Prolonged exposure to drugs of abuse leads to severe alterations in mesocorticolimbic dopamine circuitry deeply implicated in substance use disorders. Despite considerable efforts, few medications to reduce relapse rates are currently available. To solve this issue, researchers are uncovering therapeutic opportunities offered by the endocannabinoid system. The cannabinoid receptor type 1 (CB1R), and its endogenous ligands, participate in orchestration of cue-triggered and stress-triggered responses leading to obtain natural and drug rewards. Here, we review the evidence supporting the use of CB1R neutral antagonists, allosteric modulators, indirect agonists, as well as multi-target compounds, as improved alternatives compared to classical CB1R antagonists. The promising therapeutic value of other substrates participating in endocannabinoid signaling, like peroxisome proliferator-activated receptors, is also covered. Overall, a wide body of pre-clinical evidence avails novel pharmacological strategies interacting with the endocannabinoid system as clinically amenable candidates able to counteract drug-induced dopamine maladaptations contributing to increased risk of relapse.
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