BACKGROUND AND AIMS: Initial use of drugs such as tobacco and alcohol may lead to subsequent more problematic drug use-the 'gateway' hypothesis. However, observed associations may be due to a shared underlying risk factor, such as trait impulsivity. We used bidirectional Mendelian randomization (MR) to test the gateway hypothesis.

DESIGN: Our main method was inverse-variance weighted (IVW) MR, with other methods included as sensitivity analyses (where consistent results across methods would raise confidence in our primary results). MR is a genetic instrumental variable approach used to support stronger causal inference in observational studies.

SETTING AND PARTICIPANTS: Genome-wide association summary data among European ancestry individuals for smoking initiation, alcoholic drinks per week, cannabis use and dependence, cocaine and opioid dependence (n = 1749-1 232 091). Measurements were genetic variants for exposure.

FINDINGS: We found evidence of causal effects from smoking initiation to increased drinks per week, cannabis use and cannabis dependence. We also found evidence of an effect of cannabis use on the increased likelihood of smoking initiation. We did not find evidence of an effect of drinks per week on other substance use outcomes, except weak evidence of an effect on cannabis use. We found weak evidence of an effect of opioid dependence on increased drinks per week.

CONCLUSIONS: Bidirectional Mendelian randomization testing of the gateway hypothesis reveals that smoking initiation may lead to increased alcohol consumption, cannabis use and cannabis dependence. Cannabis use may also lead to smoking initiation and opioid dependence to alcohol consumption. However, given that tobacco and alcohol use typically begin before other drug use, these results may reflect a shared risk factor or a bidirectional effect for cannabis use and opioid dependence.

[See also, Michael M Vanyukov, letter to the editor: There is no causality in the ‘gateway hypothesis’: another test gone amiss, Addiction, October 2021]