Given interactions between the eCB and stress regulatory systems, as well as documented main effects of early life adversity on cannabis use disorders and HPA-axis and eCB-related function, it is possible that eCB-related genetic variation only confers risk for cannabis involvement in the context of stress exposure. Such Gene × Environment interactions (GxE) can emerge in a variety of forms. For instance, genetic effects might be potentiated or exacerbated in the context of environmental exposure. As an example, Meyers and colleagues found that the G allele of ADH1B rs1229984, which is associated with decreased conversion of alcohol to acetaldehyde and increased problematic alcohol use, has a stronger influence on heavy drinking and alcohol dependence in individuals with a prior history of CSA (Meyers et al., 2013). In contrast, certain genotypes might suppress risk or protection afforded by the environment. For instance, a synonymous polymorphism within CNR1 (rs1049353) has been found to attenuate the pathogenic effects of childhood physical abuse on later vulnerability to anhedonia (Agrawal, Nelson, et al., 2012; but see also Pearson et al., 2013). In that study, carriers of the minor allele were protected from the pathogenic effects of childhood abuse on anhedonia.
