{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T09:03:23Z","timestamp":1778317403139,"version":"3.51.4"},"reference-count":74,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Reward Deficiency Syndrome (RDS) is defined as a breakdown of reward neurotransmission that results in a wide range of addictive, compulsive, and impulsive behaviors. RDS is caused by a combination of environmental (epigenetic) influences and DNA-based (genetic) neurotransmission deficits that interfere with the normal satisfaction of human physiological drives (i.e., food, water, and sex). An essential feature of RDS is the lack of integration between perception, cognition, and emotions that occurs because of (1) significant dopaminergic surges in motivation, reward, and learning centers causing neuroplasticity in the striato-thalamic-frontal cortical loop; (2) hypo-functionality of the excitatory glutamatergic afferents from the amygdala\u2013hippocampus complex. A large volume of literature regarding the known neurogenetic and psychological underpinnings of RDS has revealed a significant risk of dopaminergic gene polymorphic allele overlap between cohorts of depression and subsets of schizophrenia. The suggestion is that instead of alcohol, opioids, gambling disorders, etc. being endophenotypes, the true phenotype is RDS. Additionally, reward deficiency can result from depleted or hereditary hypodopaminergia, which can manifest as a variety of personality traits and mental\/medical disorders that have been linked to genetic studies with dopamine-depleting alleles. The carrying of known DNA antecedents, including epigenetic insults, results in a life-long vulnerability to RDS conditions and addictive behaviors. Epigenetic repair of hypodopaminergia, the causative basis of addictive behaviors, may involve precision DNA-guided therapy achieved by combining the Genetic Addiction Risk Severity (GARS) test with a researched neutraceutical having a number of variant names, including KB220Z. This nutraceutical formulation with pro-dopamine regulatory capabilities has been studied and published in peer-reviewed journals, mostly from our laboratory. Finally, it is our opinion that RDS should be given an ICD code and deserves to be included in the DSM-VI because while the DSM features symptomology, it is equally important to feature etiological roots as portrayed in the RDS model.<\/jats:p>","DOI":"10.3390\/jpm12101719","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T02:29:46Z","timestamp":1665973786000},"page":"1719","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Should Reward Deficiency Syndrome (RDS) Be Considered an Umbrella Disorder for Mental Illness and Associated Genetic and Epigenetic Induced Dysregulation of Brain Reward Circuitry?"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6727-803X","authenticated-orcid":false,"given":"Kenneth","family":"Blum","sequence":"first","affiliation":[{"name":"The Kenneth Blum Behavioral & Neurogenetic Institute, LLC., Austin, TX 78701, USA"},{"name":"Center for Behavioral Health & Sports, Exercise, Psychiatry, Western University Health Sciences, Pomona, CA 91766, USA"},{"name":"Institute of Psychology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, Kazinczy u. 23\u201327, 1075 Budapest, Hungary"},{"name":"Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel 40700, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine A.","family":"Dennen","sequence":"additional","affiliation":[{"name":"The Kenneth Blum Behavioral & Neurogenetic Institute, LLC., Austin, TX 78701, USA"},{"name":"Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Elman","sequence":"additional","affiliation":[{"name":"Medicine, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Cambridge Health Alliance, Harvard Medical School, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-0688","authenticated-orcid":false,"given":"Abdalla","family":"Bowirrat","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel 40700, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panayotis K.","family":"Thanos","sequence":"additional","affiliation":[{"name":"Behavioral Neuropharmacology and Neuroimaging Laboratory, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Clinical Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA"},{"name":"Department of Psychology, University at Buffalo, Buffalo, NY 14260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5586-5114","authenticated-orcid":false,"given":"Rajendra D.","family":"Badgaiyan","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Medical Center, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2096-8265","authenticated-orcid":false,"given":"B. William","family":"Downs","sequence":"additional","affiliation":[{"name":"Division