Glucagon-like Peptide-1 Receptor Agonists for Substance Use Disorders: Comprehensive Review of Circuit Mechanisms and Clinical Evidence

Substance use disorders (SUDs) are a leading cause of preventable death worldwide, yet approved pharmacotherapies exist for only three of them: alcohol, tobacco, and opioid use disorders. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), established in metabolic medicine, are candidates for repurposing across multiple SUDs. This review synthesizes preclinical mechanistic evidence, pharmacoepidemiologic data, and randomized trials, comprehensively for human studies and selectively for preclinical work establishing circuit-level mechanisms. GLP-1 RAs attenuate the peak amplitude and frequency of drug-evoked dopamine release in the nucleus accumbens through shared mesolimbic mechanisms while engaging substance-specific circuits, including the lateral septum for alcohol and psychostimulants and the medial habenula–interpeduncular pathway for nicotine. Evidence from CB1–incretin interaction studies suggests a distinct rationale for cannabis use disorder, in which GLP-1 RA administration may correct a drug-induced suppression of incretin tone; this framing is theoretical and has not been tested against addiction endpoints. Clinical evidence is most robust for alcohol use disorder, where convergent pharmacoepidemiologic signals and the SEMALCO randomized trial demonstrate efficacy in individuals with comorbid obesity; data for opioid, tobacco, cocaine, and cannabis use disorders remain limited. Translational barriers include dose–response relationships that remain uncharacterized because no trial has performed dose-ranging against an addiction endpoint, safety concerns in patients with eating pathology, and metabolic phenotype as a moderator, with directionally opposite effects across body mass index strata. Whether GLP-1 RAs achieve transdiagnostic utility will likely depend on patient selection and agent choice, but no validated selection criteria exist and this remains a hypothesis to be tested.