In 1986, the Food and Drug Administration approved a synthetic, oral form of marijuana's main psychoactive component, delta-9-tetrahydrocannabinol (dronabinol) for treating chemotherapy-induced nausea and vomiting. A randomized, controlled trial demonstrated that dronabinol increased self- reported appetite but not weight in patients with AIDS-related wasting syndrome, leading to an expansion of the labeling indication for this use in 1992. Patients with AIDS-related wasting syndrome, a preterminal manifestation of AIDS before the advent of highly active antiretroviral therapy, often reported they preferred smoked marijuana to dronabinol because it was easier to titrate the dose to achieve the desired effect.

With the increased availability of protease inhibitor- containing antiretroviral regimens in the mid-1990s, the incidence of AIDS-related wasting syndrome decreased markedly. Protease inhibitors, which can inhibit or stimulate the hepatic cytochrome P-450 enzyme system, are subject to many drug-drug interactions, and the potential for drug-drug 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.

Considering the potential for both a protease inhibitor- cannabinoid interaction and an effect of smoked marijuana on the immune system, the authors designed this study to determine the safety or toxicity profile of cannabinoids (smoked or oral) in persons with HIV infections. They chose HIV RNA levels as the 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.

Study participants were required to be at least 18 years old, have documented HIV infection, and be receiving a stable antiretroviral treatment regimen of either indinavir or nelfinavir for at least eight weeks before enrollment. 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.

Of the 69 study participants admitted to the inpatient study unit, 67 were randomly assigned between May 1998 and May 2000. Thirty-seven patients were receiving nelfinavir-containing regimens and 30 patients were receiving indinavir-containing regiments. Of these, three and two patients, respectively, left the study prior to the pharmacokinetic analysis on day 14. The remaining 62 participants completed the 21-day inpatient intervention and were eligible for all end points (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Participants were randomly assigned to a 3.95 percent-tetrahydrocannabinol marijuana cigarette, a 2.5 mg dronabinol capsule, or a placebo capsule three times daily before meals.

Most patients were men (89 percent) older than age 40 (68 percent), and half were of nonwhite ethnicity. More patients in the marijuana and dronabinol groups than in the placebo group had previous AIDS diagnoses and detectable HIV RNA than in the placebo group. Overall, 58 percent had undetectable HIV RNA levels (<50 copies/mL); only five patients had HIV RNA levels greater than 10,000 copies/mL, four of whom were receiving nelfinavir-containing regimens. Baseline CD4+ and CD8+ cell counts were similar in all groups.

Over the 21-day follow-up period, increases in CD8+ cell counts were on average 20 percent (CI, 7 percent to 38 percent) greater for patients receiving marijuana than for patients receiving placebo, and marginally greater (10 percent [CI, -5 percent to 29 percent]) for patients receiving dronabinol than for those receiving placebo. In the adjusted repeated-measures model, the cannabinoid effects were similar (lower confidence bounds: marijuana group, 4 percent; dronabinol group, -3 percent). An analysis of expanded immune system phenotypes and functions revealed few statistically significant effects.

The study provides evidence that short-term use of cannabinoids, either oral or smoked, does not substantially elevate viral load in individuals with HIV infection who are receiving stable antiretroviral regimens containing nelfinavir or indinavir. Neither CD4+ nor CD8+ cell counts seemed to be adversely affected by the cannabinoids during the study; lower confidence bounds on estimated cannabinoid effects typically exceeded 0, indicating benefit rather than harm. The short- duration clinical trial suggests acceptable safety in a vulnerable immune- compromised patient population. "Further studies investigating the therapeutic potential of marijuana and other cannabinoids in patients with HIV infection and other populations are ongoing and should provide additional safety information over longer exposure periods," determined the authors.

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