Although cannabis does not have high abuse liability as other drugs, it is clear that some individuals are more susceptible to becoming dependent on cannabis even at a young age. Decreased negative reward/avoidance behavior conferred by DRD2 individual genetic differences has been hypothesized to account for such vulnerability. While we replicated previous findings showing a role of DRD2 in negative reward learning [18], [19], [32], cannabis-dependence vulnerability did not appear to be driven by this association. Instead, the results suggest for the first time to our knowledge that there are fundamental biological differences driven by genetic impairments in the opioid system in cannabis-dependent individuals compared to those who used the drug but did not become dependent. The study further revealed that Neuroticism, in contrast to other traits characteristic of cannabis-dependent subjects or compared to reward learning and inhibitory control performance, significantly mediates the association between functional SNPs of PENK (which we now know are associated with mRNA expression levels in regions relevant to negative emotional states) and cannabis dependence. The finding that cannabis dependence is significantly enhanced in a synergistic
