Incretin-Based Therapies: A Novel Pathway in Addiction Treatment

Addiction poses a major global public health challenge. It is characterized by high prevalence, chronic relapse and limited efficacy of available pharmacotherapies across different substance use disorders. Increasing evidence demonstrates that incretin-based therapies directly modulate metabolic signaling pathways that intercross with central reward and motivational circuits, including hypothalamic-mesolimbic networks and dopaminergic neurotransmission. As a result, agents such as glucagon-like peptide 1 receptor agonists, originally developed for the treatment of type 2 diabetes and obesity, are now being actively investigated for their role in addiction treatment. This narrative review summarizes the current knowledge on the role of incretin-based therapies in the neurobiology of addiction. Evidence from preclinical models and human studies supports the potential therapeutic effect of glucagon-like peptide 1 receptor agonists in the treatment of alcohol use disorder, nicotine dependence, and the administration of other psychoactive substances, including psychostimulants, opioids, and cannabinoids. Preclinical studies consistently demonstrate that glucagon-like peptide 1 receptor agonists reduce substance intake, attenuate reward-related behaviors, and suppress relapse-like responding. So far, human evidence remains limited and is largely derived from observational studies. Preliminary research suggests potential reductions in substance use severity and overdose risk among individuals treated with incretin-based agents. While these findings highlight incretin signaling as a promising therapeutic option in addiction, the current evidence is insufficient to support their routine clinical use in the treatment of substance dependence. Therefore, further research is required to clarify underlying mechanisms and establish clinical efficacy. In particular, well-designed randomized controlled trials are needed to determine safety, tolerance and effectiveness of incretin-based therapies across different substance use disorders.