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Gay Men's Health Crisis
Medical Marijuana: Research Priority, Hoax or Civil Right?
Elisa H. Nelan
January 15, 1997
GMHC Treatment Issues 1997 Jan 15; 11(1): 1

Medical marijuana, long a subject of interest to HIV-affected persons, has become the subject of broader national interest since the elections last November and the passage of two key voter initiatives, Propositions 215 and 200 in California and Arizona, respectively. The propositions reflect popular belief that anecdotal reports of the benefits of medical marijuana warrant legal permission for that use. Heated debates continue between proponents and opponents of medical marijuana at the community, state and national political levels. Although local and state drug laws vary, much of the current debate will be waged in the federal arena. The Clinton Administration has already threatened to penalize doctors who recommend marijuana; medical marijuana advocates in response are discussing First Amendment legal action; and as a result, the ultimate consequences of the California and Arizona voter initiatives remain clouded.

The federal government's anti-marijuana stance was first enunciated in 1937 (on the heels of Prohibition), when the Marihuana Tax Act made marijuana illegal for non-medical use. That law made the procurement of marijuana even for medical purposes so difficult that it was effectively removed from the pharmacopoeia. Marijuana ultimately was designated a Schedule I drug, meaning among other things that it lacks an accepted medical use and is unsafe even under medical supervision. Although there have been continuing reports of marijuana's use by people suffering pain and complications from such maladies as cancer, glaucoma and, more recently, AIDS, there has been a consistent official denial ever since of any potential medical benefit. This political atmosphere has largely prevented scientific research to test the benefits of smoking marijuana, despite research proposals by well-respected scientists and advocates. One concession on the part of the government was the creation in 1976 of a compassionate use program that permitted a few people (reportedly fewer than ten) to receive marijuana for medical use. By 1990, with the burgeoning of the AIDS crisis, the number of applicants to the program swelled. But in 1992 the Public Health Service totally dismantled the program.

Enter Marinol Marijuana's well known anti-nausea and appetite-stimulating effects did lead to some study of the drug as an anti-emetic and appetite stimulant in people with AIDS or cancer suffering from wasting.1 Since most of this effect was attributed to tetrahydrocannabinol (THC), the psychoactive component and best studied metabolite of marijuana, a synthetic version was designed. In clinical studies, synthesized THC was shown to increase appetite and help people gain weight.2,3,4,5,6 These findings led to the approval of the pharmaceutical grade THC, dronabinol (Marinol), in 1985 as a treatment for nausea and vomiting related to chemotherapy in people who failed on conventional anti-emetic treatments. Subsequent studies in people with AIDS led to the December 1993 FDA approval of Marinol for AIDS-related anorexia associated with weight loss.7 The key study that led to the AIDS indication was a double-blind study involving 139 persons with AIDS randomized to take either Marinol or placebo. Those taking Marinol were said to experience increased appetite, decreased nausea, and "trends toward improved body weight and mood." Long-term follow-up of 94 of these participants, who took open-label Marinol for approximately one year, indicated that appetite improvement was sustained over time. However, 17% dropped out of the study because of such side effects as dizziness, muddled thinking and drowsiness.8 Developers of Marinol tout the drug for its "purity" relative to marijuana, which contains many components other than THC. Yet it is precisely some of those other components or cannabinoids that certain researchers are interested in studying. Preliminary evidence suggests that the other cannabinoids help confer the benefits experienced by people who smoke (or eat) marijuana compared to those taking Marinol. There are no actual human trials, though, to confirm this hypothetical superiority of marijuana over Marinol. Ironically, the manufacturers of Marinol note that there have been over 25 human clinical trials of Marinol but no clinical trials of smoked marijuana's safety or efficacy, apparently implying that this lack is an indication of Marinol's superiority.9 Marijuana vs. Marinol Marinol itself is not for everyone. According to Lester Grinspoon, M.D., of the Harvard Medical School and author of Marihuana: the Forbidden Medicine, (Yale University Press, 1993) "Marijuana has distinct advantages over Marinol, for a number of reasons. First, Marinol must be swallowed. Obviously, some people with nausea and vomiting, one of the indications for Marinol, may be unable to ingest it. Second, Marinol is subject to huge bioavailability variations, between individuals, but also shifting day to day for the same person. It's very difficult to define appropriate doses for the individual. Third, the therapeutic value of marijuana is dependent on many other cannabinoids than THC (which is all Marinol is). In my experience, people given a choice consistently choose marijuana over Marinol. Fourth, marijuana has an immediate effect, which is what people with migraines or epilepsy, for example, want. In contrast, the effects of Marinol may not be felt for one to two to three hours after taking it. Fifth, people smoking marijuana rarely report anxiety, whereas people taking Marinol more frequently do. This is because THC taken alone leads to anxiety. Cannabidiol, which one ingests along with THC and other cannabinoids when consuming marijuana, has an anti-anxiety effect. Finally, Marinol costs significantly more. Even at the street price inflated by what I call the prohibition tariff, marijuana is much less expensive. If it were government-approved, it would become far less expensive than it is presently; I estimate that an ounce might cost $25-30, so that a marijuana cigarette would be about 30 cents. And this is actually one of the problems: marijuana would never be a money-making proposition, and, since it would replace more expensive pharmaceuticals, the pharmaceutical industry stands to lose.

