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Saptadip Samanta,1 Debasis Bagchi,2,3 Mark S Gold,4 Rajendra D Badgaiyan,5 Debmalya Barh,6 Kenneth Blum7– 12 1Department of Physiology, Midnapore College, Midnapore, West Bengal, 721101, India; 2Department of Biology, College of Arts and Sciences, Adelphi University, Garden City, NY, USA and Department of Psychology, Gordon F. Derner School of Psychology, Adelphi University, Garden City, NY, USA; 3Department of Pharmaceutical Sciences, College of Pharmacy, Southern University, Houston, TX, 77004, USA; 4Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; 5Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 6Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur 721172, West Bengal, India; 7Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University Health Sciences, Pomona, CA, 91766, USA; 8Institute of Psychology, Eotvos Loránd University, Budapest, 1053, Hungary; 9Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Center, Dayton, OH, 45435, USA; 10Department of Psychiatry, University of Vermont, Burlington, VT, 05405, USA; 11Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX, 78701, USA; 12Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, IsraelCorrespondence: Saptadip Samanta; Debasis Bagchi, Email saptadip174@gmail.com; saptadip.samanta@midnaporecollege.ac.in; dbagchi@adelphi.eduAbstract: The human brain not only controls the various physiological functions but is also the prime regulator of circadian rhythms, rewards, and behaviors. Environmental factors, professional stress, and social disintegration are regarded as the initial causative factors of addiction behavior. Shift work, artificial light exposure at night, and chronic and acute jet lag influence circadian rhythm dysfunction. The result is impaired neurotransmitter release, dysfunction of neural circuits, endocrine disturbance, and metabolic disorder, leading to advancement in substance use disorder. There is a bidirectional relationship between chronodisruption and addiction behavior. Circadian rhythm dysfunction, neuroadaptation in the reward circuits, and alteration in clock gene expression in the mesolimbic areas influence substance use disorder (SUD), and chronotherapy has potential benefits in the treatment strategies. This review explores the relationship among the circadian rhythm dysfunction, reward circuit, and SUD. The impact of chronotherapy on SUD has also been discussed.Keywords: SCN, circadian rhythm dysfunction, melatonin, cortisol, drug addiction

Susan Sedhom,1 Nikki Hammond,1 Kyriaki Z Thanos,1 Kenneth Blum,2,3 Igor Elman,4 Abdalla Bowirrat,3 Catherine Anne Dennen,5 Panayotis K Thanos1 1Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA; 2Division of Addiction Research & Education, Center for Sports, Exercise & Global Mental Health, Western University Health Sciences, Pomona, CA, USA; 3Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, Israel; 4Department of Psychiatry, Harvard School of Medicine, Cambridge Health Alliance, Cambridge, MA, USA; 5Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USACorrespondence: Panayotis K Thanos; Kenneth Blum, Email thanos@buffalo.edu; drd2gene@gmail.comAbstract: Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.Keywords: exercise, alcohol use disorder, AUD, NMDA receptors, brain, reward

Shannon Rae Klein,1 Kenneth Blum,2 Mark S Gold,3 Panayotis K Thanos1,4 1Behavioral 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, NY, USA; 2Center for Sports, Exercise, & Mental Health, Western University Health Sciences, Pomona, CA, 91766, USA; 3Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63130, USA; 4Department of Psychology, University at Buffalo, Buffalo, NY, 14203, USACorrespondence: Panayotis K Thanos, Tel +1 716 881-7520, Email thanos@buffalo.eduAbstract: Methylphenidate (MP) is a psychostimulant commonly prescribed for individuals with attention deficit hyperactivity disorder (ADHD) but it is also taken with and without a prescription for performance enhancement. Prior research has characterized the effects of MP on behavior, cognition, and neurochemistry. This exploratory review covers the uses of MP and examined the effects of MP on gene expression in the brain following exposure. Overall, MP causes a wide-spread potentiation of genes, in a region-specific manner; consequently, inducing neuronal alterations, such as synaptic plasticity and transmission, resulting in observed behaviors and affects. Monoamine neurotransmitters and post-synaptic density protein genes generally had a potentiating effect in gene expression after exposure to MP.Keywords: addiction, substance abuse, methylphenidate, gene expression, monoamine neurotransmitters postsynaptic density proteins, reward deficiency syndrome

Kenneth Blum,1– 7 Igor Elman,8 Abdalla Bowirrat,1 David Baron,1 Panayotis K Thanos,9 Colin Hanna,9 Rajendra D Badgaiyan,10 Mark S Gold11 1Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel; 2Division of Addiction Research & Education, Center for Exercise Sports, Mental Health, Western University Health Sciences, Pomona, CA, USA; 3Institute of Psychology, Eötvös Loránd University, Budapest, Hungary; 4Department of Psychiatry, Boonshoft School of Medicine, Wright University, Dayton, OH, USA; 5Department of Psychiatry, Human Integrated Services Unit, University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA; 6Sunder Foundation, Palm Springs, CA, USA; 7PEAKLOGIC, LLC., Del Mar, CA, USA; 8Department of Psychiatry, Harvard College of Medicine, Cambridge, MA, USA; 9Behavioral 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; 10Department of Psychiatry, Case Western Reserve University and MetroHealth System, Cleveland, OH, USA; 11Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USACorrespondence: Kenneth Blum, Tel +1 404 234 5433, Email drd2gene@gmail.com

Abdalla Bowirrat,1 Igor Elman,2 Catherine A Dennen,3 Marjorie C Gondré-Lewis,4 Jean Lud Cadet,5 Jag Khalsa,6 David Baron,7 Diwanshu Soni,8 Mark S Gold,9 Thomas J McLaughlin,10 Debasis Bagchi,11 Eric R Braverman,12 Mauro Ceccanti,13 Panayotis K Thanos,14,15 Edward Justin Modestino,16 Keerthy Sunder,17,18 Nicole Jafari,19,20 Foojan Zeine,21,22 Rajendra D Badgaiyan,23 Debmalya Barh,24,25 Milan Makale,26 Kevin T Murphy,27 Kenneth Blum1,7,10,12,18,20,24,28,29 1Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel; 2Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, 02139, USA; 3Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA; 4Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, 20059, USA; 5Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Bethesda, MD, 20892, USA; 6Department of Microbiology, Immunology and Tropical Medicine, George Washington University, School of Medicine, Washington, DC, USA; 7Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA, 91766, USA; 8Western University Health Sciences School of Medicine, Pomona, CA, USA; 9Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA; 10Division of Reward Deficiency Clinics, TranspliceGen Therapeutics, Inc, Austin, TX, USA; 11Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy, Houston, TX, USA; 12Division of Clinical Neurology, The Kenneth Blum Institute of Neurogenetics & Behavior, LLC, Austin, TX, USA; 13Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, 00185, Italy; 14Behavioral 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, 14203, USA; 15Department of Psychology, State University of New York at Buffalo, Buffalo, NY, 14203, USA; 16Department of Psychology, Curry College, Milton, MA, USA; 17Karma Doctors & Karma TMS, and Suder Foundation, Palm Springs, CA, USA; 18Department of Medicine, University of California, Riverside School of Medicine, Riverside, CA, USA; 19Department of Human Development, California State University at Long Beach, Long Beach, CA, USA; 20Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, CA, USA; 21Awareness Integration Institute, San Clemente, CA, USA; 22Department of Health Science, California State University at Long Beach, Long Beach, CA, USA; 23Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY, USA; 24Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur, WB, 721172, India; 25Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil; 26Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, CA, 92093-0819, USA; 27Department of Radiation Oncology, University of California San Diego, La Jolla, CA, USA; 28Department of Psychiatry, University of Vermont School of Medicine, Burlington, VA, USA; 29Institute of Psychology, ELTE Eötvös Loránd University, Budapest, HungaryCorrespondence: Igor Elman; Kenneth Blum, Email dr.igorelman@gmail.com; drd2gene@gmail.comAbstract: Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.Keywords: addiction, affective, alcohol, anti-reward, anxiety, depression, dopamine, cancer, genes, cardiovascular, cognitive, medical, motivation, social isolation, reward deficiency

