12

MARIJUANA'S MEDICAL FUTURE

While much of the IOM team's efforts focused on reviewing the accumulated scientific evidence of marijuana's medical risks and benefits, the team also charted a course for future research. With this goal in mind, the authors of the IOM report issued six recommendations regarding the continued study and use of marijuana and cannabinoids for medicinal purposes. This chapter discusses those proposals in detail, compares the conclusions of the IOM report with several other recent reports on medical marijuana, and considers the implications of the IOM team's findings for the future of marijuana-based medicine.

THE IOM RECOMMENDATIONS

A complete list of the study team's recommendations, exactly as they appear in Marijuana and Medicine: Assessing the Science Base, is shown in Box 12.1. Appropriately, the first of these recommendations supports the continuation of basic studies to learn more about how the active ingredients in marijuana affect the body. Over the past two decades research in this area has begun to demonstrate how THC and related natural and synthetic cannabinoids exert their effects on individual cells. Scientists have also discovered that the human body produces substances that



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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy 12 MARIJUANA'S MEDICAL FUTURE While much of the IOM team's efforts focused on reviewing the accumulated scientific evidence of marijuana's medical risks and benefits, the team also charted a course for future research. With this goal in mind, the authors of the IOM report issued six recommendations regarding the continued study and use of marijuana and cannabinoids for medicinal purposes. This chapter discusses those proposals in detail, compares the conclusions of the IOM report with several other recent reports on medical marijuana, and considers the implications of the IOM team's findings for the future of marijuana-based medicine. THE IOM RECOMMENDATIONS A complete list of the study team's recommendations, exactly as they appear in Marijuana and Medicine: Assessing the Science Base, is shown in Box 12.1. Appropriately, the first of these recommendations supports the continuation of basic studies to learn more about how the active ingredients in marijuana affect the body. Over the past two decades research in this area has begun to demonstrate how THC and related natural and synthetic cannabinoids exert their effects on individual cells. Scientists have also discovered that the human body produces substances that

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy Box 12.1 IOM Recommendations on Marijuana and Medicine RECOMMENDATION 1: Research should continue into the physiological effects of synthetic and plant-derived cannabinoids and the natural function of cannabinoids found in the body. Because different cannabinoids appear to have different effects, cannabinoid research should include, but not be restricted to, effects attributable to THC alone. Scientific data indicate the potential therapeutic value of cannabinoid drugs for pain relief, control of nausea and vomiting, and appetite stimulation. This value would be enhanced by a rapid onset of drug effect. RECOMMENDATION 2: Clinical trials of cannabinoid drugs for symptom management should be conducted with the goal of developing rapid-onset, reliable, and safe delivery systems. The psychological effects of cannabinoids are probably important determinants of their potential therapeutic value. They can influence symptoms indirectly which could create false impressions of the drug effect or be beneficial as a form of adjunctive therapy. RECOMMENDATION 3: Psychological effects of cannabinoids such as anxiety reduction and sedation, which can influence medical benefits, should be evaluated in clinical trials. Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory diseases, but the data that could conclusively establish or refute this suspected link have not been collected. RECOMMENDATION 4: Studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent. Because marijuana is a crude THC delivery system that also

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy delivers harmful substances, smoked marijuana should generally not be recommended for medical use. Nonetheless, marijuana is widely used by certain patient groups, which raises both safety and efficacy issues. RECOMMENDATION 5: Clinical trials of marijuana use for medical purposes should be conducted under the following limited circumstances: trials should involve only short-term marijuana use (less than six months), should be conducted in patients with conditions for which there is reasonable expectation of efficacy, should be approved by institutional review boards, and should collect data about efficacy. If there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives. Isolated cannabinoids will provide more reliable effects than crude plant mixtures. Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the development of nonsmoked rapid-onset cannabinoid delivery systems. RECOMMENDATION 6: Short-term use of smoked marijuana (less than six months) for patients with debilitating symptoms (such as intractable pain or vomiting) must meet the following conditions: failure of all approved medications to provide relief has been documented, the symptoms can reasonably be expected to be relieved by rapid-onset cannabinoid drugs, such treatment is administered under medical supervision in a manner that allows for assessment of treatment effectiveness, and involves an oversight strategy comparable to an institutional review board process that could provide guidance within 24 hours of a submission by a physician to provide marijuana to a patient for a specified use.

