Introduction Over the past decade, obesity trends have reached epidemic standards.1 In this context, the understanding of glucagon-like peptide-1 (GLP-1)–based mechanisms and related anorectic properties of GLP-1 receptor agonists (RAs) have revolutionized the treatment of obesity.2 In addition to enhancing glucose-dependent insulin release, GLP-1 RAs may reduce glucagon secretion as well as gastric emptying.2 Originally introduced for the treatment of type 2 diabetes, the effect of GLP-1 RAs on weight loss soon caught research attention.3 The weight loss properties of liraglutide and semaglutide quickly went viral on social media, leveraging their promotion as lifestyle drugs not just for patients with diabetes4 and leading to a global shortage.5 Currently, it is estimated that approximately 10% of patients with type 2 diabetes in the US are prescribed GLP-1 RAs.6 Accordingly, regulatory authorities over the world have urged health care professionals to direct available supplies to patients with type 2 diabetes who are inadequately managed with other medications over off-label prescriptions.7,8 Despite the promising potential of GLP-1 RAs, serious concerns have been raised about their safety.9,10 On July 3, 2023, a series of reports for suicidal or self-harming thoughts associated with liraglutide or semaglutide triggered an ongoing review by the European Medicines Agency (EMA).11 Previously, in the approval trials, 9 of the 3384 patients treated with liraglutide (0.27%) had reported suicidal ideation compared with 2 of 1941 patients allocated to the placebo group (0.10%).12 On the other hand, no patients using semaglutide for obesity had developed suicidal ideation,13,14 and no mental health differences were observed in adolescents, with a lower percentage of participants in the semaglutide group than in the placebo group reporting psychiatric adverse events (7% vs 15%).15 The EMA-led investigation might have a global impact, given that liraglutide and semaglutide are administered to more than 20 million people per year.11 This investigation was expected to be completed in November 2023, but ultimately updated in April 2024 after requesting further clarifications.16 In the meantime the British Medicines and Healthcare Products Regulatory Agency and the US Food and Drug Administration (FDA) also announced a similar investigation.17 So far both EMA and FDA declared that they did not find any clear demonstration of a relationship between GLP-1 RAs and suicide based on the available evidence, although the FDA investigation is still ongoing.18,19 Marketing companies stated that warnings about suicidal behavior and ideation are formally required for medications prescribed for chronic weight management affecting the central nervous system.20 The first 2 pharmacovigilance studies on the topic only included partial data from the US,21,22 and a report from the EMA pharmacovigilance database did not assess disproportionality.23 Typically, patients with suicidality are excluded from clinical trials; therefore, the reports from clinical trials may be less precise in capturing the risk of suicidal or self-injurious adverse drug reactions (ADRs) in later practice. In this context, we aimed to assess suicidal and/or self-injurious ADRs associated with liraglutide or semaglutide at a global level, using a World Health Organization (WHO) database of individual case safety reports (ICSRs).