Kenneth Blum,1– 5 Panayotis K Thanos,6 Colin Hanna,6 Mark S Gold,7 David Baron,2 Igor Elman8 1Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel; 2Division of Addiction Research & Education, Center for Exercise Sports, Mental Health, Western University Health Sciences, Pomona, CA, USA; 3Institute of Psychology, Eötvös Loránd University Budapest, Budapest, Hungary; 4Department of Psychiatry, Boonshoft School of Medicine, Wright University, Dayton, OH, USA; 5Department of Psychiatry, Human Integrated Services Unit, University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA; 6Behavioral 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; 7Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; 8Department of Psychiatry, Harvard University College of Medicine, Cambridge, MA, USACorrespondence: Kenneth Blum, Email drd2gene@gmail.comAbstract: Since 1990, there have been thousands of published studies on addiction psychiatry. Several from Blum et al showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance abuse and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, reactions have been mixed. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al 1990; a significant association between the minor DRD2 allele, Taq A1 and severe alcoholism. Additionally, the DRD2 rs1800497 is robustly associated with suicidal behaviors. Furthermore, DNA polymorphic alleles underlying substance use disorder (SUD) with multiple substances were mapped via chromatin refolding, revealing that the DRD2 gene and associated polymorphism(s) as the top gene signal. Based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being one determinant of Reward Deficiency Syndrome (RDS) first reported in 1996.Keywords: GWAS, candidate genes, DRD2 gene, polymorphisms, hypodopaminergia, reward deficiency, addictive and non-addictive behaviors

Kenneth Blum,1– 5 Bruce Steinberg,6 Marjorie C Gondre-Lewis,7 David Baron,1 Edward J Modestino,6 Rajendra D Badgaiyan,8– 10 B William Downs,11 Debasis Bagchi,11 Raymond Brewer,5 Thomas McLaughlin,12 Abdalla Bowirrat,13 Mark Gold14 1Center for Psychiatry, Medicine & Primary Care, Division of Addiction Research & Education, Graduate College, Western University Health Sciences, Pomona, CA, USA; 2Eötvös Loránd University, Institute of Psychology, Budapest, Hungary; 3Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Center, Dayton, OH (IE), USA; 4Department of Psychiatry, University of Vermont, Burlington, VT, USA; 5Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX, USA; 6Department of Psychology, Curry College, Milton, MA, USA; 7Developmental Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, USA; 8Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 9Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, USA; 10Long School of Medicine, University of Texas Medical Center, San Antonio, TX, USA; 11Division of Nutrigenomics, Victory Nutrition International, Inc., Harleysville, PA, USA; 12Department of Psychopharmacology, Center for Psychiatric Medicine, Lawrence, MA, USA; 13Adelson School of Medicine & Department of Molecular Biology, Ariel University, Ariel, Israel; 14Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USACorrespondence: Bruce SteinbergDepartment of Psychology, Curry College, Milton, MA, USATel +1 617-333-2226Fax +1 617-333-2316Email Bsteinbe4@gmail.comAbstract: This is a review of research on “Precision Behavioral Management” of substance use disorder (SUD). America is experiencing a high prevalence of substance use disorder, primarily involving legal and illegal opioid use. A 3000% increase in treatment for substance abuse has occurred between 2000 and 2016. Unfortunately, present day treatment of opioid abuse involves providing replacement therapy with powerful opioids to, at best, induce harm reduction, not prophylaxis. These interventions do not enhance gene expression and restore the balance of the brain reward system’s neurotransmitters. We are proposing a generalized approach called “Precision Behavioral Management”. This approach includes 1) using the Genetic Addiction Risk Severity (GARS, a 10 candidate polymorphic gene panel shown to predict ASI-alcohol and drug severity) to assess early pre-disposition to substance use disorder; 2) using a validated reward deficiency syndrome (RDS) questionnaire; 3) utilization of the Comprehensive Analysis of Reported Drugs (CARD™) to assess treatment compliance and abstinence from illicit drugs during treatment, and, importantly; 4) utilization of a “Pro-dopamine regulator (KB220)” (via IV or oral [KB220Z] delivery systems) to optimize gene expression, restore the balance of the Brain Reward Cascade’s neurotransmitter systems and prevent relapse by induction of dopamine homeostasis, and; 5) utilization of targeted DNA polymorphic reward genes to direct mRNA genetic expression profiling during the treatment process. Incorporation of these events can be applied to not only the under-considered African-American RDS community, but all victims of RDS, as a demonstration of a paradigm shift that uniquely provides a novel putative “standard of care” based on DNA guided precision nutrition therapy to induce “dopamine homeostasis” and rebalance neurotransmitters in the Brain Reward Cascade. We are also developing a Reward Deficiency Syndrome Diagnostic Criteria (RDSDC) to assist in potential tertiary treatment.Keywords: substance use disorder, SUD, genomic disparity, dopamine, pro-dopamine regulation, KB220, GARS, homeostasis