Introduction
Depression and anxiety outcomes
Effects on reward-related and behavioral disorders
Why study findings differ
Effects in severe mental illness
Safety concerns and adverse psychiatric signals
Limitations of current evidence
References
Medicines that change appetite also influence brain circuits that govern emotion and reward, raising questions about their role in psychiatric care.
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Introduction
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) treat type 2 diabetes and obesity and are being investigated for their effects on mental health.1,4 GLP-1 receptors are distributed throughout the central nervous system (CNS), including brain regions like the amygdala, hippocampus, hypothalamus, and prefrontal cortex that regulate emotion, memory, and motivation.1,3 The presence of GLP-1 receptors in the ventral tegmental area and nucleus accumbens, two structures central to reward processing, provides a plausible mechanistic basis for observed changes in mood and behavior that are associated with GLP-1 therapy.1,2
Preclinical studies link GLP-1 receptor activation with anti-inflammatory effects, reduced oxidative stress, increased neurogenesis, and modulation of dopamine and serotonin signaling.1,2 GLP-1 activation may attenuate dopamine responses in the midbrain to rewarding stimuli, a mechanism under investigation for treating compulsive and addictive behaviors.2,3
GLP-1 signaling also modulates corticotropin-releasing hormone neurons in the hypothalamus and dopaminergic neurons in the ventral tegmental area, suggesting that stress and reward pathways may both contribute to psychiatric effects. These mechanisms do not establish therapeutic efficacy in humans.2,4
Depression and anxiety outcomes
GLP-1 RAs have been reported to reduce depressive symptoms, with one meta-analysis of cohort studies and randomized controlled trials (RCTs) identifying a statistically significant but small reduction in depression rating scale scores among GLP-1 RA users. The reduction was more pronounced among individuals diagnosed with type 2 diabetes.4 A separate meta-analysis of 80 RCTs found no significant change in depressive symptoms, indicating that the pooled evidence does not consistently support an antidepressant effect.4
In a post hoc analysis of the Semaglutide Treatment Effect in People with Obesity (STEP) trials, a statistically significant, though clinically negligible, reduction in depressive symptoms was reported. These findings concerned participants without known major psychiatric illness and do not establish semaglutide as a treatment for major depression.4
Contradictory findings have also been documented. A large retrospective cohort study using U.S. TriNetX records and involving 324,506 matched adults with obesity reported a significantly greater risk of anxiety disorders and major depressive disorder among GLP-1 RA users as compared to people not prescribed GLP-1 RAs. This association does not demonstrate that treatment caused these disorders.1,3,4 Other observational studies in people with type 2 diabetes have reported lower anxiety risk or no increase, leaving the clinical effects on anxiety uncertain.4
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GLP-1 receptor signaling in the nucleus accumbens and ventral tegmental area modulates dopaminergic reward circuits. Preclinical studies across multiple substance classes have demonstrated that GLP-1 RA treatment can reduce substance intake, drug-seeking, and relapse-like behaviors, but findings vary by substance and experimental model.2
For alcohol use disorder, observational studies have associated semaglutide and liraglutide with fewer alcohol-related hospitalizations, while randomized trial results are mixed.1,2 A small randomized trial with semaglutide documented reduced alcohol intake in a controlled laboratory setting, whereas dulaglutide led to a 29% reduction in weekly alcohol intake in a secondary analysis of a smoking cessation trial.
An exenatide trial found no overall reduction in heavy drinking days, with a benefit observed in a subgroup with obesity. This exploratory subgroup finding requires confirmation.2
Preclinical evidence suggests that reduced alcohol-induced dopamine release in the nucleus accumbens may contribute to these effects. However, this mechanism has not been established as the explanation for clinical outcomes.2
For binge eating disorder, significant reductions in Binge Eating Scale scores have been observed among individuals treated with GLP-1 RAs. Appetite regulation and altered responses to food rewards are proposed mechanisms, but clinical evidence remains preliminary. Research into bulimia is limited, and appetite suppression warrants particular caution in anorexia nervosa and restrictive eating disorders because it could worsen restriction.4
Why study findings differ
Differences in study populations, comparators, and psychiatric assessments help explain the conflicting findings.1,3,4 Although higher pooled odds of depression-related outcomes have been observed among GLP-1 RA users (odds ratio 1.49), this estimate describes odds, not probability, and cannot be interpreted as a 49% increase in an individual patient’s probability of depression.
