Effects of Δ9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism.
A family history (FH) of alcoholism accounts for approximately 50% of the risk of developing alcohol problems. Several lines of preclinical evidence suggest that brain cannabinoid receptor (CB1R) function may mediate the effects of alcohol and risk for developing alcoholism including the observations that reduced CB1R function decreases alcohol-related behaviors and enhanced CB1R function increases them. In this first human study, we probed CB1R function in individuals vulnerable to alcoholism with the exogenous cannabinoid Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Healthy volunteers (n 30) participated in a three test day study during which they received 0.018 and 0.036 mgkg of Δ(9)-THC, or placebo intravenously in a randomized, counterbalanced order under double-blind conditions. Primary outcome measures were subjective high, perceptual alterations, and memory impairment. Secondary outcome measures consisted of stimulatory and depressant subjective effects, attention, spatial memory, executive function, Δ(9)-THC and 11-hydroxy-THC blood levels, and other subjective effects. FH was calculated using the Family Pattern Density method and was used as a continuous variable. Greater FH was correlated with greater high and perceptual alterations induced by Δ(9)-THC. This enhanced sensitivity with increasing FH was specific to Δ(9)-THCs rewarding effects and persisted even when FH was calculated using an alternate method. Enhanced sensitivity to the rewarding effects of Δ(9)-THC in high-FH volunteers suggests that alterations in CB1R function might contribute to alcohol misuse vulnerability.