Genetic and sociodemographic risk factors potentially associated with cannabis use (CU) were investigated in 40 cannabis users and 96 control subjects. DNA methylation analyses were also performed to explore the possibility of epigenetic changes related to CU. We conducted a candidate gene association study that included variants involved in the dopaminergic (ANKK1, NCAM1 genes) and endocannabinoid (CNR1, CNR2 gene) pathways. Sociodemographic data included gender, marital status, level of education, and body mass index. We used MeDIP-qPCR to test whether variations in DNA methylation might be associated with CU. We found a significant association between SNP rs1049353 of CNR1 gene (p = 0.01) and CU. Differences were also observed related to rs2501431 of CNR2 gene (p = 0.058). A higher education level appears to decrease the risk of CU. Interestingly, females were less likely to use cannabis than males. There was a significantly higher level of DNA methylation in cannabis users compared to controls in two of the genes tested: hypermethylation at exon 8 of DRD2 gene (p = 0.034) and at the CpG-rich region in the NCAM1 gene (p = 0.0004). Both genetic variants and educational attainment were also related to CU. The higher rate of DNA methylation, evidenced among cannabis users, may be either a marker of CU or a consequence of long-term exposure to cannabis. The identified genetic variants and the differentially methylated regions may represent biomarkers and/or potential targets for designs of pharmacological therapeutic agents. Our observations also suggest that educational programs may be useful strategies for CU prevention.