Coupling Genetic Addiction Risk Score (GARS) and Pro Dopamine Regulation (KB220) to Combat Substance Use Disorder (SUD)
Kenneth Blum1-10*, Margaret A Madigan4, Lyle Fried7, Eric R Braverman6, John Giordano5 and Rajendra D Badgaiyan9
Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, USA
Department of Psychiatry and Behavioral Sciences, Keck Medicine University of Southern California, USA
Division of Applied Clinical Research & Education, Dominion Diagnostics, USA
Department of Neurogenetics, Igene, USA
National Institute for Holistic Addiction Studies, USA
Department of Clinical Neurology, Path Foundation NY, USA
Division of Neuroscience Based Addiction Therapy, The Shores Treatment & Recovery Center, USA
Eötvös Loránd University, Institute of Psychology, Europe
Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Center, US
Division of Reward Deficiency Syndrome, Nupathways, Inc., Innsbrook, MO, USA
Submission: February 11, 2017; Published: February 23, 2017
*Corresponding author: Kenneth Blum, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, USA; Tel:352-294-4911;Fax:352-392-9887; Email:drd2gene@gmail.com
How to cite this article: Kenneth B, Margaret A M, Lyle F, Eric R B, John G, Rajendra D B.Coupling Genetic Addiction Risk Score (GARS) and Pro 002 Dopamine Regulation (KB220) to Combat Substance Use Disorder (SUD). Glob J Add & Rehab Med. 2017; 1(2): 555556. DOI: 10.19080/GJARM.2017.01.555556
Abbreviations: RDS: Reward Deficiency Syndrome; SMART™: Systematic Medical Approach to Reward Transformation; GARS: Genetic Addiction Risk Score; DNA: Deoxyribonucleic Acid; DRD2: Dopamine Receptor D2 Gene; MOA: Monoamine Oxidase; SNPs: Single-Nucleotide Polymorphisms; SSRs: Simple Sequence Repeats
Introduction
We are proposing a generalized approach based on the Reward Deficiency Syndrome (RDS) conceptualization called the Systematic Medical Approach to Reward Transformation (SMART™). This system consists of: early pre-disposition diagnosis (even in children) using the Genetic Addiction Risk Score (GARS) [1]; a validated RDS questionnaire [2]; urine drug testing during actual treatment that uses comprehensive analysis of reported drugs to determine compliance with prescription medications and non-abstinence illicit drugs [3]; and adjunctive treatment with a glutaminergic-dopaminergic optimization nutraceutical (KB220) to prevent relapse by induction of dopamine homeostasis [4].
Understanding reward deficiency syndrome (RDS)
I. RDS conceptualizationThe biological processes of reward that underlie addiction to substances and all addictive, compulsive and impulsive behaviors are the basis of the RDS conceptualization [5,6]. RDS then is a deficiency, a hypodopaminergic condition that results from some combination of genetic variations, environmental stressors, and adverse molecular effects or blunting due to prolonged substance use or behavioral habituation [7-9]. The RDS concept was developed based on animal and human research that explored the molecular biology of neurotransmission, and behavioral genetics [8,10,11]. Understanding this concept, explained in the following paragraphs, is central to treating the abnormal psychology of personality and spectrum disorders, as well as, substance and non-substance (behavioral) addictions. To feel ordinary pleasure, complex interactions of neurotransmitters regulate the dopaminergic activity of the brain in the reward center -the mesolimbic system, particularly the nucleus accumbens. Individuals, who suffer from a lack of ordinary pleasure in their lives, are predisposed to use any means; substance or behavior, to activate dopamine release, relieve stress and feel healthy pleasure [12,13].
Genes are deoxyribonucleic acid (DNA), which directs the functional properties of proteins like neurotransmitters. Genetic alleles are unusual versions of a gene that can change genetic function they are called polymorphisms or variants. Early in the 1990’s a statistically significant association of severe alcoholism with a variant, the A1 allele of the Dopamine Receptor D2 Gene (DRD2) was discovered [14]. This variant was later associated with numerous other addictive, compulsive and impulsive behaviors. At the same time, a binding availability study found that functionally, the presence of the A1 allele resulted in lower dopamine receptor availability in the parts of the brain known to effect reward [15]. Other earlier studies had explored the role of neurotransmitters in pleasure. In the limbic neural circuitry serotonin, enkephalin, GABA, and dopamine work together in a complex cascade of activation and inhibition that result in the release of dopamine. Dopamine was identified as one of the most powerful neurotransmitters that control feelings of well-being and reward. Negative emotions and craving are the results of disruption of the intercellular brain reward cascade that leads to reduced dopamine availability [16].
