Glucagon‐Like Peptide‐1 Receptor Agonists in Cocaine Use Disorder: Clinical Observations and Underlying Mechanisms

BACKGROUND: Cocaine use disorder (CUD) remains a major public health concern, characterized by high relapse rates and the absence of approved pharmacological treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RA), widely prescribed for metabolic disorders, modulate mesolimbic reward pathways and have been proposed as potential modulators of addictive behaviors. OBJECTIVES: To describe clinical observations of GLP-1RA exposure in individuals with CUD identified through the French national vigilance system and to contextualize these findings through a structured narrative review of preclinical and clinical evidence. METHODS: Cases involving GLP-1RA exposure in individuals with ongoing cocaine use were identified through the French national vigilance system and described. A structured literature search (MEDLINE, Embase, Google Scholar) identified original preclinical and clinical studies examining the effects of GLP-1 receptor activation on cocaine-related behavioral and neurobiological outcomes. RESULTS: Two cases involving patient-initiated off-label GLP-1RA use motivated by perceived anti-craving effects were identified through the vigilance system. The literature synthesis included 22 original publications (17 preclinical and 5 human studies). Across experimental models, GLP-1 receptor activation reduced cocaine self-administration, conditioned reward, and relapse-like behaviors. These effects were associated with the attenuation of mesolimbic dopamine signaling, including reduced cocaine-evoked dopamine release and modulation of dopamine transporter function. Human evidence remains limited and heterogeneous. CONCLUSION: GLP-1 receptor signaling represents a biologically plausible target in CUD. However, current clinical evidence remains preliminary. Patient-driven observations underscore the need for controlled clinical trials and continued vigilance monitoring.