On the other hand, the central role of Neuroticism in the association between PENK/DRD2 genes and cannabis-use outcomes in our sample has important implications. Both clinical reports and research data have suggested that coping with stress and negative mood states is a common motive for use among heavy abusers [35], which would be consistent with self-medicating subthreshold anxiety and negative affect induced by PENK dysfunction. Interestingly, previous studies that have addressed the self-medication hypothesis showed that cannabis is more likely to exacerbate mood symptoms than to alleviate them [36]. Cannabis exposure and negative affect may thus interact in a complex way within a vicious cycle where cannabis may be used to cope with subthreshold symptoms, but paradoxically further increase them in the long term. That our population consisted of non-depressed subjects underscores the fact that subthreshold symptoms that are not captured by DSM-IV may well have an impact on the emergence and course of a clinically significant disorder such as cannabis dependence.
