Longitudinal studies, particularly with assessments preceding onset of cannabis use, are ideally suited to disentangle effects of cannabis on the developing brain from pre-existing differences. Such study designs have shown that smaller orbitofrontal cortex (OFC) volumes predict later cannabis initiation in adolescents8 yet also find emerging deficits in white matter as a consequence of heavy alcohol and cannabis use9. However, even in cross-sectional studies, twins/siblings discordant for cannabis exposure provide a unique opportunity for differentiating predispositional/familial factors from causal effects of cannabis on the brain. As monozygotic (MZ) twins share all genetic material identical-by-descent, neural differences between MZ twins discordant for cannabis exposure can be potentially attributed to causal effects of cannabis10,11. In contrast, if no differences are found, then large causal effects of cannabis on the brain are unlikely, and instead, the association might be attributed to genetic factors/familial environment. For instance, Gilbertson and colleagues found that PTSD severity in combat-exposed veterans negatively correlated with their hippocampal volume as well as volumes of their non-combat-exposed MZ co-twins, implicating predispositional rather than causal mechanisms12. In contrast, Lessov-Schlaggar et al. found
