Kenneth Blum^{1,2 ,5 ,14,18,19}*, Alireza Sharafshah³, Chynna Fieleglman⁴, Kai-Uwe Lewandrowski^5-7,14, David Baron⁸, Alexander PL Lewandrowski⁹, Catherine A Dennen¹⁰, Albert Pinhasov², Abdalla Bowirrat², Nicole Jafari¹¹, Foojan Zeine¹², Rossano Kepler Alvim Fiorelli¹³, Sergio Schmidt¹⁴, Edward J Modestino¹⁵, Mark S Gold¹⁶, Debasis Bagchi¹⁷, Yatharth Mahajan¹⁸, Shaurya Mahajan¹⁸, Keerthy Sunder^1,19, Milan Makale²⁰, Kyriaki Z Thanos²¹, Kavya Mohankumar^18,19, Anand Swaroop²², Morgan P Lorio²³, Igor Elman^2,24, Panayotis K Thanos^2,25 and Rajendra D Badgaiyan²⁶

¹Division of Addiction Research and Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA, USA
²Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel
³Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
⁴Department of Psychology, St. John’s University, Queens, NYC., NY., USA
⁵Division of Personalized Pain and Education, Center for Advanced Spine Care of Southern Arizona, Tucson AZ, USA
⁶Department of Orthopaedics, Fundación Universitaria Sanitas Bogotá D.C. Colombia
⁷Department of Orthopaedics, Universidade Federal do Estado do Rio de Janeiro and Department of Spine Surgery, Arizonia University, School of Medicine, Tucson, AX., USA
⁸Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA., USA
⁹Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA
¹⁰Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA
¹¹Department of Applied Clinical Psychology, The Chicago School of Professional Psychology, Los Angeles, CA., USA
¹²Department of Health Science, California State University at Long Beach, Long Beach, CA., USA
¹³Department of General and Specialized Surgery, Gaffrée e Guinle Universitary Hospital, Federal University of the State of Rio de Janeiro (UNIRIO)
¹⁴Post-Graduate Program in Neurology, Federal University of the State of Rio de Janeiro, Brazil
¹⁵Brain and Behavior laboratory, Cury College, Milton, MA.,USA
¹⁶Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA
¹⁷Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy, Houston, TX, USA
¹⁸Division of Clinical Neurology, The Blum Institute for Neurogenetics and Behavior, LLC., Austin, TX.,USA
¹⁹Division of Neuromodulation Research, Karma Doctors and Karma TMS, Palm Springs, CA, USA
²⁰Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA
²¹Department of Psychology, University of Buffalo, NY., USA
²²Cepham, Inc. , Somerset, NJ, USA
²³Advanced Orthopedics , Altamonte Springs, FL. USA
²⁴Department of Psychiatry, Harvard University School of Medicine, Cambridge, MA., USA
²⁵Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, and Department of Psychology, University at Buffalo, Buffalo, NY, USA
²⁶Department of Psychiatry, Texas Tech University Health Sciences, School of Medicine, Midland, TX., USA

*Corresponding Author: Kenneth Blum, Division of Addiction Research and Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA, USA.

Received: June 09, 2025; Published: June 18, 2025

Abstract

Mental illness affects approximately one in five children in the United States, with many individuals experiencing comorbid psychiatric conditions such as anxiety, depression, and substance use disorders. Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacologic treatment for generalized anxiety disorder, while benzodiazepines and certain SNRIs serve as second-line options. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and weight management, have recently raised concerns due to their emerging neuropsychiatric side effects. Recent research has shown that GLP-1RAs modulate functional connectivity in key brain networks involved in mood regulation, including the default mode, salience, and frontoparietal networks. Adverse psychiatric outcomes such as mood instability, anxiety, and suicidal ideation have been reported in post-marketing surveillance and case studies, prompting regulatory review. This case report presents a 58-year-old female with a long history of anxiety who experienced a severe psychiatric decline, including insomnia, weight loss, and suicidal ideation, following semaglutide use for weight loss. Despite multiple medication trials, only repetitive transcranial magnetic stimulation (rTMS) achieved sustained symptom relief. The patient retrospectively attributed her decline to GLP-1 agonist exposure, describing the experience as traumatic. While most large-scale studies have not shown significant increases in suicidality with GLP-1RA use, growing evidence suggests the importance of pre-treatment psychiatric screening and genetic vulnerability assessment. This case underscores the potential for adverse neuropsychiatric outcomes in vulnerable individuals and supports the call for more rigorous investigation into the central effects of GLP-1RAs and personalized approaches to prescribing these medications.

Keywords: Semaglutide Injection; GLP1; Suicidal Ideation; Female; Long-standing Anxiety

References

1. Southammakosane C and Schmitz K. “Pediatric Psychopharmacology for Treatment of ADHD, Depression, and Anxiety”. Pediatrics 136 (2015): 351-359.
2. Faraone SV. “The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities”. Neuroscience and Biobehavioral Reviews 87 (2018): 255-270.
3. Jakovljević M and Ostojić L. “Comorbidity and multimorbidity in medicine today: Challenges and opportunities for bringing separated branches of medicine closer to each other”. Psychiatria Danubina 25. S1 (2023): 18-28.
4. Yeh HH., et al. “Diagnosed Mental Health Conditions and Risk of Suicide Mortality”. Psychiatric Services 9 (2019): 750-757.
5. Strawn JR., et al. “Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: An evidence-based treatment review”. Expert Opinion on Pharmacotherapy 19 (2018): 1057-1070.v
6. Bushnell GA., et al. “Treating Pediatric Anxiety: Initial Use of SSRIs and Other Antianxiety Prescription Medications”. The Journal of Clinical Psychiatry 79 (2018): 16m11415.
7. Dhaliwal JS., et al. “StatPearls [Internet] StatPearls Publishing; Treasure Island, FL, USA: 2023. Duloxetine (2023). 
8. Uthman OA and Abdulmalik J. “Comparative efficacy and acceptability of pharmacotherapeutic agents for anxiety disorders in children and adolescents: A mixed treatment comparison meta-analysis”. Current Medical Research and Opinion 26 (2010): 53-59.
9. Liebrenz M., et al. “Agonist substitution-A treatment alternative for high-dose benzodiazepine-dependent patients?” Addiction 105 (2010): 1870-1874.
10. Locke AB., et al. “Diagnosis and management of generalized anxiety disorder and panic disorder in adults”. American Family Physician 91 (2015): 617-624. 
11. Vasile RG., et al. “Results of a naturalistic longitudinal study of benzodiazepine and SSRI use in the treatment of generalized anxiety disorder and social phobia”. Depression and Anxiety 22 (2005): 59-67.
12. Miroddi M., et al. “Passiflora incarnata L.: Ethnopharmacology, clinical application, safety and evaluation of clinical trials”. Journal of Ethnopharmacology 150 (2013): 791-804.
13. Blum K GPK. “Ethanol and neuromodulator interaction: a cascade model of reward”. Ollat H, Parvez S, Parvez H, editors. The Netherlands: VSP Press Utrecht (1990).
14. Perez-Montes., et al. “Obesity and GLP-1”. Minerva Endocrinology (Torino)2 (2021): 168-176.
15. Htike ZZ., et al. “Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis”. Diabetes, Obesity and Metabolism 4 (2017): 524-536.
16. Gerstein HC., et al. “Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial”. Lancet10193 (2019): 121-130.
17. Marso SP., et al. “Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes”. The New England Journal of Medicine 19 (2016): 1834-1844.
18. Marso SP., et al. “Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes”. The New England Journal of Medicine 4 (2016): 311-322.
19. Kanie T., et al. “Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis”. The Cochrane Database of Systematic Reviews10 (2021): Cd013650.
20. Pontes-da-Silva RM., et al. “Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist”. International Journal of Obesity1 (2022): 21-29.
21. Hernandez NS., et al. “GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA”. Molecular Psychiatry 8 (2021): 4394-4408.
22. Farokhnia M., et al. “Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use”. Scientific Reports 1 (2022): 13027.
23. Au HCT., et al. “A systematic review in effects of gluc“Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use”. agon-like peptide-1 (GLP-1) mono-agonists on functional connectivity: Target engagement and rationale for the development in mental disorders”. Journal of Affective Disorders 370 (2025): 321-327.
24. Hayman MME., et al. “Association of GLP1R locus with mental ill-health endophenotypes and cardiometabolic traits: A trans-ancestry study in UK Biobank”. Diabetes, Obesity and Metabolism 4 (2025): 1845-1858.
25. GLP-1 receptor agonists and suicidality”. BMJ 388 (2025):
26. Maideen NMP and Al Rashid S. “Suicidal Thoughts and Self-injurious Behavior Associated With Glucagon- Like Peptide-1 Receptor Agonists - A Review”. Current Drug Safety 3 (2025): 253-257.
27. Di Stefano R., et al. “Glucagon-Like Peptide-1 receptor agonists, dual GIP/GLP-1 receptor agonist tirzepatide and suicidal ideation and behavior: A systematic review of clinical studies and pharmacovigilance reports”. Diabetes, Metabolic Syndrome 4 (2025): 103238.
28. Kim TH., et al. “Adverse drug reaction patterns of GLP-1 receptor agonists approved for obesity treatment: Disproportionality analysis from global pharmacovigilance database”. Diabetes, Metabolic Syndrome 6 (2025): 3490-3502.
29. Lu W., et al. “Neuropsychiatric adverse events associated with Glucagon-like peptide-1 receptor agonists: a pharmacovigilance analysis of the FDA Adverse Event Reporting System database”. European Psychiatry 1 (2025): e20.
30. Almeida OP. “Risk of depression and dementia among individuals treated with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists”. Current Opinion in Psychiatry (2025).
31. Pierret ACS., et al. “Glucagon-Like Peptide 1 Receptor Agonists and Mental Health: A Systematic Review and Meta-Analysis”. JAMA Psychiatry(2025).
32. Sharafshah A., et al. “In Silico Pharmacogenomic Assessment of Glucagon-like Peptide-1 (GLP1) Agonists and the Genetic Addiction Risk Score (GARS) Related Pathways: Implications for Suicide Ideation and Substance Use Disorder”. Current Neuropharmacology (2025).
33. Blum K., et al. “Hypothesizing glucagon-like peptide 1 (GLP-1), agonists promote hypodopaminergia, resulting in heightened addictive reward-seeking and altered mood: Breaking the bubble and adding salt to a wound”. Medical Hypotheses 198 (2025): 111612.

Citation

Citation: Kenneth Blum., et al. “Semaglutide Injection, a GLP1 Agonist, Induced Depression and First Time Suicidal Ideation in a Female with Long-standing Anxiety".Acta Scientific Neurology 8.7 (2025): 14-21.

Copyright

Copyright: © 2025 Kenneth Blum., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.