of Precision Nutrition, Victory Nutrition International, LLC., Lederoch, PA 19438, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debasis","family":"Bagchi","sequence":"additional","affiliation":[{"name":"Division of Precision Nutrition, Victory Nutrition International, LLC., Lederoch, PA 19438, USA"},{"name":"Department of Pharmaceutical Science, College of Pharmacy & Health Sciences, Texas Southern University, Houston, TX 77004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Baron","sequence":"additional","affiliation":[{"name":"Center for Behavioral Health & Sports, Exercise, Psychiatry, Western University Health Sciences, Pomona, CA 91766, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric R.","family":"Braverman","sequence":"additional","affiliation":[{"name":"The Kenneth Blum Behavioral & Neurogenetic Institute, LLC., Austin, TX 78701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-2755","authenticated-orcid":false,"given":"Ashim","family":"Gupta","sequence":"additional","affiliation":[{"name":"Future Biologics, Lawrenceville, GA 30043, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Green","sequence":"additional","affiliation":[{"name":"The Kenneth Blum Behavioral & Neurogenetic Institute, LLC., Austin, TX 78701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"The Kenneth Blum Behavioral & Neurogenetic Institute, LLC., Austin, TX 78701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2557-7768","authenticated-orcid":false,"given":"Debmalya","family":"Barh","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur 721172, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark S.","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.neubiorev.2020.04.021","article-title":"Pre-clinical models of reward deficiency syndrome: A behavioral octopus","volume":"115","author":"Bassey","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s12035-014-8726-5","article-title":"Genetic Addiction Risk Score (GARS): Molecular neurogenetic evidence for predisposition to Reward Deficiency Syndrome (RDS)","volume":"50","author":"Blum","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Blum, K., Bowirrat, A., Braverman, E.R., Baron, D., Cadet, J.L., Kazmi, S., Elman, I., Thanos, P.K., Badgaiyan, R.D., and Downs, W.B. (2021). Reward Deficiency Syndrome (RDS): A Cytoarchitectural Common Neurobiological Trait of All Addictions. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph182111529"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Blum, K., Soni, D., Badgaiyan, R.D., and Baron, D. (J. Osteopat. Med., 2022). Overcoming reward deficiency syndrome by the induction of \u201cdopamine homeostasis\u201d instead of opioids for addiction: Illusion or reality?, J. Osteopat. Med., ahead of print.","DOI":"10.1515\/jom-2021-0026"},{"key":"ref_5","first-page":"2","article-title":"Summary Document Research on RDS Anti-addiction Modelling: Annotated Bibliography","volume":"8","author":"Blum","year":"2022","journal-title":"J. Syst. Integr. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1556\/2006.2020.00033","article-title":"Co-occurrences of substance use and other potentially addictive behaviors: Epidemiological results from the Psychological and Genetic Factors of the Addictive Behaviors (PGA) Study","volume":"9","author":"Kotyuk","year":"2020","journal-title":"J. Behav. Addict."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"528","DOI":"10.2174\/1389201021666191210112108","article-title":"Hypodopaminergia and \u201cPrecision Behavioral Management\u201d (PBM): It is a Generational Family Affair","volume":"21","author":"Fried","year":"2020","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.2147\/PRBM.S292958","article-title":"A Review of DNA Risk Alleles to Determine Epigenetic Repair of mRNA Expression to Prove Therapeutic Effectiveness in Reward Deficiency Syndrome (RDS): Embracing \u201cPrecision Behavioral Management\u201d","volume":"14","author":"Blum","year":"2021","journal-title":"Psychol. Res. Behav. Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.yfrne.2010.12.004","article-title":"Genes, hormones, and circuits: An integrative approach to study the evolution of social behavior","volume":"32","author":"Hofmann","year":"2011","journal-title":"Front. Neuroendocr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Blum, K., Gondr\u00e9-Lewis, M., Steinberg, B., Elman, I., Baron, D., Modestino, E.J., Badgaiyan, R.D., and Gold, M.S. (2018). Our evolved unique pleasure circuit makes humans different from apes: Reconsideration of data derived from animal studies. J. Syst. Integr. Neurosci., 4.","DOI":"10.15761\/JSIN.1000191"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1080\/02791072.2012.662112","article-title":"Sex, Drugs, and Rock \u2018N\u2019 Roll: Hypothesizing Common Mesolimbic Activation as a Function of Reward Gene Polymorphisms","volume":"44","author":"Blum","year":"2012","journal-title":"J. Psychoact. Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1001\/jama.1990.03440150063027","article-title":"Allelic association of human dopamine D2 receptor gene in alcoholism","volume":"263","author":"Blum","year":"1990","journal-title":"JAMA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1001\/archpsyc.1991.01810310066012","article-title":"Allelic Association of the D2 Dopamine Receptor Gene with Receptor-Binding Characteristics in Alcoholism or Gene ism","volume":"48","author":"Noble","year":"1991","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.3109\/10826088509047251","article-title":"Diffusion of an Idea: Jellinek\u2019s Disease Concept in Latin America","volume":"20","author":"Caetano","year":"1985","journal-title":"Int. J. Addict."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1007\/s00213-021-06013-4","article-title":"Is addiction a brain disease? A plea for agnosticism and heterogeneity","volume":"239","author":"Pickard","year":"2022","journal-title":"Psychopharmacology"},{"key":"ref_16","first-page":"37","article-title":"The D2 dopamine receptor gene as a predictor of compulsive disease: Bayes\u2019 theorem","volume":"10","author":"Blum","year":"1995","journal-title":"Funct. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1018","DOI":"10.1038\/tp.2016.289","article-title":"Further support for association between GWAS variant for positive emotion and reward systems","volume":"7","author":"Lancaster","year":"2017","journal-title":"Transl. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/s41593-021-00860-2","article-title":"Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions","volume":"24","author":"Levey","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gupta, A., Bowirrat, A., Gomez, L.L., Baron, D., Elman, I., Giordano, J., Jalali, R., Badgaiyan, R.D., Modestino, E.J., and Gold, M.S. (2022). Hypothesizing in the Face of the Opioid Crisis Coupling Genetic Addiction Risk Severity (GARS) Testing with Electrotherapeutic Nonopioid Modalities Such as H-Wave Could Attenuate Both Pain and Hedonic Addictive Behaviors. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19010552"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuron.2015.11.027","article-title":"Common Brain Mechanisms of Chronic Pain and Addiction","volume":"89","author":"Elman","year":"2016","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117137","DOI":"10.1016\/j.jns.2020.117137","article-title":"Neurological correlates of brain reward circuitry linked to opioid use disorder (OUD): Do homo sapiens acquire or have a reward deficiency syndrome?","volume":"418","author":"Gold","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1038\/sj.npp.1301051","article-title":"Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents","volume":"31","author":"Elman","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1097\/00008571-199712000-00006","article-title":"D2 dopamine receptor gene (DRD2) Taql A polymorphism: Reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele","volume":"7","author":"Thompson","year":"1997","journal-title":"Pharmacogenetics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fpsyt.2018.00029","article-title":"Threat Response System: Parallel Brain Processes in Pain vis-\u00e0-vis Fear and Anxiety","volume":"9","author":"Elman","year":"2018","journal-title":"Front. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1176\/appi.ajp.2016.16030353","article-title":"Using Neuroscience to Help Understand Fear and Anxiety: A Two-System Framework","volume":"173","author":"LeDoux","year":"2016","journal-title":"Am. J. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1748","DOI":"10.1002\/mpr.1748","article-title":"The psychological and genetic factors of the addictive behaviors (PGA) study","volume":"28","author":"Kotyuk","year":"2019","journal-title":"Int. J. Methods Psychiatr. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Vereczkei, A., Barta, C., Magi, A., Farkas, J., Eisinger, A., Kir\u00e1ly, O., Belik, A., Griffiths, M.D., Szekely, A., and Sasv\u00e1ri-Sz\u00e9kely, M. (2022). FOXN3 and GDNF Polymorphisms as Common Genetic Factors of Substance Use and Addictive Behaviors. J. Pers. Med., 12.","DOI":"10.3390\/jpm12050690"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3109\/00952998709001520","article-title":"Alcohol and Opioid Peptides: Neuropharmacological Rationale for Physical Craving of Alcohol","volume":"13","author":"Trachtenberg","year":"1987","journal-title":"Am. J. Drug Alcohol Abus."