Same dose, different impact: acute cannabis intoxication impairs visuospatial working memory in both sexes, with disproportionate male vulnerability

Introduction – With expanding global cannabis legalization and rising usage rates, elucidating the specific neurocognitive impact of acute cannabis intoxication across biological sexes is critical. Methods – Using a 2 × 2 factorial design, we examined 154 adults: 77 individuals who use cannabis regularly (≥ 5 days/week for ≥ 1 year; 46 males, 31 females) and 77 matched controls (32 males, 45 females). Participants completed standardized Wechsler Memory Scale subtests assessing four distinct memory domains during the peak pharmacokinetic window (45 min post-consumption of medical-grade cannabis: 16.1% THC, < 1% CBD). Results – Results demonstrated notable neuropsychological specificity: visuospatial working memory was selectively impaired, whereas auditory-verbal and short-term memory domains remained completely intact—a pattern strongly implicating disruption of fronto-parietal networks rich in CB1 receptors. Crucially, a significant Group × Sex interaction, F(1, 150) = 9.74, p < 0.01, ηp² = 0.061, revealed differential vulnerability: males exhibited a disproportionately larger deficit relative to male controls (Cohen’s d = −0.87, p < 0.001)—nearly double the impairment magnitude observed in females (d = −0.48, p < 0.05). Discussion – These findings advance our understanding of cannabis neuropharmacology by demonstrating that cognitive vulnerability is both domain-specific and sex-dependent, with direct implications for precision medicine approaches to cannabis therapeutics and sex-informed harm reduction strategies.