Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection

Context Because the same systems metabolize cannabinoids and protease inhibitors, cannabinoids might alter viral loads in HIV-infected patients taking protease inhibitors. Contribution In this randomized trial, 62 HIV-infected patients taking indinavir or nelfinavir received a marijuana cigarette, dronabinol capsule, or placebo capsule three times daily for 21 days. Half of the patients in all three groups had undetectable viral loads during the study, and average changes in viral load with marijuana and dronabinol, relative to placebo, were small. Cautions The findings of no large harmful effects on viral loads with either smoked or oral cannabinoids need to be confirmed in larger and longer trials. The Editors Marijuana has been smoked for medicinal purposes for centuries (1). Introduced into western medicine in 1842, marijuana was used to treat various illnesses on the basis of its purported analgesic, anticonvulsant, sedative, hypnotic, and antispasmodic properties. With the passage of the Marihuana Tax Act in 1937, use of marijuana as a therapeutic agent in the United States waned until the substance was removed from the U.S. Pharmacopoeia in 1942. The Controlled Substances Act of 1970 placed marijuana in the Schedule I category along with other substances deemed to have no medicinal value and high potential for abuse. In 1986, the U.S. Food and Drug Administration approved a synthetic, oral form of marijuana's main psychoactive component, delta-9-tetrahydrocannabinol (dronabinol, Marinol, Roxane Laboratories, Columbus, Ohio), for treating chemotherapy-induced nausea and vomiting (2-5). A randomized, controlled trial demonstrated that dronabinol increased self-reported appetite but not weight in patients with AIDS-related wasting syndrome; these findings led to an expansion of the labeling indication for this use in 1992 (6, 7). Before the advent of highly active antiretroviral therapy in the 1990s, many patients infected with HIV-1 experienced wasting as a preterminal manifestation of the disease (8). Patients with AIDS-related wasting syndrome often reported that they preferred smoked marijuana to dronabinol because it was easier to titrate the dose to achieve the desired effect; smoked marijuana delivers cannabinoids to the bloodstream much more rapidly than dronabinol (9). By the mid-1990s, cannabis buyers' clubs in the San Francisco Bay area were reportedly selling marijuana to 11 000 patients with HIV infection (10-12). With the increased availability of protease inhibitorcontaining antiretroviral regimens in the mid-1990s, the incidence of AIDS-related wasting syndrome decreased markedly, as did most of the other late-stage opportunistic manifestations of advanced HIV disease (13-15). Protease inhibitors, which can inhibit or stimulate the hepatic cytochrome P-450 enzyme system, are subject to many significant drugdrug interactions with other agents used in treating HIV infection and its complications (16, 17). The potential for a drugdrug interaction between protease inhibitors and marijuana is worrisome since many HIV-infected patients continue to smoke marijuana as an appetite stimulant or to decrease nausea associated with their antiretroviral therapy (18, 19). The likelihood of such an interaction is supported by the facts that cannabinoids are metabolized by some of the same cytochrome P-450 enzyme isoforms that metabolize the more widely prescribed protease inhibitors and that tetrahydrocannabinol has been shown to inhibit the metabolism of other drugs (20-23). Although few recent clinical trials have evaluated the potential therapeutic effects of smoked marijuana, significant progress has been made in understanding the pharmacology of cannabinoids in humans. Of the two cannabinoid receptors identified, CB1 (found mainly in cells of the central nervous system) is thought to be responsible for the neurologic and behavioral effects of marijuana (24, 25). The identification of a CB2 receptor, found predominantly on B lymphocytes and natural killer cells, suggests that cannabinoids may also affect the immune response. Some studies suggest that marijuana can impair the immune system through B-lymphocyte modulation, tumor necrosis factor inhibition, or changes in the phenotype and function of circulating lymphocytes (26-29). The hallmark of successful antiretroviral therapy is sustained suppression of HIV RNA levels associated with increasing CD4+ cell counts (30-32). Considering the potential for both a protease inhibitorcannabinoid interaction and an effect of smoked marijuana on the immune system, we designed a study to determine the safety or toxicity profile of cannabinoids (smoked and oral) in persons with HIV infection. We chose HIV RNA levels as our primary outcome because an intervention that interacted unfavorably with either the antiretroviral agent pharmacokinetics or the immune system directly could cause a perturbation of viral suppression. We report