Glucagon-like peptide-1 (GLP-1) therapies are under investigation for a growing number of neuropsychiatric conditions, including substance use disorders. Cigarette smoking accounts for the largest proportion of substance use-related morbidity and mortality, in part reflecting increased risk for cardiometabolic disease among people who smoke. Given modest quit rates with approved smoking cessation therapies, medications with novel mechanisms of action are needed to expand the available monotherapy and combination treatment options. Treatments that prevent post-cessation weight gain could further reduce relapse and cardiometabolic risks following smoking cessation. Preclinical findings show that GLP-1 receptor agonists (GLP-1RA) modulate nicotine reward, reduce nicotine self-administration, and prevent withdrawal-related hyperphagia. Early clinical investigations suggest that GLP-1RA prevent post-cessation weight gain, while potentially improving cessation or reducing craving. These findings, combined with the efficacy of GLP-1RA for cardiometabolic risk reduction, position GLP-1 medicines as a promising therapeutic class for people who smoke. This review addresses the therapeutic potential of GLP-1-based therapies for smoking cessation, emphasizing emerging findings from randomized trials and other human investigations. Potential neural mechanisms for effects of GLP-1RA on nicotine reward are reviewed, and priorities for future clinical and translational studies are discussed. Those with metabolic disorders or psychiatric disorders are proposed as clinical subgroups for which therapeutic benefits of GLP-1 medicines may prove important based on elevated risk for tobacco-related morbidity and mortality.
