5

MARIJUANA AND AIDS

Although no comprehensive surveys have been conducted on medical marijuana users in the United States, small-scale polls indicate that most are seeking relief from symptoms of AIDS. For example, each of the three California cannabis buyers' clubs—organizations that provide marijuana to patients—visited by the IOM team reported that more than 60 percent of their members requested the drug for AIDS treatment.

Age is often cited as the reason why such a large proportion of medical marijuana users in the United States are people with AIDS (this is not the case elsewhere; in Great Britain, for example, multiple sclerosis appears to predominate among medical marijuana users). Because HIV has disproportionately infected members of a generation that grew up experimenting with marijuana, so the theory goes, AIDS patients tend to be comparatively willing to use it as a medicine. By contrast, cancer patients, who are on average older and thus less likely to have tried marijuana, are far less inclined to seek it out. If this reasoning is correct, increasing numbers of cancer patients should turn to medical marijuana as the baby boom generation ages.

Another factor also may contribute to the popularity of medicinal marijuana among people with AIDS: the drug's purported ability to soothe a variety of debilitating symptoms. Many such patients echo the comments of the HIV-positive man cited in



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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy 5 MARIJUANA AND AIDS Although no comprehensive surveys have been conducted on medical marijuana users in the United States, small-scale polls indicate that most are seeking relief from symptoms of AIDS. For example, each of the three California cannabis buyers' clubs—organizations that provide marijuana to patients—visited by the IOM team reported that more than 60 percent of their members requested the drug for AIDS treatment. Age is often cited as the reason why such a large proportion of medical marijuana users in the United States are people with AIDS (this is not the case elsewhere; in Great Britain, for example, multiple sclerosis appears to predominate among medical marijuana users). Because HIV has disproportionately infected members of a generation that grew up experimenting with marijuana, so the theory goes, AIDS patients tend to be comparatively willing to use it as a medicine. By contrast, cancer patients, who are on average older and thus less likely to have tried marijuana, are far less inclined to seek it out. If this reasoning is correct, increasing numbers of cancer patients should turn to medical marijuana as the baby boom generation ages. Another factor also may contribute to the popularity of medicinal marijuana among people with AIDS: the drug's purported ability to soothe a variety of debilitating symptoms. Many such patients echo the comments of the HIV-positive man cited in

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy Chapter 2 who claimed that marijuana calmed his stomach after taking medication, stimulated his appetite, eased his pain, and lifted his mood. Because HIV attacks the immune system, it wreaks havoc throughout the body. Besides providing a foothold for opportunistic infection and cancer, the virus also triggers a potentially lethal wasting syndrome, painful nerve damage, and dementia. Finally, in addition to the physical discomforts inflicted by HIV, many people with AIDS also struggle with depression and anxiety. Marijuana, some patients say, eases all of these problems and more. NAUSEA AND VOMITING Even the recent success of combination therapy—which, by keeping HIV in check, has transformed AIDS from a terminal illness to a chronic disorder—has a downside. The very drugs that give people with HIV a future can make their day-to-day life miserable. As this 41-year-old Virginia theater technician told the IOM team: Thirteen years ago I found out that I was HIV-positive. Since then I have taken AZT, ddI, d4T, Crixivan, Viracept, Viramune, Bactrim, Megace, and others. All these drugs have two things in common: they gave me hope and they also made me sick. Nausea, diarrhea, fatigue, vomiting, and loss of appetite became a way of life for me. After three years of these side effects ruling my life, a doctor suggested a simple and effective way to deal with many of them. This remedy kept me from slowly starving to death, as I had seen many of my friends do. It helped me rejoin the human race as a responsible, productive citizen. It also made me a criminal, something I have never been before. This remedy, of course, is medical marijuana. Like this man, increasing numbers of AIDS patients appear to be using marijuana to counteract the side effects of prescribed medicines as well as to treat disease symptoms. In particular, those who take highly effective antiviral drugs called protease inhibitors often suffer from nausea and vomiting similar to that experienced by cancer patients during chemotherapy. Just how effectively marijuana and cannabinoids reduce the

