Given the modest number of studies in Table 2 of cannabis dependence , there is only limited evidence for the role of CNR1 in cannabis dependence [43-45]. Moreover, the extent to which CNR1 mediates reward related to earlier stages of cannabis involvement, such as initiation and regular use is largely unknown. When Chen and colleagues [46] examined the influence of CNR1 on cigarette smoking initiation and dependence, they found stronger associations with dependence. The hypothesis that the contribution of CNR1 to cannabis-related behaviors is specific is complicated by positive associations with general substance dependence [47], nicotine dependence [46], the rewarding effects of alcohol [48] and for alcohol dependence in the absence of comorbid drug dependence [39]. None of these studies attempted to exclude cannabis dependence from their definition of ‘substance dependence’ (or nicotine and alcohol dependence) to examine whether the association signal was attributable to comorbid cannabis use problems. Therefore, while we can hypothesize that CNR1 is related to a general vulnerability to substance dependence and not just to cannabis dependence, we cannot rule out the hypothesis that comorbid cannabis dependence is responsible for these associations.
