Smoking initiation as a mediator: investigating the causal relationship between sedentary lifestyles and cannabis use disorder through Mendelian randomization.

Background: Cannabis Use Disorder (CUD) involves compulsive cannabis use, leading to significant impairment and distress. Previous research indicates lower physical activity and higher sedentary behavior among cannabis users, but the causal relationship remains unclear. This study aims to use Mendelian randomization (MR) to investigate the causal link between exercise, sedentariness, and CUD.

Methods: We analyzed genetic associations for (1) moderate-to-vigorous physical activity (MVPA), (2) leisure screen time (LST), (3) sedentary commuting behavior (SCB), and (4) sedentary behavior at work (SBW). Genetic instruments for smoking initiation were identified from the GSCAN study. Genetic associations for CUD were derived from the largest Genome-wide association studies (GWAS) of CUD. We selected significant genetic variants, harmonized data. We conducted MR analyses using IVW, assessing heterogeneity and pleiotropy with Cochran's Q test and MR-Egger regression, and performed leave-one-out analyses.

Results: SBW showed a protective causal relationship with CUD (OR = 0.61, 95% CI = 0.42-0.90, p = 0.012). LST increased the risk of CUD (OR = 1.43, 95% CI = 1.20-1.70, p < 0.001). LST also showed a significant causal relationship with smoking initiation (OR = 1.28, 95% CI = 1.21-1.36, p < 0.001), which was associated with increased CUD risk. Smoking initiation mediated 54.08% of the increased CUD risk associated with LST (95% CI = 53.72-54.44%).

Conclusions: A sedentary lifestyle may lead to CUD through smoking. Addressing sedentariness and promoting physical activity may reduce the risk of smoking initiation and subsequent cannabis-related problems.