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy act on cannabinoid receptors and that this “cannabinoid system” appears to influence movement, memory, immunity, and pain sensation (see Chapter 2). The more research reveals about the diverse effects of various cannabinoids, the greater the likelihood that scientists will develop cannabinoid drugs that effectively treat specific symptoms, with a minimum of adverse side effects. The second recommendation encourages the development and clinical testing of cannabinoid medicines for a few promising indications: pain relief, control of nausea and vomiting, and appetite stimulation. It also emphasizes the need to develop safer and more effective methods for administering these drugs to patients. While smoking marijuana allows cannabinoids to take effect rapidly and permits patients to titrate their dose—that is, to inhale just enough to achieve relief from their symptoms—it also has numerous drawbacks, particularly for people with health problems (see Chapter 3). Oral THC (in the form of dronabinol, sold as Marinol) has received approval from the FDA for treatment of nausea and vomiting as well as appetite loss. But Marinol takes effect slowly and cannot be effectively titrated by the user. Vomiting, in particular, would be far more amenable to treatment by inhalation than with a pill that needs to stay down. The IOM team also urged, in its third recommendation, that clinical trials be designed to gauge the psychological effects of cannabinoid drugs. Marijuana's active ingredients, especially THC, produce feelings of well-being, calm, and sedation in many people. These effects could augment other therapeutic benefits of cannabinoids for some patients, but others may mistake good feelings for relief from their symptoms. The more researchers learn about how cannabinoids' physical and psychological effects interact, the better they can put the compounds to medical use. Marijuana smoking clearly harms the cells of the respiratory system, in much the same way tobacco smoke does. But since no definitive study has shown that smoking marijuana causes cancer or chronic obstructive pulmonary disease, the IOM team called for such research in its fourth recommendation. Many studies suggest that marijuana smoke plays a role in causing respiratory disease, but no firm evidence exists to either support or refute this conclusion. This question is particularly important to AIDS patients who smoke marijuana to soothe several symptoms

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy of their chronic disease and to combat adverse side effects of life-saving medications. Although the authors of the IOM report did not generally endorse the medical use of smoked marijuana, they concluded that its safety should be studied because significant numbers of patients use it to medicate themselves. The IOM team also recommended pursuing clinical trials to determine how well smoked marijuana relieves certain medical symptoms. Such studies, the report suggests, should be conducted only under extremely limited circumstances and should be subject to review and approval by a board of experts. Patients with symptoms that are likely to be relieved by smoking marijuana would do so for six months or less, and their response to treatment would be recorded. Such experiments would not be directed toward establishing crude smoked marijuana as a conventional treatment but with the goal of assisting the development of a rapid smokeless method for administering pure cannabinoids. The IOM team's final recommendation concerns short-term use of smoked marijuana by individual patients to relieve such symptoms as debilitating pain or nausea that have defied all conventional treatments. Physicians would present a scientifically and ethically based protocol for a single patient clinical trial to a regulatory board and apply for permission to prescribe marijuana to such patients on an experimental basis. In light of patients' acute discomfort, the board should provide a quick response—within 24 hours of a doctor's request. Physicians would not only supervise patients ' use of the drug but would also collect data on how effectively it relieved their symptoms. OTHER REPORTS ON MARIJUANA AS MEDICINE During the three years preceding publication of the IOM's study on marijuana and medicine, several important reports on the same subject were released by other panels of scientific and medical experts. A summary of some of their conclusions, along with those of the IOM report, appears in Table 12.1. Readers should bear in mind that each of these reports was written for a different purpose, so it is difficult to make many direct comparisons. Nevertheless, all reached the same general conclusions: that marijuana can be moderately effective in treating a variety of