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy nausea and vomiting brought on by AIDS medications remains to be determined in the clinic. Research on marijuana's antinausea properties has focused on chemotherapy-induced emesis (vomiting) in cancer patients and is discussed in depth in the next chapter. Several different types of antiemetic drugs (including substituted benazamides, serotonin receptor antagonists, and corticosteroids) have been used successfully by both AIDS patients and cancer patients, so there is reason to believe that cannabinoids could help both groups. On the other hand, clinical studies indicate that marijuana and THC do not control nausea and vomiting as effectively as do other medications. Since a wide variety of factors influence emesis and each person responds to them differently, it is possible that certain patients would get better relief from marijuana-based medicines than from conventional treatments. That this is the case remains to be substantiated by controlled studies. In the meantime, some people with AIDS who take THC in the form of dronabinol (Marinol) to combat weight loss may also find that it reduces their feelings of nausea. AIDS patients who took the drug in a four-week clinical study showed a trend toward decreased nausea compared with those who took a placebo, as well as a significant increase in appetite.1 AIDS WASTING SYNDROME While both nausea and appetite loss play a role in wasting, the latter is the primary reason AIDS patients take Marinol. Weight loss is one of two indications for which the U.S. Food and Drug Administration has approved the drug for sale (the other is nausea and vomiting associated with cancer chemotherapy). For people with HIV, loss of as little as 5 percent of their body weight appears to be life threatening. Death from wasting generally occurs when patients drop to more than one-third below their ideal weight. The Centers for Disease Control and Prevention defines AIDS wasting syndrome as the involuntary loss of more than 10 percent of body weight, accompanied by diarrhea or fever that lasts more than 30 days and is not attributable to another illness. Wasting occurs through a combination of two different physiological

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy processes, cachexia and starvation. Cachexia (pronounced kah-KEK-see-uh) results from tissue injury and causes a disproportionate loss of lean tissue mass, such as muscle or liver; the same process also occurs during the final stages of cancer. Starvation, by contrast, results from food or nutrient deprivation; it causes a loss of body fat before lean tissues become depleted. While starvation can be cured simply by eating, curing cachexia generally requires controlling the disease that triggered it and artificially stimulating the body 's metabolism. Research indicates that people begin losing muscle and other lean tissues even before developing full-blown AIDS, possibly as a result of the body's response to viral infection. Later, opportunistic infections or ulcers of the mouth, throat, or esophagus make eating difficult. Other infectious organisms cause diarrhea, which reduces nutrient absorption, as does the overgrowth of microbes that naturally inhabit the digestive tract. Depression, fatigue, and poverty may further exacerbate malnutrition in AIDS patients. Standard therapy for AIDS wasting focuses on stimulating the patient 's appetite, usually with the drug megestrol acetate (Megace). Although approved for this purpose, Marinol is prescribed far less often. Clinical studies indicate that Megace stimulates weight gain more effectively than Marinol and that patients get no additional benefit by using the drugs in combination.2 People who take Megace typically increase their food consumption by about 30 percent, but gain mostly fat, rather than lean tissue or muscle mass. Like Megace, Marinol reverses starvation but has no effect on cachexia. Presumably, the same is true of marijuana. To date, THC is the only cannabinoid that has been evaluated in the clinic for its ability to stimulate appetite and thereby counteract AIDS wasting. In short-term (six weeks) and long-term (one year) studies, patients who received THC in the form of Marinol tended to experience increased appetite while maintaining a stable weight. 3 In addition, five patients in a preliminary study gained an average of 1 percent body fat after taking the drug for five weeks.4 Some patients in these and other studies have experienced unpleasant side effects from the drug, ranging from dry mouth to psychological distress. These problems are exacerbated by the dif-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy ficulty of fine-tuning the dosage of THC in pill form. Moreover, when taken orally, THC tends to be slow to act and to clear from the body. For these reasons some AIDS patients—and also some cancer patients who have used Marinol to combat wasting and chemotherapy-induced nausea—report that they prefer smoking marijuana to swallowing THC. Smoking, they say, allows them to inhale just enough of the drug to relieve their symptoms. They also cite “the munchies”—well known among marijuana users and documented in laboratory studies of normal, healthy adults who gained both appetite and weight while using marijuana.5 Unfortunately, there have been no controlled studies to date on the benefits of marijuana smoking on appetite, weight gain, or body composition among people with HIV. In May 2000, Donald Abrams, a medical researcher at the University of California at San Francisco, completed the first controlled study of the short-term safety of smoked marijuana in HIV patients. The results showed that patients who smoked marijuana for 21 days did not show any increase in the HIV virus during the study period. Clearly, there is a need for medications that can prevent or restore the loss of lean tissues that occurs during AIDS wasting. Preliminary studies of anabolic compounds such as testosterone or growth hormone appear encouraging. Researchers are also investigating whether inhibitors of cytokines—chemical messengers believed to stimulate the inflammatory process that provokes cachexia—could be used to increase lean body mass. While marijuana derivatives do not appear to reverse cachexia, they could potentially form part of a combination treatment for wasting. For example, cannabinoid drugs might be used to boost patients' food consumption while they undergo physical therapy or take medications designed to increase the proportion of lean tissues in their bodies. PAIN In addition to appetite stimulation, marijuana-based medicines may prove helpful in treating a variety of painful symptoms associated with AIDS. In particular, many AIDS patients suffer

