AIMS: An effective medication for cannabis use disorder (CUD) has yet to be identified. Evidence of sex differences in the behavioral and biological correlates of CUD suggests that personalized treatment approaches may improve outcomes. This study examined whether sex and medication type influenced treatment response across multiple clinical trials for CUD.

METHODS: Data were pooled from five randomized, controlled medication trials (N = 570; 179 females); primary outcome data was available for N = 382 participants (125 females). Medications were grouped by primary mechanism of action: glutamatergic, serotonergic, or nicotinic. Primary outcomes during the final four weeks of treatment were at least a 75% reduction in cannabis use amount, 50% reduction in weekly use days, and abstinence, assessed by self-report and urine drug testing. Propensity score weighted models evaluated overall treatment response (active vs. placebo), sex differences, and whether sex moderated outcomes by medication category.

RESULTS: Males were overall more likely than females to achieve self-reported abstinence (p = 0.012), particularly when receiving active medication (p < 0.001). These sex differences were driven mainly by trials involving nicotinic (p = 0.01) and serotonergic (p = 0.048) medications. Urine-confirmed abstinence showed a similar pattern, with males on active medication demonstrating higher abstinence rates than females (p = 0.004). Greater reductions in cannabis use were also observed among males receiving active medication (p < 0.001), again primarily in nicotinic (p = 0.001) and serotonergic (p = 0.04) trials.

CONCLUSIONS: Males exhibited more positive responses to candidate CUD medications, especially those targeting nicotinic and serotonergic mechanisms. These findings highlight the importance of investigating sex-specific biological mechanisms and developing more effective treatments for women.