},{"key":"ref_29","first-page":"1000196","article-title":"Would induction of dopamine homeostasis via coupling genetic addiction risk score (GARS\u00ae) and pro-dopamine regulation benefit benzodiazepine use disorder (BUD)?","volume":"3","author":"Blum","year":"2018","journal-title":"J. Syst. Integr. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1080\/13651500510018347","article-title":"Obsessive\u2013compulsive disorder and spectrum across the life span","volume":"9","author":"Hollander","year":"2005","journal-title":"Int. J. Psychiatry Clin. Pract."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1177\/014107689608900711","article-title":"The D2 dopamine receptor gene as a determinant of reward deficiency syndrome","volume":"89","author":"Blum","year":"1996","journal-title":"J. R. Soc. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1556\/2006.8.2019.57","article-title":"Smartphone addiction in students: A qualitative examination of the components model of addiction using face-to-face interviews","volume":"8","author":"Jameel","year":"2019","journal-title":"J. Behav. Addict."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116952","DOI":"10.1016\/j.jns.2020.116952","article-title":"Neurobiology of cue-reactivity, craving, and inhibitory control in non-substance addictive behaviors","volume":"415","author":"Antons","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1038\/npp.2016.265","article-title":"Dopamine and Opioid Neurotransmission in Behavioral Addictions: A Comparative PET Study in Pathological Gambling and Binge Eating","volume":"42","author":"Majuri","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.pnpbp.2015.05.013","article-title":"Alterations in DNA-methylation of the dopamine-receptor 2 gene are associated with abstinence and health care utilization in individuals with a lifetime history of pathologic gambling","volume":"63","author":"Hillemacher","year":"2015","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.psychres.2016.03.021","article-title":"Dopamine-receptor 2 gene-methylation and gambling behavior in relation to impulsivity","volume":"239","author":"Hillemacher","year":"2016","journal-title":"Psychiatry Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1556\/2006.2020.00095","article-title":"Prerequisites for stakeholder framework: Consumer advocacy and health protection in the digital industry","volume":"9","author":"Lee","year":"2020","journal-title":"J. Behav. Addict."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/j.1369-1600.2010.00255.x","article-title":"A genome-wide association study of DSM-IV cannabis dependence","volume":"16","author":"Agrawal","year":"2011","journal-title":"Addict. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.mehy.2005.04.037","article-title":"Are dopaminergic genes involved in a predisposition to pathological aggression?: Hypothesizing the importance of \u201csuper normal controls\u201d in psychiatricgenetic research of complex behavioral disorders","volume":"65","author":"Chen","year":"2005","journal-title":"Med. Hypotheses"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Al-Eitan, L.N., Rababa\u2019H, D.M., and Alghamdi, M.A. (2021). Genetic susceptibility of opioid receptor genes polymorphism to drug addiction: A candidate-gene association study. BMC Psychiatry, 21.","DOI":"10.1186\/s12888-020-03006-z"},{"key":"ref_41","first-page":"94","article-title":"Doubling Down: Increased Risk-Taking Behavior Following a Loss by Individuals with Cocaine Use Disorder Is Associated with Striatal and Anterior Cingulate Dysfunction","volume":"2","author":"Gowin","year":"2017","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s13311-017-0525-z","article-title":"Reward Circuitry in Addiction","volume":"14","author":"Cooper","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s10571-021-01064-9","article-title":"The Roles of Serotonin in Neuropsychiatric Disorders","volume":"42","author":"Pourhamzeh","year":"2021","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41583-021-00465-5","article-title":"Cannabis and synaptic reprogramming of the developing brain","volume":"22","author":"Bara","year":"2021","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Blum, K., McLaughlin, T., Bowirrat, A., Modestino, E.J., Baron, D., Gomez, L.L., Ceccanti, M., Braverman, E.R., Thanos, P.K., and Cadet, J.L. (2022). Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It \u201cBlowin\u2019 in the Wind\u201d?. J. Pers. Med., 12.","DOI":"10.3390\/jpm12020321"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"669","DOI":"10.2741\/4509","article-title":"Dopamine homeostasis brain functional connectivity in reward deficiency syndrome","volume":"22","author":"Blum","year":"2017","journal-title":"Front. Biosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5837","DOI":"10.2174\/1381612822666160719111346","article-title":"Neuronutrient amino-acid therapy protects against reward deficiency syndrome: Dopaminergic key to homeostasis and neuroplasticity","volume":"22","author":"Blum","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.2741\/4544","article-title":"Neurogenetics of acute and chronic opiate opioid abstinence treating symptoms and the cause","volume":"22","author":"Blum","year":"2017","journal-title":"Front. Biosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1080\/10826084.2016.1244551","article-title":"Hypothesizing That Neuropharmacological and Neuroimaging Studies of Glutaminergic-Dopaminergic Optimization Complex (KB220Z) Are Associated With \u201cDopamine Homeostasis\u201d in Reward Deficiency Syndrome (RDS)","volume":"52","author":"Blum","year":"2017","journal-title":"Subst. Use Misuse"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"188","DOI":"10.3810\/pgm.2010.11.2236","article-title":"Acute Intravenous Synaptamine Complex Variant KB220\u2122 \u201cNormalizes\u201d Neurological Dysregulation in Patients during Protracted Abstinence from Alcohol and Opiates as Observed Using Quantitative Electroencephalographic and Genetic Analysis for Reward Polymorphisms: Part 1, Pilot Study with 2 Case Reports","volume":"122","author":"Miller","year":"2010","journal-title":"Postgrad. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1080\/02791072.2012.737727","article-title":"Early Intervention of Intravenous KB220IV- Neuroadaptagen Amino-Acid Therapy (NAAT)\u2122 Improves Behavioral Outcomes in a Residential Addiction Treatment Program: A Pilot Study","volume":"44","author":"Miller","year":"2012","journal-title":"J. Psychoact. Drugs"},{"key":"ref_52","unstructured":"Blum, K., Modestino, E.J., Gondre-Lewis, M.C., Baron, K., Steinberg, B., Thanos, K.P., Downs, W.B., Siwicki, D., Lott, L., and Braverman, R.E. (2018). Pro-Dopamine Regulator (KB220) A Fifty Year Sojourn to Combat Reward Deficiency Syndrome (RDS): Evidence Based Bibliography (Annotated). CPQ Neurol. Psychol., 1, Available online: https:\/\/www.cientperiodique.com\/journal\/fulltext\/CPQNP\/1\/2\/13."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Febo, M., Blum, K., Badgaiyan, R.D., Perez, P.D., Colon-Perez, L.M., Thanos, P.K., Ferris, C.F., Kulkarni, P., Giordano, J., and Baron, D. (2017). Enhanced functional connectivity and volume between cognitive and reward centers of na\u00efve rodent brain produced by pro-dopaminergic agent KB220Z. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174774"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1080\/00325481.2015.994879","article-title":"rsfMRI effects of KB220Z\u2122 on neural pathways in reward circuitry of abstinent genotyped heroin addicts","volume":"127","author":"Blum","year":"2015","journal-title":"Postgrad. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3810\/pgm.2010.11.2237","article-title":"Overcoming qEEG abnormalities and reward gene deficits during protracted abstinence in male psychostimulant and polydrug abusers utilizing putative dopamine D2 agonist","volume":"122","author":"Blum","year":"2010","journal-title":"Postgrad. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nn.3694","article-title":"Excessive cocaine use results from decreased phasic dopamine signaling in the striatum","volume":"17","author":"Willuhn","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"15827","DOI":"10.1523\/JNEUROSCI.1935-13.2013","article-title":"Chronic cocaine dampens dopamine signaling during cocaine intoxication and unbalances D1 over D2 receptor signaling","volume":"33","author":"Park","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"887","DOI":"10.2174\/138945008785909356","article-title":"Enkephalinase Inhibitors: Potential Agents for the Management of Pain","volume":"9","author":"Thanawala","year":"2008","journal-title":"Curr. Drug Targets"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/bs.vh.2019.05.007","article-title":"Enkephalinase regulation","volume":"111","author":"Prieto","year":"2019","journal-title":"Vitam. Horm."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3727\/036012990816358252","article-title":"Studies on the enhanced effect of acupuncture analgesia and acupuncture anesthesia by d-phenylalanine (2nd report)\u2014Schedule of administration and clinical effects in low back pain and tooth extraction","volume":"15","author":"Kitade","year":"1990","journal-title":"Acupunct. Electro. Ther. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0304-3959(88)90010-3","article-title":"A combined treatment with d-amino acids and electroacupuncture produces a greater analgesia than either treatment alone; naloxone reverses these effects","volume":"8","author":"Cheng","year":"1980","journal-title":"Pain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"116733","DOI":"10.1016\/j.jns.2020.116733","article-title":"Molecular neurological correlates of endorphinergic\/dopaminergic mechanisms in reward circuitry linked to endorphinergic deficiency syndrome (EDS)","volume":"411","author":"Blum","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Blum, K., Modestino, E.J., Gondr\u00e9-Lewis, M., Downs, B.W., Baron, D., Steinberg, B., Siwicki, D., Giordano, J., McLaughlin, T., and Neary, J. (2017). \u201cDopamine homeostasis\u201d requires balanced polypharmacy: Issue with destructive, powerful dopamine agents to combat America\u2019s drug epidemic. J. Syst. Integr. Neurosci., 3.","DOI":"10.15761\/JSIN.1000183"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1126\/science.7089531","article-title":"Reduced Leucine-Enkephalin\u2014Like Immunoreactive Substance in Hamster Basal Ganglia After Long-Term Ethanol Exposure","volume":"216","author":"Blum","year":"1982","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6510","DOI":"10.1073\/pnas.80.21.6510","article-title":"Ethanol acceptance as a function of genotype amounts of brain [Met]enkephalin","volume":"80","author":"Blum","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0741-8329(87)90084-X","article-title":"Enkephalinase inhibition: Regulation of ethanol intake in genetically predisposed mice","volume":"4","author":"Blum","year":"1987","journal-title":"Alcohol"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/0741-8329(88)90087-0","article-title":"Enkephalinase inhibition and precursor amino acid loading improves inpatient treatment of alcohol and polydrug abusers: Double-blind placebo-controlled study of the nutritional adjunct SAAVE","volume":"5","author":"Blum","year":"1988","journal-title":"Alcohol"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/02791072.1990.10472542","article-title":"Neurodynamics of Relapse Prevention: A Neuronutrient Approach to Outpatient DUI Offenders","volume":"22","author":"Brown","year":"1990","journal-title":"J. Psychoact. Drugs"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/nrn3621","article-title":"DSM-5 and RDoC: Progress in psychiatry research?","volume":"14","author":"Casey","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1177\/02698811211069102","article-title":"Development and validation of the Reward Deficiency Syndrome Questionnaire (RDSQ-29)","volume":"36","author":"Hende","year":"2022","journal-title":"J. Psychopharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"170","DOI":"10.2174\/2211556010666210215153513","article-title":"Epigenetic Repair of Terrifying Lucid Dreams by Enhanced Brain Reward Functional Connectivity and Induction of Dopaminergic Homeo\u2014static Signaling","volume":"10","author":"Blum","year":"2021","journal-title":"Curr. Psychopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"181","DOI":"10.2174\/2211556010666210215155509","article-title":"Exploration of Epigenetic State Hyperdopaminergia (Surfeit) and Genetic Trait Hypodopaminergia (Deficit) during Adolescent Brain Development","volume":"10","author":"Blum","year":"2021","journal-title":"Curr. Psychopharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"120404","DOI":"10.1016\/j.jns.2022.120404","article-title":"Why haven\u2019t we solved the addiction crisis?","volume":"442","author":"Blum","year":"2022","journal-title":"J. Neurol. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1089\/cap.2014.0146","article-title":"Neurogenetic and epigenetic correlates of adolescent predisposition to and risk for addictive behaviors as a function of prefrontal cortex dysregulation","volume":"25","author":"Blum","year":"2015","journal-title":"J. Child Adolesc. Psychopharmacol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/10\/1719\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:54:19Z","timestamp":1760144059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/10\/1719"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,14]]},"references-count":74,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jpm12101719"],"URL":"https:\/\/doi.org\/10.3390\/jpm12101719","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,14]]}}}