"In the new edition of our book Marijuana: the Forbidden Medicine, we list about 30 medicinal uses for marijuana. For example, the new antiemetic drug ondansetron costs $120 to $160 for oral administration but, because of nausea and vomiting, often requires IV administration which raises the cost to $600. If marijuana were legal and available for use with chemotherapy, you could prescribe someone to smoke a marijuana cigarette about 20 minutes before their cancer treatment -- at a cost of $0.30. That would prevent nausea just as well. Even if marijuana therapy was reimbursable under a patient assistance program, the extreme low cost would hardly endanger payment for other treatments."10 Although Marinol is generally well tolerated, some people report intolerable levels of psychotropic side effects, i.e., an unacceptably "stoned" feeling. To ameliorate this effect, there have been suggestions that an anti-emetic drug called prochlorperazine could be used in combination with Marinol.11 However, many people report that the individualized dosing and administration schedule permitted by smoking marijuana easily prevents the ill effects associated with Marinol. Still other people with AIDS, who cannot take Marinol or other oral antinausea medications because of gastrointestinal difficulties (like the severe vomiting giving rise to the need for the medication in the first place), report that they can better achieve the desired antinausea benefits from smoking.

Marijuana, Wasting and TNF Although people with HIV/AIDS have used marijuana for diverse reasons, including relief of pain and nausea, one of the most prominent reasons for use is appetite stimulation, especially by those with wasting. However, wasting or cachexia is not simply a loss of weight or appetite; various factors and mechanisms contribute to the syndrome. One of the most significant factors in AIDS-related wasting is a disproportionate loss of lean body mass (muscle). A syndrome with a complex etiology, wasting may occur even in spite of an apparently adequate dietary intake. Recombinant human growth hormone (Serostim, manufactured by Serono) is the only approved drug that has been shown to increase lean muscle mass (with the possible exception of anabolic steroids), but its exorbitantly high price currently renders it a non-option for many HIV-infected people.

Tumor necrosis factor alpha (TNFa), which the immune system produces as part of the inflammatory response to infection, plays a particular role in the development of wasting -- by contributing to lean body mass destruction -- and in a number of other chronic disease-related conditions.12,13,14 TNFa also stimulates HIV proliferation.15 There are no studies that establish that reducing TNFa levels, which are notoriously difficult to measure, will be beneficial in people with HIV. Researchers nevertheless have been pressing ahead to find ways to reduce those levels. Among other agents, THC has been shown to reduce TNFa in the test tube. In a study involving macrophages exposed to the excitory cytokine interferon gamma (IFNg) along with bacterial lipopolysaccharides (LPS), the addition of THC to the mix was shown to impair macrophage activation. The macrophages altered their responses to normal "triggers" like IFNg and LPS by failing to carry out their normal sequential expression of various proteins. One of the proteins the THC-exposed macrophages were unable to express was TNFa.16 Another study looked specifically at the effect of "physiologically relevant" concentrations of THC on TNFa synthesis by human large granular lymphocytes (LGL), a type of white blood cells Researchers found that THC decreased two primary LGL functions, TNFa production and anti-tumor activity.17 But other components of marijuana may also be involved in reducing undesirable inflammatory factors. Cell culture studies show that the essentially nonpsychoactive cannabidiol (CBD), in particular, potently reduces levels of TNFa as well as IL-1,18,19 another inflammatory white blood cell secretion involved in wasting and HIV replication.20 Watzl and others studied the in vitro effects of both psychoactive and nonpsychoactive components of marijuana on white blood cells. They found that concentrations of THC and CBD comparable to what would be found in the blood after smoking marijuana decreased cells' secretion of IL-1 and TNFa, increased IFNg and had no effect on IL-2. The effect of these other marijuana constituents on TNFa especially provides a rationale for the clinical evaluation of marijuana in people with AIDS-related wasting.