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy from neuropathic pain, a burning sensation of the skin that occurs spontaneously or is triggered by even the most gentle touch. While some AIDS patients report that smoking marijuana relieves neuropathic pain, that claim has not been confirmed by a clinical study. As discussed in the previous chapter, researchers have found THC to be moderately effective in treating cancer pain, which includes neuropathy. These results suggest that THC might also provide relief for AIDS-related pain. EFFECTS ON MOOD AIDS exacts a toll not only on the body but also on the emotions. Even patients whose disease is effectively controlled must deal with the side effects of medications and cope with having a chronic illness for the rest of their lives. Few escape feeling bereft or anxious from time to time, feelings that often coincide with depression. But some people with AIDS say that, when they use marijuana to relieve their pain or stimulate their appetite, they also improve their mood. Distinguishing between the medical use of marijuana to treat anxiety or depressed mood and the recreational pursuit of a “high” is not a simple matter, and some would say no such distinction exists. This is an especially thorny issue among AIDS patients, many of whom discover the drug's medical benefits through recreational experience. But there are also patients who, although they began using marijuana to relieve physical symptoms, have come to appreciate the psychological lift it provides. How often such appreciation of marijuana's psychological effects leads to dependence or abuse remains to be determined. THC, in the form of Marinol, has been found to produce psychological (as well as physiological) dependence in healthy people. But a recent study concluded that for AIDS and cancer patients euphoria was a “desirable side effect” of treatment with Marinol. The study, conducted at San Francisco 's Haight Ashbury Clinic, also found that Marinol has a low potential for abuse by patients and that the drug is rarely, if ever, diverted to the black market.6 Not everyone, though, reacts positively to marijuana and its active ingredients. Some—typically those who have never used