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy TABLE 12.1 Conclusions1 Report Conditions recommended for treatment in clinical trials of smoked marijuana Promising targets for cannabinoid drugs Recommended research on potential harms of marijuana and cannabinoids? Use of whole and/or smoked marijuana as medicine Primary goals of cannabinoid drug development Institute of Medicine2 Various, including nausea and vomiting, wasting, pain Various, including nausea and vomiting, wasting, pain Yes, especially on smoking-related harms Whole marijuana is not a modern medicine Safe, reliable, rapid-onset delivery method for cannabinoids House of Lords (U.K.)3 Multiple sclerosis, chronic pain Not discussed None recommended Hazards of marijuana smoke noted Rapid-onset, smoke-free delivery systems (e.g., inhalation, under the tongue, and rectal suppositories) World Health Organization4 Not discussed Nausea and vomiting; muscle spasticity Various, including infertility, respiratory damage, immune dysfunction, schizophrenia, and “amotivational syndrome” Hazards of marijuana smoke noted Not discussed National Institutes of Health5 (U.S.) Wasting, chemotherapy-induced nausea and vomiting, neurological and movement disorders, glaucoma Nausea and vomiting, neuropathy, possibly muscle spasticity, certain dystonias and epilepsy None recommended Should be held to same standards of safety and efficacy as other FDA-approved drugs Smoke-free inhaled delivery systems for marijuana and cannabinoids British Medical Association6 Not discussed Muscle spasticity, neurodegenerative disorders, epilepsy None recommended Cigarettes and crude marijuana preparations should not be used Novel cannabinoid analogs for new uses American Medical Association7 Various, including AIDS, wasting, chemotherapy-induced nausea and vomiting, MS, spinal cord injury, neuropathy Not discussed None recommended Not recommended Smoke-free inhaled delivery system for marijuana and cannabinoids

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy 1  Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. pp. 244-255. 2   Institute of Medicine 1999. 3   House of Lords (United Kingdom Parliament). Science and Technology Committee 9th Report. Cannabis: The Scientific and Medical Evidence. London: Her Majesty's Stationery Office. 4   World Health Organization. 1997. Cannabis: a health perspective and research agenda. 5   National Institutes of Health. 1997. Workshop on the medical utility of marijuana. Bethesda, MD: National Institutes of Health. 6   British Medical Association. 1997. Therapeutic uses of cannabis. Harwood Academic Publishers, United Kingdom. 7   Report of the Council on Scientific Affairs. 1997. Report to the AMA House of Delegates. Subject: Medical Marijuana.

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy symptoms and that more research on the medical use of marijuana is needed. One recent report that does not appear in Table 12.1 is a 1996 publication from the Health Council of the Netherlands. 1 Unlike the six reports summarized in the table, the Health Council study concluded that not enough evidence existed to justify medical use of marijuana or THC, despite the fact that THC is an approved medicine in the United States (in the form of dronabinol) and in Britain (in the form of nabilone). It is important to note that the Health Council committee did not address the question of whether enough evidence exists to justify clinical trials of marijuana-based medicine. Instead, they were charged with determining whether marijuana or cannabinoids warrant prescription in their current form. And although they answered that question with a “no”—perhaps surprisingly since recreational use of marijuana has been decriminalized in the Netherlands—the Health Council noted that hospitals in the Netherlands tolerate marijuana use among patients with terminal illnesses. The council also said it “did not wish to judge patients who consume marihuana . . . because it makes them feel better.” While most of the reports in Table 12.1 spoke to the importance of developing smokeless delivery systems for cannabinoid medications, many echoed the IOM's conclusion that clinical trials of smoked marijuana may be appropriate until researchers develop safer ways to administer cannabinoids. Along with the IOM, the American Medical Association House of Delegates, the National Institutes of Health, and the British Medical Association have recommended clinical trials of smoked marijuana for much the same variety of symptoms. The British Medical Association stated that marijuana itself is “unsuitable for medical practice” but nonetheless recommended that drug regulations be modified to facilitate research on the plant material. The British House of Lords report reached a similar conclusion, adding—in disagreement with the British Medical Association—that British doctors should be allowed to prescribe marijuana preparations until smokeless versions become available. Only the National Institutes of Health report recommends clinical studies of marijuana for the treatment of glaucoma. In addition to considering reports from expert and govern-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy mental bodies, readers may be interested to learn what advocates both for and against the medical use of marijuana have to say on the subject. Every popular book with which we are familiar was written in support of the medical use of marijuana. For an opposing view, perhaps the best existing source is a scholarly review that appeared in the Annals of Internal Medicine in 1997.2 Several major scientific and medical journals have reviewed the above publications, including most recently Science3 and the Journal of the American Medical Association.4 INTO THE FUTURE During the past two decades researchers have taken important steps toward understanding how cannabinoids exert their effects on the human body. These advances, summarized in Table 12.2, lay the foundation for the possible development of novel medicines from marijuana. Although the marijuana plant represents a rich source of cannabinoids, and of THC in particular, chemists are also synthesizing new versions of cannabinoids with properties that may improve their usefulness as medications, such as increased solubility in water. In the early 1980s researchers had yet to determine whether THC acted on specific cellular receptors—as it is now known to do—or whether the cannabinoid acted nonspecifically, altering any cell with which it came in contact. The discovery of cannabinoid receptors means that it should be possible to design medicines that target the cells and tissues bearing the receptors. For example, researchers have found cannabinoid receptors in moderate abundance in areas of the brain and spinal cord that control pain perception and also in peripheral nerve cells, which detect pain sensations on the body's surface. Perhaps a drug based on THC, which slows nerve impulses when it binds to one class of cannabinoid receptors, or a chemical derivative of that compound could be used to reduce pain sensations along these nerve pathways. On the strength of these findings, along with the results of experiments in animals and a few clinical studies, the IOM study team concluded that cannabinoids hold particular promise as pain relievers. This is an instance where basic research has played

