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

Alireza Sharafshah, Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
Kai-Uwe Lewandrowski, Department of Orthopaedics, Fundación Universitaria Sanitas Bogotá D.C. Colombia.
Mark S. Gold, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO., USA.
Brian Fuehrlein, Department of Psychiatry, Yale University School of Medicine, New Haven CT., USA.
J Wes Ashford, Center of Excellence in Gaming Research and Yale Program for Research on Impulsivity and Impulse Control Disorders, Department of Psychiatry, Yale University School of Medicine, New Haven, CT., USA.
Panayotis K. Thanos, Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY., USA.
Gene Jack Wang, Laboratory of Neuroimaging, National Institute of Alcohol Abuse & Alcoholism, Bethesda, MD, United States.
Colin Hanna, Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY., USA.
Jean Lud Cadet, Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Bethesda, MD., USA.
Eliot L. Gardner, Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Md., the USA.
Jag H. Khalsa, Division of Therapeutics and Medical Consequences, Medical Consequences of Drug Abuse and Infections Branch, National Institute on Drug Abuse, NIH, Special Volunteer, Industrial Drive, Gaithersburg, MD. The USA.
Eric R. Braverman, The Kenneth Blum Behavioral & Neurogenetic Institute, LLC., Austin, TX., USA.
David Baron, Center for Sports, Exercise, Mental Health, Western University Health Sciences, Lebanon, OR., USA.
Igor Elman, Cambridge Health Alliance, Harvard Medical School, Cambridge, MA., USA.
Catherine A. Dennen, Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA., USA.
Abdalla Bowirrat, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel.
Albert Pinhasov, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel.
Edward J. Modestino, Brain & Behavior Laboratory, Department of Psychology, Curry College, Milton, MA., 02186, USA.
Paul R. Carney, Departments of Pediatrics and Neurology, University of Missouri School of Medicine, Columbia, 65212, Missouri, USA.
Rene Cortese, Departments of Pediatrics and Obstetrics, Gynecology and Women's Health. School of Medicine. University of Missouri, Columbia, MO, 65212, USA.
Rossano Kepler Fiorelli, Department of General and Specialized Surgery, Gaffrée e Guinle University Hospital, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil.
Sergio Schmidt, Post-Graduate Program in Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
Aryeh R. Pollack, The Kenneth Blum Behavioral & Neurogenetic Institute, LLC., Austin, TX., 78701, USA.
Rajendra D. Badgaiyan, Division Personalized Pain Research and Education, Center for Advanced Spine Care of Southern Arizona, Tucson, AZ., 85712, USA.
Kenneth Blum, Center For Advanced Spine Care of Southern Arizona Division Personalized Pain Research and Education Tucson United States.

Document Type

Journal Article

Publication Date

1-24-2025

Journal

Current neuropharmacology

DOI

10.2174/011570159X349579241231080602

Keywords

GLP1; In-depth in silico; Ozempic; Substance Use Disorder; Suicide Ideation; dopamine homeostasis

Abstract

INTRODUCTION: Glucagon-Like Peptide-1 Receptor (GLP1R) agonists have become widespread anti-obesity/diabetes pharmaceuticals in the United States. AIM: This article aimed to provide our current knowledge on the plausible mechanisms linked to the role of Ozempic (Semaglutide), which is generalized as one of the anti-addiction compounds. METHODS: The effects of GLP1R agonists in Alcohol Use Disorder (AUD) and substance use disorder (SUD) are mediated, in part, through the downregulation of dopamine signaling. We posit that while GLP1R agonism could offer therapeutic advantages in hyperdopaminergia, it may be detrimental in patients with hypodopaminergia, potentially leading to long-term induction of Suicidal Ideation (SI). The alleged posit of GLP1 agonists to induce dopamine homeostasis is incorrect. This study refined 31 genes based on the targets of Ozempic, GLP1R, and related enzymes for SI and 10 genes of the Genetic Addiction Risk Score (GARS) test. STRING-MODEL refined 29 genes, and further primary analyses indicated associations of GLP1R with DRD3, BDNF, CREB1, CRH, IL6, and DPP4. RESULTS: In-depth silico enrichment analysis revealed an association between candidate genes and depressive phenotypes linked with dopaminergic signaling. Finally, through primary and in-depth silico analyses, we demonstrated multiple findings supporting that GLP1R agonists can induce depression phenotypes. CONCLUSION: Our findings suggest that associated polymorphisms seem to have overlapping effects with addictive behaviors of Reward Deficiency Syndrome (RDS) and dopamine regulation. Consequently, GLP1R agonists may represent a double-edged sword, potentially triggering both antiaddictive effects and SI by exacerbating depressive phenotypes. Thus, we encourage the scientific community to perform further empirical clinical studies to confirm this proposed pathway.

Department

Microbiology, Immunology, and Tropical Medicine

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