Molecular and structural insights into the 5-HT_2C receptor as a therapeutic target for substance use disorders

Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological function of the serotonin 2C receptor (5-HT_2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5-HT₂ receptors, have indicated potential for the treatment of SUD, implicating the 5-HT_2C receptor. The modern psychedelic movement has rekindled interest in the 5-HT_2C receptor, resulting in many new studies, especially structural analyses. This review explores the structural, molecular and cellular mechanisms governing 5-HT_2C receptor function in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration.