AbstractThe purpose of this study was to explore the effects of cannabidiol (CBD) on binge drinking and evaluate potential gender‐related differences. To this aim, male and female C57BL/6J mice (n = 60 per sex) were exposed to the drinking in the dark (DID) model for 4 weeks (DID‐1 to DID‐4). Dose‐response effects of CBD on the ethanol intake were tested by acute (day‐4 of DID‐3) or repeated administration (day‐1 to 4 of DID‐4) (experiment 1: CBD 15, 30, and 60 mg/kg, i.p.; experiment 2: CBD 90 mg/kg, i.p.). Finally, we analyzed the relative gene expression of tyrosine hydroxylase (TH) and μ‐opioid receptor (OPRM1) and cannabinoid CB1 receptor (CB1r) in the ventral tegmental area (VTA) and in the nucleus accumbens (NAc), respectively, by real‐time quantitative PCR. Females exhibited higher ethanol intake during each DID session. Interestingly, females also showed higher expression of TH and OPRM1, without any difference in CB1r. Only the acute administration of CBD at the highest dose (90 mg/kg) reduced significantly ethanol consumption in both sexes. Chronic CBD administration (30, 60 and 90 mg/kg) reduced ethanol intake in males, whereas in females a significant reduction was only achieved with the highest dose (90 mg/kg). Repeated administration with CBD (60 mg/kg) significantly reduced TH and OPRM1 in males. In addition, CBD (30 and 60 mg/kg) significantly reduced CB1r in males. No effect was observed in females. Taken together, these findings suggest that CBD may be of interest for treating binge‐drinking patterns and that gender‐related difference may affect the treatment outcome.