Extreme between-study heterogeneity, meaning the extent to which study results differ, was approximately 99%. This inconsistency, along with differences in study designs and outcome definitions, limits interpretation of this estimate as a general treatment effect. Small changes in symptom scores and new diagnoses of depression measure different outcomes, often in different populations; therefore, these findings are not directly interchangeable.3,4
Comparator selection also matters, as comparing treatment with another diabetes medicine can reduce some differences between groups that remain when users are compared with people not receiving GLP-1 RAs.1 For example, one study in older adults with type 2 diabetes found no significant difference in depression risk compared with sodium-glucose cotransporter 2 (SGLT2) inhibitors, though a lower risk was observed when compared to dipeptidyl peptidase-4 (DPP-4) inhibitors.4
A United Kingdom-based active-comparator cohort study of over 270,000 patients with type 2 diabetes found no significant increase in suicidality after adjusting for confounding when comparing GLP-1 RAs with these two medication classes.1,3 A large Nordic cohort study with a mean follow-up period of approximately 2.5 years found no statistically significant increase in suicide death. The upper confidence limit corresponded to an absolute risk increase of 0.16 events for every 1,000 person-years.1,4
A post hoc analysis of the STEP 1-3 and STEP 5 semaglutide trials involving over 3,600 participants with overweight or obesity found no significant increase in these outcomes in the studied population.3,4 By comparison, a spontaneous-report database analysis identified disproportionate reporting of suicidal ideation with semaglutide among reports also listing benzodiazepine or antidepressant use. These analyses compare how often an event appears across different report groups; thus, they cannot estimate patients’ absolute risk or establish a drug interaction or causation.4
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Effects in severe mental illness
GLP-1 RAs have been studied in patients with schizophrenia spectrum disorders, where antipsychotic-induced weight gain and metabolic syndrome are major sources of morbidity and treatment non-adherence. Trials of liraglutide and exenatide have reported metabolic benefits, though their effects on body weight and glycemic control vary by agent and trial.1,4
A non-randomized pilot study found that patients receiving semaglutide for antipsychotic-induced weight gain experienced improvements in quality of life and reductions in psychiatric symptoms. Without random assignment, these findings cannot establish that semaglutide caused the improvements.4
Other findings have been neutral: a meta-analysis reported no change in psychiatric symptom severity after liraglutide or exenatide treatment, while another analysis found that GLP-1 RA exposure was not associated with antipsychotic medication use across longitudinal, case-control, or cross-sectional study designs. Antipsychotic medication use is an indirect measure and cannot establish an effect on psychotic symptoms.4
Taken together, GLP-1 RAs appear to be metabolically beneficial in selected patients with schizophrenia, with no consistent evidence of psychiatric worsening in the available studies. Evidence for direct psychiatric benefits remains insufficient, and findings in schizophrenia cannot be generalized to all severe mental illnesses.1,4
Safety concerns and adverse psychiatric signals
Spontaneous reports submitted to pharmacovigilance systems include mood changes, depressive episodes, and suicidal thoughts in association with GLP-1 RA use. Possible explanations include hormonal changes accompanying rapid weight loss and difficulties adapting when food is used less to regulate emotions.
Reduced leptin and increased cortisol have been proposed as contributors; however, their role in treatment-related depression has not been demonstrated. These hypotheses provide possible avenues for research, rather than evidence that GLP-1 RAs cause psychiatric harm.3
In January 2026, the U.S. Food and Drug Administration (FDA) reported that its evaluation found no increased risk of suicidal ideation or behavior. Its meta-analysis of 91 placebo-controlled trials involving 107,910 patients also found no increased risk of anxiety, depression, irritability, or psychosis.5 New or worsening psychiatric symptoms still require clinical assessment, regardless of whether they are related to treatment.1,5
Limitations of current evidence
Current evidence on the benefits of GLP-1 RAs in mental health disorders is constrained by methodological limitations, as most studies have not been designed to assess psychiatric outcomes as primary endpoints.3 The exclusion of people with significant psychiatric illness or high suicide risk from many randomized trials limits generalizability to relevant patient populations. Dedicated trials with standardized psychiatric assessments are needed to determine whether these medicines offer clinically meaningful benefits for specific disorders.1,3,4
Heterogeneity in drug type, dosage, follow-up duration, and depression assessment methods makes synthesis and pooled estimates difficult to interpret. Confounding variables, particularly the overlap between obesity, metabolic disease, and baseline psychiatric vulnerability, remain a persistent challenge in observational studies. Studies must also distinguish direct CNS effects from changes associated with weight loss, improved metabolic health, and quality of life before psychiatric treatment benefits can be established.1,3,4
References
- Kim J. (2025). Glucagon-like peptide-1 receptor agonists and mental health: a narrative review of emerging benefits and risks. Journal of Yeungnam Medical Science 42; 61. DOI: 10.12701/jyms.2025.42.61. https://www.e-jyms.org/journal/view.php?doi=10.12701/jyms.2025.42.61
- Völker, K. M., Prechtl, B. L. H., Bormann, N. L., & Choi, D. S. (2026). The potential role of GLP-1 receptor agonists in substance use disorders - a systematic review. Frontiers in Pharmacology 16. DOI: 10.3389/fphar.2025.1702448. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1702448/full
- Bi, Z., Jiao, Z., Li, J., & Fang, Z. (2026). Glucagon-like peptide-1 receptor agonists and risk of depression: a systematic review and meta-analysis. BMC Psychiatry 26(1). DOI: 10.1186/s12888-026-08016-x. https://link.springer.com/article/10.1186/s12888-026-08016-x
- Sa, B., Maristany, A., Subramaniam, A., et al. (2026). Psychiatric effects of GLP-1 receptor agonists: A systematic review of emerging evidence. Diabetes, Obesity & Metabolism 28(1); 50-59. DOI: 10.1111/dom.70198. https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.70198
- U.S. Food and Drug Administration. (2026). FDA Requests Removal of Suicidal Behavior and Ideation Warning from Glucagon-Like Peptide-1 Receptor Agonist (GLP-1 RA) Medications. January 13, 2026. FDA Drug Safety Communication.
Further Reading
Last Updated: Oct 19, 2026