Central Nervous System Effects of GLP-1 Receptor Agonists: A Systematic Review of Human Neuroimaging Studies

Interest in glucagon-like peptide-1 receptor agonists (GLP-1RAs) has expanded beyond obesity and diabetes, with growing preclinical and clinical evidence supporting potential applications in psychiatric and neurodegenerative disorders. However, the central nervous system (CNS) mechanisms engaged by GLP-1RAs remain poorly characterized, limiting the capacity to optimize their therapeutic potential. This systematic review synthesized the literature examining GLP-1RA-related CNS effects, focusing on treatment-related neural responsivity, temporal dynamics, and modulators of CNS response. PubMed and Embase were systematically searched from inception to January 2026 for human studies across structural magnetic resonance imaging (MRI), task-based and resting-state functional MRI, molecular imaging, and neurophysiological approaches. Thirty-seven studies met inclusion criteria. The reviewed evidence suggests that GLP-1RAs engage distributed cortical and subcortical brain systems. Attenuation of reward-related responsivity following acute GLP-1RA administration was among the more consistent findings. Notably, evidence suggests that GLP-1RAs differentially modulate reward-related processes rather than uniformly attenuate reward function, with neural effects further varying according to metabolic status and underlying phenotype. Several studies additionally indicated that CNS effects evolve over the course of treatment, with more pronounced neural modulation during short-term treatment and diminished or altered effects following prolonged exposure. However, the current neuroimaging literature is constrained by small sample sizes and methodological heterogeneity, limiting direct comparisons across studies and underscoring the need for greater standardization. This review provides insight into the neurobiological mechanisms engaged by GLP-1RAs, identifies emerging patterns of CNS response with potential implications for mechanistically informed treatment strategies, and highlights key mechanistic considerations and priorities for future neuroimaging research.