GLP-1 receptor agonists in addiction and affective disorders: Implications for dual disorders

Substance use disorders and affective disorders frequently coexist and share overlapping neurobiological mechanisms involving reward processing, stress regulation, neuroinflammation, and metabolic dysfunction. However, few pharmacological approaches currently target these interconnected pathways simultaneously. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for the treatment of type 2 diabetes and obesity, have recently attracted interest because of their central nervous system effects extending beyond metabolic regulation. This narrative review summarizes preclinical, translational, and emerging clinical evidence regarding the potential role of GLP-1 receptor signalling in addiction and affective disorders. Experimental studies suggest that GLP-1 receptor activation may influence dopaminergic, glutamatergic, and GABAergic neurotransmission within mesolimbic and corticolimbic circuits involved in reward-related behaviours. In animal models, GLP-1 RAs have been associated with reductions in drug-seeking behaviours and cue-induced reinstatement across several substances. Early clinical studies, particularly in alcohol use disorders, have reported reductions in alcohol intake, craving, and cue-reactivity. Additional preliminary evidence from metabolic and psychiatric populations suggests possible effects on depressive symptoms, cognitive function, and neuroinflammatory pathways, although findings remain heterogeneous and direct evidence in dual-disorder populations involving co-occurring substance use and affective disorders remains limited. Overall, current evidence supports further investigation of GLP-1 receptor signalling as a potential mechanistic link between metabolic, reward, and affective processes. Nevertheless, the available clinical literature remains preliminary, and adequately powered randomized controlled trials specifically targeting populations with co-occurring substance use and affective disorders are needed to clarify clinical efficacy, underlying mechanisms, and patient subgroups most likely to benefit.