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy marijuana before—have reported that smoking marijuana or taking oral THC made them feel so uncomfortable that they never wanted to use either drug again. Rather than calming them, marijuana or THC seemed to make these people even more anxious; they also described feeling dizzy, disconnected from reality, even psychotic. According to medical marijuana advocates, such patients rarely experience adverse psychological reactions if they are given adequate guidance about what to expect before using marijuana for the first time. This claim has not been objectively tested, however. The fact that the psychoactive effects of marijuana vary widely from user to user must be anticipated among the potential side effects of any marijuana-based medicine. Unquestionably, marijuana compromises users' cognitive abilities but it remains to be determined whether long-term marijuana or cannabinoid use actually causes structural damage to the brain (see Chapter 3). REDUCING MARIJUANA'S RISKS While the possibility of cognitive impairment may deter some people with HIV from using marijuana-based medicines, this hazard pales in comparison to the health risks incurred by smoking marijuana. As discussed in Chapter 3, harmful smokeborne chemicals and contaminants in crude marijuana can represent a serious danger to anyone with a weakened immune system. Research indicates that people with HIV who regularly smoke marijuana suffer higher rates of opportunistic infections and Kaposi's sarcoma. Smoking is a very efficient way to get the active chemicals in marijuana into the bloodstream, but the long-term damage smoking causes makes it a poor drug delivery system, particularly for patients with chronic illnesses such as HIV. By comparison, oral cannabinoid preparations, such as Marinol, are slow acting and difficult to dose properly. A safe and effective alternative to both routes might be a smokeless inhaler that delivers cannabinoids in an easily absorbed aerosol spray. Such devices, which are already used to administer antihistamines and asthma medications, might

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy allow people with AIDS and other chronic conditions to benefit from marijuana's active ingredients. Both anecdotal evidence and scientific research suggest that cannabinoids could soothe a variety of symptoms suffered by AIDS patients: nausea, appetite loss, pain, and anxiety. Although more effective medicines than marijuana already exist to treat these conditions, they are not equally effective for all patients, nor do they offer the broad spectrum of relief that might be obtained from cannabinoid drugs. These will only become available, however, if there is sufficient financial incentive for pharmaceutical companies to produce marijuana-based medicines or if public funding supports similar research and development. The perils and possibilities of these alternatives are explored in Chapter 10. But what about the immediate needs of AIDS patients who have not found relief except by smoking marijuana? The IOM team suggested that people suffering from chronic conditions, including AIDS wasting, could be treated as participants in single-patient clinical trials, carefully monitored and conducted with institutional approval. Once admitted to such trials, patients would be permitted to smoke marijuana under medical supervision but only after being fully informed of their status as experimental subjects and of the harms inherent in using smoking as a delivery system. Each patient's condition would be closely monitored and carefully documented as long as he or she continued to use marijuana. In this way not only would AIDS patients be assured of receiving the best possible treatment, but their experiences would further medical knowledge of marijuana's risks and benefits. NOTES 1. Beal JE, Olson RLL, Morales JO, Bellman P, Yangco B, Lefkowitz L, Plasse TF, Shepard KV. 1995. “Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS.” Journal of Pain and Symptom Management 10:89-97. 2. Timpone JG, Wright DJ, Li N, Egorin MJ, Enama ME, Mayers J, Galetto G. 1997. “The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome.” The DATRI 004 Study Group. AIDS Research and Human Retroviruses 13:305-315.

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy 3. Beal JE, et al. 1995; Beal JE, Olson R, Lefkowitz L, Laubenstein L, Bellman P, Yangco B, Morales JO, Murphy R, Powderly W, Plasse TF, Mosdell KW, Shepard KV. 1997. “Long-term efficiency and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. ” Journal of Pain Management 14:7-14. 4. Struwe M, Kaempfer SH, Geiger CJ, Pavia AT, Plasse TF, Shepard KV, Ries K, Evans TG. 1993. “Effect of dronabinol on nutritional status in HIV infection.” Annals of Pharmacotherapy 27:827-831. 5. Foltin RW, Fischman MW, Byrne MF. 1988. “Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory.” Appetite 11:1-14; Mattes RD, Engelman K, Shaw LM, ElSohly MA. 1994. “Cannabinoids and appetite stimulation.” Pharmacology, Biochemistry and Behavior 49:187-195. 6. Calhoun SR, Galloway GP, Smith DE. 1998. “Abuse potential of dronabinol (Marinol).” Journal of Psychoactive Drugs 30:187-196.