The existence of biological rhythms disruption in addicted subjects has been described including disturbances in their sleep-wake pattern, rest-activity rhythms, and feeding schedules. Circadian rhythms have also been related to psychiatric diseases, including mood and anxiety disorders and the regulation of dopaminergic transmission, especially in reward circuitry in substance abusers. The relationship between them remained enigmatic and no data on the role of clock genes variants on cannabis dependence have been documented. We aimed at exploring the role of clock gene genotypes as potential predisposing factor to cannabis addiction, using a high throughput mass spectrometry methodology that enables the large-scale analysis of all the known clinically-relevant polymorphisms of the core human clock genes. We have conducted a case-control study on 177 Caucasians categorizing between cannabis-addicted subjects (n = 83) and casual cannabis consumers (n = 94). We report here a strong association between the TT* genotype RS1442849 in PER1/HES7 gene and a significantly higher risk of vulnerability to be dependent to cannabis. Moreover, this SNP was overrepresented in the subsets of cannabis users with more severe characteristics like personal psychiatric history, unemployed status, and beginning of cannabis use early in lifetime as well as large weekly consumption. HES7 gene is a newly described gene with a circadian expression regulated by reactive oxygen species in many cell types including neural stem cells. The HES7 TT* genotype RS1442849 gene could intervene on the dopamine reward systems. This genotype thus represents the first potential biomarker for stratification of cannabis consumers for the risk to develop a true dependence.