II. Hypodopaminergic function Genes are deoxyribonucleic acid (DNA), which directs the functional properties of proteins like neurotransmitters. Genetic alleles are unusual versions of a gene that can change genetic function they are called polymorphisms or variants. Early in the 1990’s a statistically significant association of severe alcoholism with a variant, the A1 allele of the Dopamine Receptor D2 Gene (DRD2) was discovered [14]. This variant was later associated with numerous other addictive, compulsive and impulsive behaviors. At the same time, a binding availability study found that functionally, the presence of the A1 allele resulted in lower dopamine receptor availability in the parts of the brain known to effect reward [15]. Other earlier studies had explored the role of neurotransmitters in pleasure. In the limbic neural circuitry serotonin, enkephalin, GABA, and dopamine work together in a complex cascade of activation and inhibition that result in the release of dopamine. Dopamine was identified as one of the most powerful neurotransmitters that control feelings of well-being and reward. Negative emotions and craving are the results of disruption of the intercellular brain reward cascade that leads to reduced dopamine availability [16].
III. The epigenetics of stress and prolonged exposure In addition to genetic polymorphisms, which reduce the availability of dopamine in the synapse, prolonged stress and long -term substance abuse also result in reduced cascade function and decreased dopamine release and may have a cumulative effect on vulnerability to addiction and other RDS Behaviors [19,20]. Harmful molecular effects or blunting occur due to prolonged substance use [21,22]. The repeated release of high amounts of dopamine into the synaptic cleft induces prolonged, heightened postsynaptic receptor activity, resulting in receptor down-regulation and, for this reason, further decreases dopamine function. Also, hypodopaminergic function, caused by genetic variations impacted by epigenetics, can induceimpairments in the pre-frontal cortex-cingulated gyrus, which in turn leads to poor judgment and potential habit reinstatement or relapse [20,22].
Receptor down-regulation reported, in both obese rats and drug-addicted humans, is the reason habituated addicts require ever increasing substance or behavior to maintain the rewarding effect [20,23]. However after prolonged abstinence dopamine receptor super-sensitivity, an enhanced biochemical response develops, and reinstatement at the previous level of habituation in the case of substance abuse may lead to fatalities [24]. Environmentally induced epigenetic effects on the chromatin structure of the DNA due to stress or triggered by cues can increase craving. Stress-triggered craving involves the neurotransmitters corticotrophin-releasing factor and norepinephrine. These neurotransmitters necessitate the abundant release of dopamine (100X times resting state) and subsequently, temporary hypodopaminergic functioning, repeated, or prolonged stress can induce a chronic hypodopaminergic state. Cue-triggered craving involves the basolateral nucleus of the amygdala, the hippocampus, and through glutaminergic activation, causes the increased release of dopamine that if chronic ultimately leads to a hypodopaminergic state. Due to this hypodopaminergic trait (genetic) and state (environmental), it is known that drug intake or aberrant behaviors will escalate [25,26].
Genetic addiction risk score (GARS)
The Genetic Addiction Risk Score (GARS), is the first test to accurately predict vulnerability to pain, addiction, and other obsessive and compulsive behaviors, identified as RDS [27]. There is a need to classify patients at genetic risk to alcohol and drug-seeking behavior and relapse before or upon entry to pain and residential and or non-residential chemical dependency programs. Based on an extensive literature review, an addiction risk index consisting of 11 polymorphisms in 10 genes, involved in the neurological processing of reward, were identified and tested. The resulting genetic addiction risk score (GARS) included; six single-nucleotide polymorphisms (SNPs) in the DRD1, DRD2, DRD3, DRD4, COMT, and OPRM1 genes; four simple sequence repeats (SSRs) in the DAT1, DRD4, MAOA, and 5HTT transporter genes; and a dinucleotide polymorphism in the GABRA3 gene [9]. Blum’s laboratory sought to address genetic risk for alcohol and drug by evaluating whether the combined effect of reward gene polymorphisms that contribute to a hypodopaminergic trait, associate with RDS related substance abuse risk. Among those who consented to provide a saliva sample for DNA genotyping, 273 (derived from seven centers) also had ASI phenotypic information.
