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ORIGINAL RESEARCH ARTICLE

Pre-addiction phenotype is associated with dopaminergic dysfunction: Evidence from 88.8 million genome-wide association study-based samples

Kenneth Blum1,2,3,4,5,6,7,8,9, 10,11,12,13* ,  Alireza Sharafshah14 ,  Kai-Uwe Lewandrowski12,13,15,16 ,  Sérgio Luís Schmidt13 ,  Rossano Kepler Alvim Fiorelli13 ,  Albert Pinhasov1 ,  Abdalla Bowirrat1 ,  Mark S. Gold17 ,  Eliot L. Gardner18 ,  Panayotis K. Thanos1,19 ,  Brian Fuehrlein20 ,  David Baron2,21 ,  Igor Elman1,22 ,  Catherine A. Dennen23 ,  Nicole Jafari9, 24 ,  Foojan Zeine10,25 ,  Alexander P.L. Lewandrowski26 ,  Milan Makale27 ,  Edward J. Modestino28 ,  Keerthy Sunder2,7,29 ,  Kevin T. Murphy5 ,  Chynna Fliegelman30 ,  Shaurya Mahajan3,7 ,  Yatharth Mahajan3 ,  Rajendra D. Badgaiyan31
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1 Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel
2 Division of Addiction Research and Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, California, United States of America
3 Division of Clinical Neurology, The Blum Institute of Neurogenetics and Behavior, Austin, Texas, United States of America
4 Brain and Behavior Laboratory, Department of Psychology, Curry College, Milton, Massachusetts, United States of America
5 Division of Personalized Neuromodulation, PeakLogic, Del Mar, California, United States of America
6 Department of Psychology, Institute of Psychology, Eotvos Lorand University Budapest, Budapest, Hungary
7 Division of Precision Neuromodulation, Sunder Foundation, Palm Springs, California, United States of America
8 Department of Psychiatry, University of Vermont, Burlington, Massachusetts, United States of America
9 Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, California, United States of America
10 Division Psychological Therapy, Awareness Integration Institute, San Clemente, California, United States of America
11 Department of Psychiatry, Wright University, Boonshoff School of Medicine, Dayton, Ohio, United States of America
12 Division of Personalize Pain Modulation, Center for Advanced Spine Care of Southern Arizona, Tucson, Arizona, United States of America
13 Programa de Pós-Graduação em Neurologia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
14 Cellular and Molecular Research Center, School of Medicine, Guilin University of Medical Sciences, Rasht, Iran
15 Department of Orthopedics, Sanitas University Foundation, Bogotá, Washington D.C., United States of America
16 Department of Spine Surgery, University of Arizona, School of Medicine, Tucson, Arizona, United States of America
17 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
18 Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America
19 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, New York, United States of America
20 Yale University School of Medicine, Yale-New Haven Hospital, New Haven, Connecticut, United States of America; Psychiatric Emergency Room, VA Connecticut, Yale University, United States of America
21 Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California, United States of America
22 Department of Psychiatry, Harvard University, College of Medicine, Cambridge, Massachusetts, United States of America
23 Department of Family Medicine, Jefferson Health Northeast, Philadelphia, Pennsylvania, United States of America
24 Department of Applied Clinical Psychology, The Chicago School of Professional Psychology, Los Angeles, California, United States of America
25 Department of Health Science, California State University at Long Beach, Long Beach, California, United States of America
26 Department of Biological Sciences, Dornsife College of Letters, Arts & Sciences, University of Southern California, Los Angeles, California, United States of America
27 Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, California, United States of America
28 Brain and Behavior Laboratory, Curry College, Milton, Massachusetts, United States of America
29 Department of Medicine, University of California, Riverside School of Medicine, Riverside, California, United States of America
30 Department of Psychology, St. John’s University, Queens, New York City, New York, United States of America
31 Department of Psychiatry, Texas Tech University Health Sciences, School of Medicine, Midland, Texas, United States of America
GPD, 8090 https://doi.org/10.36922/gpd.8090
Received: 20 December 2024 | Revised: 6 May 2025 | Accepted: 6 May 2025 | Published online: 3 July 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

The convergence of neurogenetics, epigenetics, and functional neuroimaging presented in this article marks a critical inflection point in our understanding and management of reward deficiency syndrome (RDS) and its behavioral expressions across pain and addiction medicine. The evidence for a hypodopaminergic state, now supported by decades of molecular, clinical, and imaging data, has culminated in the formulation of a scientifically grounded, personalized, and preventative paradigm— anchored by the concept of early genetic testing to provide risk information linked to “prediction” predominantly due to dopaminergic dysfunction. From a translational standpoint, this model offers more than a framework for understanding neurobiological vulnerability; it provides a practical roadmap for early identification of “pre-addiction,” informed opioid prescribing, relapse prevention, and long-term neurorecovery. The coupling of Genetic Addiction Risk Severity (GARS) with dopaminergic modulation—via safe, non-addictive interventions—could redefine standard treatment algorithms not only for substance use disorders but also for a broader spectrum of compulsive and comorbid behaviors. This study by members of the RDS Consortium explores the concept of “pre-addiction” within addiction biology through a comprehensive in silico analysis of 88,788,381 genome-wide association study-based samples from 1,373 studies, identifying 18 significant genes (e.g., APOE with p=1.0E-126) linked to opioids, pain, aging, and apoptosis pathways. It aims to correlate these genes with GARS, which includes 10 specific genes, and highlights the most connected genes, such as MAOA, COMT, APOE, and SLC4A6, through a STRING model. The analysis expanded to 27 unique genes, emphasizing significant interactions with hsa-miR-16-5p and hsa-miR-24-3p, especially SLC6A4. Through pharmacogenomics mining, 1,173 variant annotations were identified for these genes. Enrichment analysis and meta-analysis further validated these findings, illustrating the pivotal role of dopaminergic pathways in connecting addictive behaviors and depressive symptoms. The results support the conceptualization of RDS as the fundamental preaddiction phenotype, with pain, opioid dependence, aging, and apoptosis as critical endophenotypes.

Graphical abstract
Keywords
Pre-addiction
Genetic addiction risk severity
Dopaminergic pathways
Reward deficiency syndrome
APOE
Opioid dependence
Aging
Apoptosis
Funding
This study was funded by the grant (R41 MD012318/MD/ NIMHD NIH HHS/United States; K.B. and M.G.L.).
Conflict of interest
Dr. Kenneth Blum, the senior author, is credited with more than 100 worldwide patents on the GARS test and KB220 and patents pending for gene editing. Dr. Blum has licensed one of his patents (10,894,024) to Victory Nutrition International (VNI). He is a paid scientific advisor to some companies, including Electronic Waveform Labs (Huntington Beach, CA); PEAK LOGIC (Del Mar, CA); Center for Advanced Spine Care of Southern Arizona (Tucson); and Sunder Foundation (Palm Springs, CA). Dr. Kenneth Blum is also the Associate Editor and Kai Uwe Lewandowski and Rajendra D Badgaiyan are the Editorial Board Members of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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