Tolerance to chronic delta-9-tetrahydrocannabinol (Δ⁹-THC) in rhesus macaques infected with simian immunodeficiency virus.

Although Delta(9)-THC has been approved to treat anorexia and weight loss associated with AIDS, it may also reduce well-being by disrupting complex behavioral processes or enhancing HIV replication. To investigate these possibilities, four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure, and administered vehicle or Delta(9)-THC before and after inoculation with simian immunodeficiency virus (SIVmac251, 100 TCID50/ml, i.v.). Prior to chronic Delta(9)-THC and SIV inoculation, 0.032-0.32 mg/kg of Delta(9)-THC produced dose-dependent rate-decreasing effects and small, sporadic error-increasing effects in the acquisition and performance components in each subject. Following 28 days of chronic Delta(9)-THC (0.32 mg/kg, i.m.) or vehicle twice daily, delta-9-THC-treated subjects developed tolerance to the rate-decreasing effects, and this tolerance was maintained during the initial 7-12 months irrespective of SIV infection (i.e., +THC/-SIV, +THC/+SIV). Full necropsy was performed on all SIV subjects an average of 329 days post-SIV inoculation, with postmortem histopathology suggestive of a reduced frequency of CNS pathology as well as opportunistic infections in delta-9-THC-treated subjects. Chronic Delta(9)-THC also significantly reduced CB-1 and CB-2 receptor levels in the hippocampus, attenuated the expression of a proinflammatory cytokine (MCP-1), and did not increase viral load in plasma, cerebrospinal fluid, or brain tissue compared to vehicle-treated subjects with Sly. Together, these data indicate that chronic Delta(9)-THC produces tolerance to its behaviorally disruptive effects on complex tasks while not adversely affecting viral load or other markers of disease progression during the early stages of infection.