Abstract
BACKGROUND: Cannabis use during adolescence and young adulthood has been associated with brain harm, yet despite a rapid increase in cannabis use among older adults in the past decade, the impact on brain health in this population remains understudied. OBJECTIVE: To explore observational and genetic associations between cannabis use and brain structure and function. METHODS: We examined 3641 lifetime cannabis users (mean (SD) age 61.0 (7.1) years) and 12 255 controls (mean (SD) age 64.5 (7.5) years) from UK Biobank. Brain structure and functional connectivity were measured using multiple imaging-derived phenotypes. Associations with cannabis use were assessed using multiple linear regression controlling for potential confounds. Bidirectional two-sample Mendelian randomisation analyses were used to investigate potential causal relationships. FINDINGS: Cannabis use was associated with multiple measures of brain structure and function. Participants with a history of cannabis use had poorer white matter integrity, as assessed by lower fractional anisotropy and higher mean diffusivity in the genu of the corpus callosum, as well as weaker resting-state functional connectivity in brain regions underlying the default mode and central executive networks. Mendelian randomisation analyses found no support for causal relationships underlying associations between cannabis use and brain structure or function. CONCLUSIONS: Associations between lifetime cannabis use and brain structure and function in later life are probably not causal in nature and might represent residual confounding. CLINICAL IMPLICATIONS: Cannabis use is associated with differences in brain structure and function. Further research is needed to understand the mechanisms underlying these associations, which do not appear to be causal.