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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

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

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– 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

John H Peniston,1 Morris S Gold,2 Matthew S Wieman,3 Lawrence K Alwine4 1Feasterville Family Health Care Center, Feasterville, PA, 2Novartis Consumer Health, Inc, Parsippany, NJ, 3Endo Pharmaceuticals Inc, Malvern, PA, 4Downingtown Family Medicine, Downingtown, PA, USA Background: Topical diclofenac sodium 1% gel (DSG) has demonstrated efficacy and tolerability in patients with osteoarthritis (OA) of the knees or hands, including elderly patients and those with an increased risk of gastrointestinal, cardiovascular, and renal adverse events (AEs). Medications known to interact with diclofenac were disallowed in a clinical trial of DSG for knee OA; however, patients were not to be discontinued for intake of disallowed treatment, unless there was a safety issue. This post hoc analysis examined the frequency and type of AEs in patients who received DSG concomitantly with drugs known to have potential interactions with diclofenac. Materials and methods: This was a post hoc analysis of a randomized controlled trial of DSG for knee OA pain. Patients (n = 254) aged ≥ 35 years with OA in one or both knees, but with clinical OA symptoms in only one knee, administered DSG topically to the target knee four times daily (total dose, 16 g/d) for 12 weeks. Drugs with the potential for major or moderate drug–drug interactions (DDIs) were identified via Drugs.com. AE rates were compared in patients with versus those without ≥1 potential DDI. Results: At least one AE was experienced by 62.6% (107/171) of patients with ≥1 DDI and by 55.4% (46/83) of patients with no DDIs. Gastrointestinal AEs (upper and lower) were reported in 5.3% (9/171) and 7.2% (6/83), cardiovascular AEs in 4.7% (8/171) and 1.2% (1/83), renal AEs in 1.2% (2/171) and 0%, and hepatic AEs in 0% and 1.2% (1/83) of patients with ≥1 DDI compared with patients with no DDIs, respectively. Conclusion: Concurrent use of DSG with medications that had potential for major to moderate DDIs had little impact on the frequency of AEs in this population. Further research is needed to consider how factors such as dose, duration, and timing of concomitant drug administration may affect the likelihood of clinically evident AEs resulting from a potential DDI. Keywords: drug interactions, nonsteroidal anti-inflammatory drugs, topical administration, knee osteoarthritis

John H Peniston,1 Morris S Gold,2 Matthew S Wieman,3 Lawrence K Alwine41Feasterville Family Health Care Center, Feasterville, PA, 2Clinical Research and Biostatistics, Novartis Consumer Health Inc, Parsippany, NJ, 3Medical Affairs, Endo Pharmaceuticals Inc, Chadds Ford, PA, 4Downingtown Family Medicine, Downingtown, PA, USABackground: Adverse events associated with nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat knee and hand osteoarthritis may be more frequent in certain patient populations. Topical NSAIDs, such as diclofenac sodium 1% gel (DSG), have equivalent efficacy and fewer adverse events compared with oral NSAIDs. This post hoc analysis assessed the long-term tolerability of DSG in elderly patients and patients with an elevated risk of gastrointestinal, cardiovascular, and renal adverse events.Methods: Patients ≥ 35 years of age with knee osteoarthritis applied DSG (4 g) to one or both knees for 12 weeks during either of two primary studies and for 9 months during a long-term extension study. Other patients entered the long-term extension study directly and applied DSG for 12 months. Safety was assessed by reported adverse events. Subpopulations were defined based on age, or the comorbidities of hypertension, type 2 diabetes mellitus, and cerebrovascular or cardiovascular disease.Results: The safety population consisted of 947 patients who received at least one dose of DSG during the primary or extension study. Patients aged < 65 years (68.2%) and ≥65 years (67.2%) experienced any adverse event at similar rates. The percentage of patients who experienced any adverse event was similar between patients with and without hypertension (65.5% versus 69.7%, respectively), type 2 diabetes mellitus (64.0% versus 68.2%), or cerebrovascular or cardiovascular disease (61.9% versus 68.5%). Among the 15 patients with all three comorbidities, the percentage of patients with any adverse event (53.3%) was less than that of patients who did not have all three comorbidities (68.0%).Conclusion: These results suggest that long-term DSG treatment is safe in patient subpopulations with an elevated risk of NSAID-related adverse events, such as the elderly and those with the comorbidities of hypertension, type 2 diabetes mellitus, and cerebrovascular or cardiovascular disease.Keywords: diclofenac, nonsteroidal anti-inflammatory drugs, osteoarthritis, topical analgesic