Association between cannabis use and brain imaging phenotypes in UK Biobank: an observational and Mendelian randomization study

Cannabis use during adolescence and young adulthood has been associated with brain structure and functional connectivity. However, despite a rapid increase in cannabis use among older adults in the past decade, the impact on brain structure and function in this population remains understudied. We examined 3,641 self-reported lifetime cannabis users (mean age = 61.00 years, standard deviation (SD) = 7.16) and 12,255 controls (mean age = 64.49 years, SD = 7.58) from the UK Biobank. Brain imaging-derived phenotypes (IDPs) were used as measures of structural and functional connectivity. Associations with cannabis use were assessed using multiple linear regression while controlling for potential confounders. After correcting for false discovery rate (FDR) for multiple testing, in exploratory analyses significant associations were observed with diffusion metrics in the genu of the corpus callosum and with resting-state functional connectivity (rsFC) between the default mode, central executive, and salience networks. Hypothesis-driven analyses did not show any significant association between cannabis use and hippocampal or amygdala volumes. Furthermore, mendelian randomization (MR) analyses did not support a causal relationship between cannabis use and brain structure or function. Our findings indicate that associations between lifetime cannabis use and later life brain structure and function are not likely causal in nature. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was undertaken using UK Biobank application numbers 55929 & 8107. Saba Ishrat is supported by the Society for the Study of Addiction (Registered Charity No. 1009826) and Anya Topiwala by a Wellcome Trust Clinical Research Career Development Fellowship (216462/Z/19/Z). The Wellcome Centre for Integrative Neuroimaging is supported by core funding from the Wellcome Trust (203139/Z/16/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank data was openly available before the initiation of the study and they can be located by the following link: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at: