Real-World Pharmacovigilance Analysis of Suicidal Ideation and Self-Injurious Behavior Associated with GLP-1 Receptor Agonists: Disproportionality and Mechanistic Insights

Abstract

Pharmacological therapies for T2DM and obesity have undergone a revolution with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide, liraglutide, dulaglutide, exenatide and tirzepatide. A number of spontaneous reports of adverse events, including suicidal ideation and self-injurious behaviour, were reported to the European Medicines Agency (EMA) and the Icelandic Medicines Agency, which were formally reviewed by the EMA, the United States Food and Drug Administration (FDA) and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA), beginning in 2023. This paper reviews the existing evidence on the actual link between exceptionally high blood pressure and certain events, based on the available cohort and case-control studies, as well as the proposed neurobiological pathways to this potential association. The results of disproportionality analyses from the FDA Adverse Event Reporting System (FAERS) and the World Health Organization's VigiBase database are inconsistent: Some large analyses have found no disproportionality signal, but individual-agent analyses have identified weak, albeit statistically significant disproportionality signals in certain subgroups, notably for semaglutide and liraglutide. Large cohort studies, matched by propensity score on electronic health records, have however, mainly reported a reduced risk of incident and recurrent suicidal ideation in GLP-1 RA users vs other anti-obesity or anti-diabetic drugs. In a French nationwide case-time-control study, no consistent elevated risk for suicide or suicide attempt was observed after accounting for psychiatric history and obesity severity in patients exposed to GLP-1 RA. On a mechanistic level, GLP-1 receptors are found in central circuits important for appetite, reward, mood, and stress reactivity, lending biological plausibility to both the beneficial (anti-inflammatory, neurotrophic) and detrimental (dysphoric, anhedonic) neuropsychiatric effects that have been observed in susceptible individuals. The evidence as it stands to date (2026) is not sufficient to support a strong causal link between GLP-1 RA use and increased suicidality at the population level; however, a group of patients with a certain risk profile may benefit from increased monitoring – those with a pre-existing psychiatric illness, rapid titration, and significant caloric restriction. Recommendations for pharmacovigilance methodology, clinical screening and future prospective research are provided.