Mechanisms of GLP-1 in Modulating Craving and Addiction: Neurobiological and Translational Insights.

Substance use disorders (SUDs) remain a major public health challenge, with existing pharmacotherapies offering limited long-term efficacy. Traditional treatments focus on dopaminergic systems but often overlook the complex interplay between metabolic signals, neuroplasticity, and conditioned behaviors that perpetuate addiction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have recently emerged as promising modulators of reward-related brain circuits. This review synthesizes current evidence on the role of glucagon-like peptide-1 (GLP-1) and its receptor in modulating craving and substance-seeking behaviors. We highlight how GLP-1 receptors are expressed in addiction-relevant brain regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), where their activation influences dopaminergic, glutamatergic, and GABAergic neurotransmission. In addition, we explore how GLP-1 signaling affects reward processing through gut-brain vagal pathways, hormonal crosstalk, and neuroinflammatory mechanisms. Preclinical studies demonstrate that GLP-1RAs attenuate intake and relapse-like behavior across a range of substances, including alcohol, nicotine, and cocaine. Early-phase clinical trials support their safety and suggest potential efficacy in reducing craving. By integrating findings from molecular signaling, neurocircuitry, and behavioral models, this review provides a translational perspective on GLP-1RAs as an emerging treatment strategy in addiction medicine. We propose that targeting gut-brain metabolic signaling could provide a novel framework for understanding and treating SUDs.