BackgroundPrevious studies have reported inconsistent results regarding the potential relationships between addictive behaviors and the risk of epilepsy. ObjectiveTo assess whether genetically predicted addictive behaviors are causally associated with the risk of epilepsy outcomes. MethodsThe causation between five addictive behaviors (including cigarettes per day, alcoholic drinks per week, tea intake, coffee intake, and lifetime cannabis use) and epilepsy was evaluated by using a two-sample Mendelian Randomization (MR) analysis. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (MR Egger, weighted median, simulation extrapolation corrected MR-Egger, and Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO)) were performed to complement IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. ResultsThe IVW analysis method indicated an approximately 20% increased risk of epilepsy per standard deviation increase in lifetime cannabis use (odds ratio [OR], 1.20; 95% confidence interval [CI]), 1.02–1.42, P = 0.028). However, there is no causal association between the other four addictive behaviors and the risk of epilepsy (cigarettes per day: OR, 1.04; 95% CI, 0.92–1.18, P = 0.53; alcoholic drinks per week: OR, 1.31; 95% CI, 0.93–1.84, P = 0.13; tea intake: OR, 1.15; 95% CI, 0.84–1.56, P = 0.39; coffee intake: OR, 0.86; 95% CI, 0.59–1.23, P = 0.41). The other MR analysis methods and further leave-one-out sensitivity analysis suggested the results were robust. ConclusionThis MR study indicated a potential genetically predicted causal association between lifetime cannabis use and higher risk of epilepsy. As for the other four addictive behaviors, no evidence of a causal relationship with the risk of epilepsy was found in this study.