Why sex alone cannot explain cannabis impairment or toxicity

Sex-related differences may influence the disposition and pharmacological effects of psychoactive substances. These differences are potentially relevant to forensic toxicology, where blood and tissue drug concentrations are interpreted in relation to impairment, toxicity, and cause of death in consequential medicolegal settings. However, the existing literature is a hodgepodge of often inconclusive or contradictory findings, and sex-related effects are frequently confounded by body size, age, tolerance, comorbidities, hormonal status, route of administration, drug-drug interactions, and gender-related behavioral or sociocultural factors. This review evaluates evidence for sex-related differences in the pharmacokinetics and pharmacodynamics of major psychoactive drug classes, including ethanol, sedative-hypnotics, cannabinoids, opioids, antidepressants, antipsychotics, and stimulants. Human studies were prioritized, while animal and mechanistic studies were used when human evidence was limited or when they clarified plausible biological mechanisms. Evidence was summarized according to biological mechanisms, drug classes, forensic relevance, and interpretive limitations. Literature supports the conclusion that biological sex may affect drug concentrations, metabolite patterns, adverse effects, and pharmacodynamic responses. The forensic relevance was identified for ethanol distribution, adverse effects of selected sedative-hypnotics such as zolpidem, opioids, QT-prolonging psychotropics, and polydrug fatalities. Nevertheless, current evidence does not support universal sex-specific correction factors for toxicological concentrations or deterministic conclusions about impairment or cause of death. Sex is accordingly best used as a contextual interpretive variable within a case-specific framework that incorporates pertinent other factors including measured concentration, specimen type, intake timing, route, tolerance, concomitant drugs, medical history, autopsy findings, and investigative circumstances.