Sex- and frequency-dependent acute pharmacokinetic and pharmacodynamic effects of smoked cannabis: a randomized controlled trial

Cannabis use is rising among women. Studies suggest females are more sensitive to the intoxicating and misuse-related effects of delta-9-tetrahydrocannabinol (THC). While preclinical studies point to sex-specific development of tolerance, this has not been translated to humans. In this randomized, double-blind, placebo-controlled crossover study, 44 participants (22 F) smoked three cannabis strengths (0% [~0 mg] THC, 4% [~20 mg] THC, 10% [~60 mg] THC), provided blood for plasma analysis, and completed subjective mood and drug effects assessments and a self-administration task. Outcomes were analyzed by cannabis strength, sex, and use frequency ( > 4 vs. ≤4 days/week; balanced across sex). Relative to placebo, active cannabis strengths increased subjective effects and plasma THC and metabolites (ps < 0.05). Exploratory follow-up of interactions (cannabis strength*frequency p < 0.10) showed the frequent-use group exhibiting significant increases from placebo in misuse-related ratings ("Like", "Take again") and self-administering more cannabis than the occasional-use group (ps < 0.05), and this was not modified by sex. Ratings of "High", Sedation/impairment, Dysphoric arousal, and "Bad effect" were higher at active strengths for occasional-use males relative to sex- and/or frequency-matched counterparts (ps < 0.05; via exploratory follow-up for "High" and Sedation/impairment). THC and metabolites tended to be highest in frequent-use males. These findings contrast with previous evidence of greater cannabis sensitivity among females and point toward future investigation into sex-dependent exposure thresholds for tolerance development/escalation. Sex and frequency of use are both implicated in cannabis use disorder risk, and consideration of their interaction is critical in characterizing the acute effects of, and tolerance to, cannabis.