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy TABLE 12.2 Recent Discoveries in Cannabinoid Science Year Discovery 1986 Development of potent new cannabinoid compounds; they are the key to discovering the cannabinoid receptor. 1988 First conclusive evidence of specific receptors for cannabinoids. 1990 Cloning of a cannabinoid receptor from the brain (CB1); this allows researchers to determine the sequence of the gene that encodes CB1 and map the distribution of cannabinoid receptors throughout the brain. 1992 Discovery of anandamide, a naturally occuring substance in the brain that acts on cannabinoid receptors. 1993 Discovery of cannabinoid receptor outside the brain (CB2) that is related to, but distinct from CB1. 1994 Development of the first compound that specifically blocks cannabinoids from binding receptors. 1998 Development of a cannabinoid receptor blocker that binds CB2 but not CB1. Source: Adapted from Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: Natoinal Academy Press, p. 34. an especially important role in identifying potential new medicines. The opposite is true of evidence that cannabinoids can relieve nausea and vomiting, most of which comes from clinical studies of cancer patients undergoing chemotherapy. Scientists have a great deal to learn about the biological mechanisms that cause nausea and vomiting before they can attempt to identify ways to use cannabinoids to control these processes. And since highly effective antiemetic medicines already exist, there are far fewer incentives to develop cannabinoid drugs for nausea and vomiting than for other indications, such as pain. In addition to pain, nausea, and vomiting, the IOM researchers identified appetite stimulation as a promising area for further development of marijuana-based medicines (i.e., in addition to oral THC). They also noted that some scientific evidence supports the possibility of treating muscle spasticity with cannabinoids but

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy that these findings are neither especially strong nor consistent. For example, published reports fail to make the distinction between reducing muscle spasticity by inhibiting specific physiological processes or simply by relieving anxiety, which is known to exacerbate spastic symptoms. Even less evidence exists to indicate that cannabinoids might relieve movement disorders, the IOM report states, while noting encouraging results from relevant animal experiments. Although researchers have yet to fully explore the variety of possible indications for marijuana-based medicines, one thing is clear: smoking marijuana is an inferior way to deliver its potential benefits. Marijuana smoke contains many of the same carcinogens and other harmful compounds found in tobacco smoke—agents that pose an even greater threat to people whose health is compromised by disease. Moreover, as is the case for other herbal remedies, whole marijuana plants contain variable mixtures of active compounds and are therefore likely to produce inconsistent results. Crude marijuana may also contain fungal spores and other potentially harmful contaminants that could pass into the respiratory tract. If there is any future in cannabinoid drugs, it lies in the safe, effective delivery of pure, active compounds. To this end, several researchers and companies are pursuing the development of a smokeless inhaled delivery method for cannabinoid medications. For example, scientists at HortaPharm B.V.—a Dutch company that also grows research-grade marijuana for a variety of applications—are testing a device that gently heats marijuana, releasing a cannabinoid vapor that patients can inhale. A British firm, GW Pharmaceuticals Ltd., has licensed another technology, known as a nebulizer, that uses mechanical means to turn whole marijuana extracts into a fine mist. It is slated for use in upcoming individual trials to test the effectiveness of the extracts in patients with a variety of disorders, using a protocol similar to that recommended by the IOM for short-term trials of smoked marijuana. Researchers have also submitted plans to Britain's Medical Research Council for two double-blind clinical trials to compare the effectiveness of inhaled marijuana extracts with oral THC and placebo. The first trial is expected to include 900 patients with

