In instances where causation has been implied (e.g. the gateway hypothesis), Mendelian randomization is an intriguing alternative possibility. Relying on the Mendelian law of random and independent assortment of alleles, this conceptualization of epidemiological causation suggests that the functional alleles that modify the likelihood of early cannabis use (i.e. exposure) should predict later outcomes to which early cannabis use is causally related (e.g. illicit drug use) (102). The allele-outcome association is considered a sound test of causation as it is unencumbered by confounding social factors. For instance, Irons et al (103) reported that the non-protective allele of the functional variant (rs671) in ALDH2, which reduces alcohol use due to reduced acetaldehyde clearance and consequently, flushing, was not associated with increased likelihood of other substance use in Asian Americans (i.e. a test of the alcohol-drug gateway). While intuitively appealing, tests of this nature are challenging in studies of cannabis exposure. First, no genomic variants have been robustly and causally implicated in the etiology of early cannabis use (or any cannabis-related measure for that matter)(104; 105). Secondly, those that have been studied
