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Background: The primary psychoactive ingredient in cannabis interacts with the endocannabinoid system, which declines with age and may alter cannabis-related effects in older adults. Animal studies suggest age-related differences in cannabis responses, though findings are mixed. Importantly, biological sex modifies the endocannabinoid system, which complicates interpreting age-related effects.Objective: This study examined how age and sex jointly influence cannabis-related outcomes in middle-aged and older adults.Methods: Self-reported measures of cannabis use behaviors, memory, mental and physical health, cannabis use disorder (CUD) symptom severity, and sleep quality were collected from 107 adults (age range = 35-78, 54 females) who use cannabis. Partial correlations examined associations between age and outcomes controlling for years of use. Self-reported biological sex was assessed as a moderator.Results: Regression analyses revealed a significant age × sex interaction for both CUD symptoms and mental health scores. Among females, CUD symptom severity decreased with age (b = -0.20, p = .03), and mental health scores improved (b = 0.59, p = .04); these age-related effects were not observed in males. Sensitivity analyses suggested that participants reporting medical-only cannabis use may exhibit a steeper age-related decline in CUD symptom severity than those reporting recreational-only use (b = 1.31, 95% CrI: -1.99 to 4.54) or hybrid use (b = 0.62, 95% CrI: -2.76 to 3.98).Conclusions: These findings suggest that factors such as sex and reason for cannabis use may be important for understanding cannabis safety profiles in aging populations and may inform individualized clinical care.