ABSTRACT
Increasingly permissive attitudes and laws surrounding cannabis have been accompanied by more prevalent use and increased perceptions of its safety.1 However, in stark contrast to this sea-change, remarkably little is known about the potential consequences and etiology of cannabis involvement. In particular, it is unclear what biological mechanisms may undergird associations with negative outcomes (eg, reduced cognition, increased psychosis, depression)2 and whether these substrates arise from cannabis use and/or represent predispositional risk factors. As cannabis remains at the forefront of public discussion and policy, it is increasingly important to identify potential biological mechanisms contributing to associations with negative outcomes and evaluate the plausibility that these represent a consequence of exposure and/or predispositional risk factors or nonetiologic correlates. The knowledge generated from this Herculean task may dam the present sea-change of increasing cannabis permissiveness and/or remove the few remaining boulders impeding it.