The patient population n=393, 17.6%, 80.7%, and 1.5% scored in the low, moderate and high severity range, respectively. The mean number of GARS alleles was 7.97 (S.D. = 2.34) and ranged between 3 and 17 alleles. The relationship between GARS genotype panel and the Alcohol Risk Severity Score using the Fishers Exact Test revealed a significant predicative relationship(Χ2 = 8.84, df = 1, p = 0.004, 2-tailed) that remained significant after controlling for age (p < 0.01). A similar, though less robust, relationship was obtained from chi-square (p = 0.05) and linear regression (b = -0.122, t = -1.91, p = 0.10, 2-tailed) analyses of the ASI Drug Severity Risk Score. Blum et al. [28,29] details the construction of a genetic addiction risk score (GARS™) and its predictive relationship with ASI -MV derived alcohol and drug severity risk scores. Innovative strategies to combat epidemic opioid/opiate abuse, and death, based on the role of dopaminergic tone in pain pathways, are proposed. Sensitivity to pain may reside in the mesolimbic projection system, where genetic polymorphisms associate with a predisposition to pain vulnerability or tolerance. Pharmacogenomic testing of candidate genes like CB1, mu receptors, and PENK might result in pharmacogenomic, personalized solutions, and improved clinical outcomes. Identifying genetic risk for all RDS behaviors, especially in compromised populations, may be a frontline tool to assist municipalities in providing better resource allocation and possibly precision medicine [30].
RDS questionnaire
In conjunction with Zsolt Demetrovics in the Eötvös Loránd University, Institute of Psychology, Budapest, Hungary, an unpublished, 29 item RDS questionnaire reduced from 51 items generated based on the RDS theory, has been validated in over 1726 individuals attending college. The general reward deficiency factor was associated with gender, sensation seeking and impulsivity. Females show ahigher degree of reward deficiency trait. Greater sensation seeking and impulsivity predict higher degrees of reward deficiency and risk seeking behaviors and are positively associated with sensation seeking and impulsivity [2].
Pro-Dopamine regulator (KB220)
A glutaminergic-dopaminergic optimization nutraceutical called KB220 has been developed that supports the brain reward system and induces “dopamine homeostasis”. This agonistic nutraceutical has been shown to safely provide substantial clinical benefit to the victims of RDS and assist in recovery from addiction to opiates/opioids and other substance and non-substance addictions and behaviors [7,17,31-33]. DNAdirected compensatory over expression of the DA D2 receptors (a form of gene therapy) has been shown to result in a significant reduction in alcohol and cocaine craving behavior in drugpreferring rodents [34,35] and acute in vitro bromocriptine a strong agonist-induced D2 receptor proliferation in rats [36]. KB220 variants formulations have been studied extensively in both animals and humans. Pre-clinical and human trials using a variety of methodologies are reported on in a detailed review article [37] and Table 1 lists the studies of KB220 variants in a multiplicity of RDS populations. Interestingly, in abstinent heroin addicts, a pilot study of a single dose of KB220Z compared to placebo found improvement of the prefrontal-cerebellaroccipital neural network and activation of the NAc [38].
Conclusion
Recently the hypothesis [39-43] that KB220Z would enhance resting connectivity patterns between reward and cognitive brain regions was tested in placebo-controlled rsfMRI experiments in the rat. Additionally, qEEG studies in humans found that KB220Z modulates theta power in the anterior cingulate cortex [44,45]. Double-blind controlled studies and others [37,46-48] have demonstrated positive effects on both craving attenuation and relapse prevention [48-50] and enhanced compliance to KB220Z treatment was significant in obese carriers of the D2 receptors A1 allele vs. carriers of the usual complement of DA D2 receptors [51,52]. The rationale for evaluating KB220Z in the present article application is the evidence of clinical benefit KB220Z can give by epigenetically changing the neuro-mechanisms involved in producing dopamine homeostasis [53]. Based on this research and current literature new strategies to treat RDS are needed. The traditionally used therapeutic agents have failed to address the reduced connectivity patterns now seen in many addictions and have had limited success in relapse prevention and effective recovery from psychoactive substance abuse [4,54]. This concept would enable genetic testing and precise treatment of genetic and epigenetic deficits with formulations of KB220 [55,56]. Recovery and good health would be the goal of this SMART, holistic program design, based on this extensive research in a diverse but stable population [57]. In a diverse but stable population like African- Americans as well as other minority groups showing high genetic risk for all RDS behaviors.
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