A Comprehensive 4-layered In Silico Pharmacogenomics Analysis of the Genetic Addiction Risk Severity (GARS) Test: Strong Genetic Evidence Supporting GARS as a Novel Personalized Pre-addiction Assessment Tool in the Opioid Crisis Era

Alireza Sharafshah; Kai-Uwe Lewandrowski; Igor Elman; David Baron; Panayotis K Thanos; Colin Hanna; Mark S Gold; Rajendra D Badgaiyan; Jean Lud Cadet; Edward J Modestino; Eric R Braverman; Catherine A Dennen; Milan Makale; Keerthy Sunder; Kevin T Murphy; Abdalla Bowirrat; Albert Pinhasov; Marjorie Gondre-Lewis; Eliot Gardner; Daniel Sipple; Nicole Jafari; Foojan Zeine; Jag Khalsa; Rossano Kepler Alvim Fiorelli; Kenneth Blum

doi:10.2174/0113892010353450250408114725

A Comprehensive 4-layered In Silico Pharmacogenomics Analysis of the Genetic Addiction Risk Severity (GARS) Test: Strong Genetic Evidence Supporting GARS as a Novel Personalized Pre-addiction Assessment Tool in the Opioid Crisis Era

Curr Pharm Biotechnol. 2025;26(13):2153-2180. doi: 10.2174/0113892010353450250408114725.

Authors

Alireza Sharafshah¹, Kai-Uwe Lewandrowski^{2

3

4}, Igor Elman⁵, David Baron⁶, Panayotis K Thanos⁷, Colin Hanna⁷, Mark S Gold⁸, Rajendra D Badgaiyan⁹, Jean Lud Cadet¹⁰, Edward J Modestino¹¹, Eric R Braverman¹², Catherine A Dennen¹³, Milan Makale¹⁴, Keerthy Sunder^{15

16}, Kevin T Murphy^{17

18}, Abdalla Bowirrat¹⁹, Albert Pinhasov¹⁹, Marjorie Gondre-Lewis²⁰, Eliot Gardner²¹, Daniel Sipple²², Nicole Jafari²³, Foojan Zeine²⁴, Jag Khalsa²⁵, Rossano Kepler Alvim Fiorelli²⁶, Kenneth Blum^{6

12

16

18

19}

Affiliations

¹ Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
² Department of Orthopaedics, Fundación Universitaria Sanitas, Bogotá D.C., Colombia.
³ Center for Advanced Spine Care of Southern Arizona, Tucson AZ, USA.
⁴ Department of Orthopaedics, Universidade Federal do Estado do Rio de Janeiro, Brazil.
⁵ Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, USA.
⁶ Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA, USA.
⁷ Behavioral 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.
⁸ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
⁹ Department of Psychiatry, Case Western Reserve University, School of Medicine, Cleveland, OH., USA.
¹⁰ Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Bethesda, MD, USA.
¹¹ Department of Psychology, Curry College, Milton, MA, USA.
¹² Division of Clinical Neurology, The Kenneth Blum Institute of Neurogenetics and Behavior, LLC, Austin, Tx., USA.
¹³ Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA.
¹⁴ Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, CA., USA.
¹⁵ Department of Medicine, University of California, Riverside School of Medicine, Riverside, CA, USA.
¹⁶ Karma Doctors & Karma TMS, and Suder Foundation, Palm Springs, CA, USA.
¹⁷ Department of Radiation Oncology, University of California San Diego, La Jolla, CA, USA.
¹⁸ Division of Personalized Neuromodulation Reseach, PeakLogic, LLC., Del Mar, CA., USA.
¹⁹ Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel.
²⁰ Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Bethesda, MD, 20892, USA.
²¹ Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
²² Physical Medicine and Rehabilitation, Midwest Brain & Spine Institute, Roseville, MN, USA.
²³ Department of Health Science, California State University at Long Beach, Long Beach, CA., 90804, USA.
²⁴ Department of Applied Clinical Psychology, The Chicago School of Professional Psychology, Los Angeles, CA., 90017, USA.
²⁵ Division of Therapeutics and Medical Consequences, Medical Consequences of Drug Abuse and Infections Branch, National Institute on Drug Abuse, NIH, Special Volunteer, 16071 Industrial Drive, Gaithersburg, MD 20877 USA.
²⁶ Department of General and Specialized Surgery, Gaffrée e Guinle Universitary Hospital, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil.

PMID: 40247807
DOI: 10.2174/0113892010353450250408114725

Abstract

Background: Overdose involving opioids is the black heart of the addiction crisis. "Pre-addiction," as an encouraging concept by NIDA and NIAAA, seems best captured with the construct of dopamine dysregulation. Referring to the abundant publications on "Reward Deficiency Syndrome" (RDS), Genetic Addiction Risk Score (GARS) test, RDSQ29, and KB220, Pre-addiction can be referred to as "reward dysregulation" as a suitable suggestion. The hypothesis is that the true phenotype is RDS, and other behavioral disorders are endophenotypes where the genetic variants play important roles, specifically in the Brain Reward Cascade (BRC).

Methods: This study tested the pharmacogenomics of the GARS panel by a multi-model in silico investigation in four layers: 1) Protein-Protein Interactions (PPIs); 2) Gene Regulatory Networks (GRNs); 3) Disease, drugs and chemicals (DDCs); and 4) Gene Coexpression Networks (GCNs).

Results: All in silico findings were combined in an Enrichment Analysis for 59 refined genes, which represented highly significant associations of dopamine pathways in the BRC and supported our hypothesis.

Conclusion: This paper provides scientific evidence for the importance of incorporating GARS as a predictive test to identify Pre-addiction, introduce unique therapeutic targets assisting in the treatment of pain, drug dosing of prescription pharmaceuticals, and identify the risk for subsequent addiction early in -life.

Keywords: Genetic Addiction Risk Score (GARS); Pre-addiction; Reward Deficiency Syndrome (RDS); dopamine dysregulation; in silico.; pharmacogenomics.

MeSH terms

Analgesics, Opioid / adverse effects
Behavior, Addictive* / genetics
Computer Simulation
Gene Regulatory Networks
Genetic Predisposition to Disease
Humans
Opioid-Related Disorders* / genetics
Pharmacogenetics* / methods
Precision Medicine / methods
Protein Interaction Maps

Substances

Analgesics, Opioid

Grants and funding

R41 MD012318/MD/NIMHDNIH HHS/United States/National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health (NIH)