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy multiple sclerosis who will test these treatments for their ability to relieve muscle spasticity. The second is a study of postoperative pain relief in 400 patients; it will also include a standard pain medication as a positive control. Both protocols were reviewed and approved, but at the time of writing only the multiple sclerosis trial had been funded. Unfortunately, the very efficiency of cannabinoid inhalers raises the likelihood that they will be abused. Unlike oral THC, inhaled cannabinoids would probably rapidly produce the same “high” (or even a more powerful or potentially more addictive high) as smoking marijuana. Thus, manufacturers will probably need to build safeguards into cannabinoid inhalers to prevent their use for nonmedical purposes and also to limit the amount of drug the devices can deliver. These protective features can already be found in medical inhalers used to administer other controlled substances, including opiate painkillers. Concern about possible abuse is but one of several barriers to developing medicines from marijuana or cannabinoids. As described in the previous two chapters, the issue of abuse has far-reaching economic and legal consequences, and the current status of marijuana as a Schedule I controlled substance represents a significant disincentive to both research and commercial development. Despite these odds, a few scientists and companies continue to pursue marijuana-based medicines. Since cannabinoid research is in its infancy, the possibility remains for future discoveries that inspire the development of important profitable drugs. Rather than becoming blockbusters, however, it seems more likely that cannabinoid drugs will continue to be used in much the same way as oral THC: as alternatives or adjuncts to established therapies for a variety of symptoms. So far, conventional medicines have generally outperformed cannabinoid drugs in clinical trials. But not all medicines work for all people, so there may well be patients who will respond better to cannabinoids than to existing medications. And since cannabinoids appear to relieve some symptoms in novel ways, they could be combined with other drugs to enhance their effects. In particular, combinations of cannabinoids and opiates may prove to relieve pain better than opiates alone while causing fewer side effects. It also appears that certain conditions may be uniquely suited

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy to treatment with marijuana-based medicines. Most people with AIDS, for example, experience multiple symptoms that appear to be relieved by cannabinoids, including wasting, nausea, vomiting, pain, and anxiety. It might therefore be preferable to offer such patients a single medication that provides less-than-perfect relief for all of these symptoms than to treat each symptom with a different but more powerful drug. Some of the most exciting possibilities that could unfold from our present medical knowledge of marijuana have little to do with the plant itself. The active compounds in marijuana may not only inspire scientists to develop a variety of useful synthetic medicines but also lead them to a greater understanding of the role of cannabinoids produced by the human body. Research has already revealed that cannabinoids influence numerous physiological processes and biochemical pathways, each of which represents a potential site of action for new highly specific drugs. With the advent of treatments designed to work with the body's own cannabinoid system, the medical use of marijuana should fade as a topic of heated debate to a footnote in the history of medicine. NOTES 1. Health Council of the Netherlands, Standing Committee on Medicine. 1996. Marihuana as Medicine. Rijswikj, The Netherlands: Health Council of the Netherlands. 2. Voth EA, Schwartz RH. 1997. “Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. ” Annals of Internal Medicine 126:791-798. 3. Hall W. 1997. “An ongoing debate.” Science 278:75. 4. Strassman RJ. 1998. “Marihuana: The Forbidden Medicine” (book review). Journal of the American Medical Association 279:963-964.

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