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, η p 2 = 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.