Objections to Smoking An often raised concern is the potential hazards of smoking any substance. Donald Kotler, M.D., an expert on AIDS-related wasting at New York's St. Luke's Roosevelt Hospital, feels that medical marijuana use by people with AIDS may be helpful, but cautions that research into the possible health hazards of smoking in people with AIDS (e.g., the risk of pneumonia), is highly desirable. Dr. Grinspoon points out that it is not exposure to THC and other cannabinoids that is at issue, but rather the burning of the vegetative or plant matter. The combustion process creates problems with noxious substances like tar and carcinogens, whether tobacco or marijuana is smoked. He emphasizes that the average medical marijuana smoker would be exposed to far fewer toxic byproducts, relative to a tobacco smoker, since she or he would be smoking very few "cigarettes." "Doctors don't like smoking, "said Dr. Grinspoon, "but it would be a simple matter to develop a vaporizing gadget for medical marijuana use that would obviate smoking-related hazards. And, speaking of financial incentives, unlike marijuana itself, which no one can patent, they definitely can patent medical devices developed to better administer it." Conducting Further Research The time is ripe for legitimate scientific research into these questions. Perhaps more than any other US researcher, Donald Abrams, M.D., of San Francisco is intimately acquainted with the difficulties of actually accomplishing this goal. His proposed study of smoked marijuana in people with AIDS has been stymied by the Drug Enforcement Agency and National Institute of Drug Abuse (NIDA),21 and the story of Abrams' attempts and the government's responses has been widely publicized over the past several months (for background, see Treatment Issues, May, 1995). His research protocol for a pilot study of smoked marijuana, approved by the Food and Drug Administration and Dr. Abrams' local Independent Review Board (IRB), was blocked by NIDA in April, 1995 and again this summer by a National Institutes of Health grant review committee. That study may get another hearing. An addiction research team at Brown University is reviewing the rejected research grant application, and collaborative meetings soon will be held to discuss strategies for meeting a May, 1997 reapplication deadline.

The federal government meanwhile continues with its anti-marijuana strategy, but that strategy now appears to be subtly softening. Clinton Administration "Drug Czar" Barry McCaffrey, a retired Army general, only this month backpedaled from his previous assertions that medical marijuana was a "cruel hoax" with no medical benefit to announce that the federal government will spend $1 million dollars on a meta-analysis of existing research on potential benefits. At a January 13 press conference, Gen. McCaffrey went further, stating, "There's an open door to approval for any substance that provides proven benefits." With all the marijuana studies so far conducted in the test tube rather than in human beings, one wonders how Barry McCaffrey's meta-analysis could possibly prove marijuana's benefits. Dr. Grinspoon believes that the government cannot ignore established anecdotal evidence, especially the vast amounts that exist for marijuana. But others feel that many questions remain that can only be resolved by further research. Dr. Kotler, for one, thinks that marijuana may be good medicine for some people, but adds, "The word of the day is combination therapy. If things aren't going well nutritionally, then relying on marijuana is probably not a comprehensive enough plan of attack." Exactly how marijuana fits into an overall regimen against HIV infection and its manifestations is still undetermined.

References: 1 Doblin RE and Kleinman MA. Journal of Clinical Oncology. July, 1991:9(7): 1314-9.

2 Beal JE, et al. Journal of Pain & Symptom Management. February, 1995:10(2): 89-97.

3 Lane M et al. Journal of Pain & Symptom Management. August 1991:6(6):352-9.

4 Cat LK and Colemann RL et al. Annals of Pharmacotherapy. May 1994:28(5):595-7.

5 Nelson K et al. Journal of Palliative Care. Spring 1994-19(1):14-8.

6 Gorter R et al. AIDS. January 1992; 6(1):127.

7 Roxane Laboratories, Inc. Marinol product information.

8 Beal JE et al. IX International Conference on AIDS. June 1993; PO-B36-2354.

9 Roxane Laboratories, Inc. op cit.

10 Grinspoon L. Personal communication. January 1997.

11 Plasse TF et al. Pharmacology, Biochemistry and Behavior. November 1991; 40(3):695-700.

12 Gearing AJ et al. Nature. August 18, 1994; 370(6490):555-7.

13 Llovera M et al. Journal of the National Cancer Institute. August 18, 1993; 85(16):1334-9.

14 Espat et al. Surgical Oncology. October 1994;3(5):255-62.

15 Goletti D et al. Journal of Virology. April 1995;69(4):2540-6.

16 Cabral GA and Fischer-Stenger K. Life Sciences. 1994; 54(23):1831-44.

17 Kusher DI et al. Cellular Immunology. March 1994;154(1):99-108.

18 Watzl B et al. International Journal of Immunopharmacology. 1991;13(8):1091-7.

19 Watzl B et al. Advances in Experimental Medicine and Biology. 1991;288:63-70.

20 Strassman G et al. Journal of Immunology. March 15; 150(6)2341-5.

21 Abrams D et al. The New England Journal of Medicine. September 7, 1995;333(10):671.

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