Abstract

Introduction: With the legalization of cannabis, concerns have emerged regarding the long-term health impact of excessive use. The current literature has struggled to address questions about the adverse effects of cannabis, particularly in the context of atherosclerotic cardiovascular disease (ASCVD). Using genetic approaches to causal inference, we explored the relationship between cannabis use disorder (CUD) and ASCVD. Methods: Genetic instruments were constructed from a multi-population GWAS comprising 64,314 individuals with and 990,051 without CUD. Outcome data for coronary artery disease (CAD), ischemic stroke, peripheral artery disease (PAD), and abdominal aortic aneurysms (AAA) were derived from multi-population GWAS. Univariable Mendelian randomization (MR) was performed using the inverse-variance weighted (IVW) method to test the association of CUD with each outcome. Multivariable MR (MVMR) was performed to assess if the impact of cardiometabolic risk factors accounted for the association of CUD with ASCVD using summary statistics from publicly available GWAS of cardiometabolic risk factors. Results: CUD was associated with increased risk of CAD (OR 1.27; 95% CI 1.17-1.38; P=<0.01), ischemic stroke (OR 1.10; 95%CI 1.03-1.19; P=<0.01), PAD (OR 1.31; 95% CI 1.17-1.46; P=<0.01), and AAA (OR 1.37; 95% CI 1.21-1.55; P=<0.01). CUD also had a significant impact on cardiometabolic risk factors including triglycerides, waist-to-hip ratio, BMI, type 2 diabetes, obesity, and heart failure. The effect of CUD on ASCVD, other than stroke, remained largely independent of traditional risk factors except for lipids and tobacco smoking. Controlling for lifetime smoking index attenuated all associations between CUD and ASCVD except CAD, which remained significant (OR 1.21; 95% CI 1.11-1.31). Conclusion: Excessive cannabis use has the potential to increase ASCVD risk, independent of cardiometabolic risk factors, although this risk may in part be attributable to shared susceptibility to lipids and tobacco use. Awareness of the long-term risks of excessive cannabis use should be considered when formulating medical advice and public policy.