Beyond diabetes management: A narrative review on the neurological and psychiatric impact of semaglutide

Abstract: Semaglutide, a glucagon-like peptide-1 receptor agonist, has attracted increasing scientific interest for its potential relevance to neurological and psychiatric conditions beyond its established indications for type 2 diabetes and obesity. Emerging evidence from preclinical models, observational human studies, and early-phase clinical investigations suggests that semaglutide engages central nervous system pathways implicated in neurodegeneration, reward processing, and behavioral regulation. Proposed mechanisms include modulation of neuroinflammatory signaling, oxidative stress, protein aggregation, autophagy, mitochondrial function, and dopaminergic neurotransmission. This narrative review synthesizes current evidence examining semaglutide’s associations with neurological and psychiatric outcomes, including Alzheimer’s disease, Parkinson’s disease, substance use disorders, and disordered eating behaviors. Large-scale epidemiological studies report consistent associations between semaglutide exposure and reduced incidence or recurrence of several substance use and eating disorders, while preclinical models demonstrate biologically plausible effects on disease-relevant pathways. However, available human data are predominantly observational, and randomized controlled trials establishing clinical efficacy for off-label neuropsychiatric indications are limited or ongoing. Evidence regarding mood and anxiety outcomes is mixed, with randomized trial data in selected populations suggesting psychiatric safety comparable to placebo, contrasted by signals of potential risk in real-world and pharmacovigilance datasets. These findings highlight the importance of careful patient selection, monitoring, and further investigation. Ongoing clinical trials and mechanistic studies will be critical to clarifying semaglutide’s central effects, defining appropriate clinical contexts, and determining whether observed associations translate into meaningful therapeutic benefit.