulation. Smoking plant material poses difficulties in standardizing testing paradigms, and components of the smoke are hazardous, especially in the immunocompromised patient. 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. World Health Organization 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 The National Institutes of Health 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 analogs that 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. 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. World Health Organization Not discussed.