Abstract In psychostimulant drug addiction, relapse is the most concerning outcome to be managed, considering there is no approved treatment for this neuropsychiatric condition. Here, we investigated the effects of the CBD treatment on the relapse behavior triggered by stress, after being submitted to the amphetamine (AMPH)-induced conditioned place preference (CPP) in rats. To elucidate the mechanisms of action underlying the CBD treatment, we evaluated the neuroadaptations on dopaminergic and endocannabinoid targets in the ventral striatum (VS) and ventral tegmental area (VTA) of the brain. Animals received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the CPP paradigm for 8 days. Following the first CPP test, animals were treated with CBD (10 mg/kg, i.p.) or its vehicle for 5 days and subsequently submitted...