Sex differences in the subjective and reinforcing effects of smoked cannabis.

Preclinical studies have shown sex-based differences in the reinforcing effects of cannabinoid 1 receptor agonists such as delta-9-tetrahydrocannabinol (THC). This study sought to test whether these sex differences translate to humans by assessing the subjective and reinforcing effects of smoked cannabis in male and female volunteers. We pooled data (n = 68; 55M, 13F) from two within-subject randomized controlled trials of healthy, ≥weekly cannabis users comparing the subjective and reinforcing effects of smoked active (~25 mg THC) versus placebo cannabis (0-mg THC). Subjective ratings of drug effects and mood were measured using visual analogue scales, and reinforcing effects were measured with a cannabis self-administration task. Sex-dependent outcomes were explored using generalized linear mixed models. Under active cannabis conditions, female participants reported greater reductions from baseline in cannabis craving and significantly higher cannabis-specific ratings of strength, liking, willingness to take again and good effect, compared with males (interaction p < 0.05). Placebo and active cannabis were self-administered by 22% and 36% of male participants, respectively, and by 15% and 54% of female participants, respectively. Receipt of active cannabis significantly increased likelihood of self-administration (p = 0.011), but a sex difference was not detected (p = 0.176). Although females were more sensitive to certain positive subjective effects of active cannabis, they were not more likely than males to self-administer it. These findings highlight the need to test sex differences as a primary objective in experimental studies and may shed light on accelerated trajectories from initiation to cannabis use disorder observed among women.