the overall safety results of this randomized, controlled inpatient clinical trial. Methods Study Group Study participants were recruited by referrals from local physicians and advertisements in newspapers. Volunteers from across the country telephoned to determine whether they might be eligible to participate. Participants were required to be at least 18 years of age, have documented HIV infection, and be receiving a stable antiretroviral treatment regimen of either indinavir (Crixivan, Merck & Co., Inc., North Wales, Pennsylvania) or nelfinavir (Viracept, Agouron Pharmaceuticals, Inc., La Jolla, California) for at least 8 weeks before enrollment. When enrolled, participants who had been taking the recently recommended dose of nelfinavir, 1250 mg twice daily, were switched to 750 mg three times daily for consistency of our pharmacokinetic evaluations (33). No additional protease inhibitors were allowed for the duration of the study. Participants were also required to have a stable viral load, defined as less than a threefold (0.5 log10) change in HIV RNA level for the 16 weeks before enrollment. All participants were required to have previous experience smoking marijuana (defined as six or more times) to ensure that they knew how to inhale and what neuropsychiatric effects to expect. The institutional review board of the University of California, San Francisco, approved the study, and signed, informed consent was obtained from each participant before enrollment. Exclusion criteria included any active opportunistic infection or malignant condition requiring acute treatment, unintentional loss of 10% or more of body weight during the previous 6 months, current substance dependence ascertained by completion of a confidential drug screening form and an alcohol screening form, methadone maintenance, use of tobacco or cannabinoids (smoked or oral) within 30 days of enrollment, history of serious pulmonary disease, pregnancy, or stage II or higher AIDS dementia complex. Laboratory exclusion criteria were hematocrit less than 0.25 and elevation of hepatic aminotransferase levels to greater than five times the upper limit of normal. Therapeutic exclusions were concurrent use within the past 8 weeks of anabolic hormones, prednisone, interleukin-2, or other agents known to alter immune system function. Study Medications The National Institute on Drug Abuse provided prerolled marijuana cigarettes, weighing on average 0.9 g and containing 3.95% delta-9-tetrahydrocannabinol. These cigarettes were kept in a locked and alarmed freezer until they were dispensed to a locked freezer in the General Clinical Research Center at the San Francisco General Hospital, where the inpatient study was conducted. The frozen marijuana cigarettes required rehydration overnight in a humidifier. Participants randomly assigned to the smoked marijuana group were housed in a room with a fan ventilating to the outside. To maximize standardization of inhaled doses, research staff monitored participants while they followed the uniform puff procedure outlined by Foltin and colleagues (34). Research staff weighed the marijuana cigarettes immediately before and after they were administered to participants and returned all leftover material to the pharmacy. Study participants smoked up to three complete marijuana cigarettes daily, as tolerated, 1 hour before meals. Study participants were randomly assigned in a double-blind fashion to the oral regimens, which were given on the same schedule as the smoked marijuana. Research staff observed participants taking all treatments. Research Design and Procedures Study clinicians admitted study participants to the General Clinical Research Center for a 4-day lead-in period to obtain baseline variables. A urine sample obtained on the day of admission (day 4) had to be negative for tetrahydrocannabinol. The second phase of the trial was a 21-day intervention period beginning with random assignment of treatments on day 0. Patients were stratified by protease inhibitor (indinavir or nelfinavir) and then allocated with equal probability in blocks of 12 to the study agents (marijuana, dronabinol, and placebo). The statistician generated the random allocation sequences, and the pharmacists maintained the sequences in a secure location and distributed the assignments to the study coordinator on day 0. Study participants were not permitted to have visitors or to leave the General Clinical Research Center unless accompanied by research personnel during the 25-day study. All clinical laboratory tests and study procedures were obtained or performed in the center. Patients were weighed on the same calibrated scale each morning while wearing a hospital gown. Baseline blood specimens were collected on days 4 and 0 to examine within-participant variation in HIV RNA level in the absence of experimental therapies. Follow-up specimens were obtained on days 2, 5, 8, 11, 14, 17, 19, and 21. Samples were stored at 70 C and batch-tested for HIV RNA at the end of