• GARS® / RestoreGen® Scientific Research

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GARS® / RestoreGen® Studies


2018

The Benefits of Genetic Addiction Risk Score (GARS) Testing in Substance Use Disorder (SUD).

Blum K, Modestino, Gondre-Lewis, Chapman, Neary, Siwicki, Baron, Hauser, Smith, Roy, Thanos, Steinberg, McLaughlin, Fried, Barh, Dunston, Badgaiyan

Abstract:

 Following 25 years of extensive research by many scientists worldwide, a panel of ten reward gene risk variants, called the Genetic Addiction Risk Score (GARS), has been developed. In unpublished work, when GARS was compared to the Addiction Severity Index (ASI), which has been used in many clinical settings, GARS significantly predicted the severity of both alcohol and drug dependency. In support of early testing for addiction and other RDS subtypes, parents caught up in the current demographic of 127 people, both young and old, dying daily from opiate/opioid overdose, need help. In the past, families would have never guessed that their loved ones would die or could be in real danger due to opiate addiction. Author, Bill Moyers, in Parade Magazine, reported that as he traveled around the United States, he found many children with ADHD and other spectrum disorders like Autism, and noted that many of these children had related conditions like substance abuse. He called for better ways to identify these children and treat them with approaches other than addictive pharmaceuticals. To our knowledge, GARS is the only panel of genes with established polymorphisms reflecting the Brain Reward Cascade (BRC), which has been correlated with the ASI-MV alcohol and drug risk severity score. While other studies are required to confirm and extend the GARS test to include other genes and polymorphisms that associate with an hypodopaminergic trait, these results provide clinicians with a non-invasive genetic test. Genomic testing, such as GARS, can improve clinical interactions and decision-making. Knowledge of precise polymorphic associations can help in the attenuation of guilt and denial, corroboration of family gene-o-grams; assistance in risk-severity-based decisions about appropriate therapies, including pain medications and risk for addiction; choice of the appropriate level of care placement (i.e., inpatient, outpatient, intensive outpatient, residential); determination of the length of stay in treatment; determination of genetic severity-based relapse and recovery liability and vulnerability; determination of pharmacogenetic medical monitoring for better clinical outcomes (e.g., the A1 allele of the DRD2 gene reduces the binding to opioid delta receptors in the brain, thus, reducing Naltrexone's clinical effectiveness); and supporting medical necessity for insurance scrutiny.

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2018

Introducing "Precision Addiction Management (PAM)" as an Adjunctive Genetic Guided Therapy for Abusable Drugs in America.

Blum K, Modestino EJ, Lott L, Siwicki D, Baron D, Howeedy A, Badgaiyan RD.

Summary:

 We believe GARS may provide valuable information to those with genetically induced dopamine deficiency. With the use of precision KB220 as a treatment adjunct to putatively induce dopamine regulation, “Dopamine Homeostasis” and improvement in the recovery of individuals with, for example, psychostimulant and poly drug abuse problems may be achievable. Given the complexity of RDS behaviors, especially related to drug-seeking, our knowledge regarding the interrelatedness of 85 billion neurons in the human brain is in a pioneering stage. However, this reductionist view as presented herein is an imperative piece of the puzzle and must be considered as we move forward in the current arena of neuroimaging and genetic interface.


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2018

Introducing Precision Addiction Management of Reward Deficiency Syndrome, the Construct That Underpins All Addictive Behaviors

Blum K, Modestino EJ, Lott L, Siwicki D, Baron D, Howeedy A, Badgaiyan RD.

Summary:

 These basic concepts underpin translational addiction-related research that can help the multitude of victims of genetically induced RDS become the recipients of better therapeutic relapse-preventive tactics. Finally, as neuroscientists and psychiatrists, working in the “addiction space” we encourage the global scientific community to take heed and reconsider the current utilization of dopaminergic blockade and instead adopt the goal of regaining dopamine homeostasis. Optimistically, early predisposition diagnosis through genetic testing; including pharmacogenetic and pharmacogenomic monitoring, with appropriate urine drug screening, and treatment with pro-dopamine regulators could conceivably reduce stress, craving, and relapse and enhance well-being in the recovery community. Following required basic and clinically directed research, the notion of genetically guided therapy may become a front-line technology with the potential to overcome, in part, the current heightened rates of substance abuse.


Scientific Paper

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2018

Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse.

Blum K, Modestino EJ, Badgaiyan RD, Baron D, Thanos PK, Elman I, Siwicki D, Febo M, Gold MS.

Abstract:

 Blum's laboratory first showed the benefits of naloxone or narcotic antagonists in the treatment of alcohol dependence. This seminal work published in Nature in the early 70's, in conjunction with many other studies, later served as the basis for the development of the narcotic antagonist (NTX) now used to treat both alcohol and opioid dependence. In 2006 an extended-release injectable of Naltrexone (XR-NTX) was approved by the FDA. Naltrexone is a relatively weak antagonist of κ- and δ-receptors and is also a potent μ-receptor antagonist. Dosages of naltrexone that effectively reduce opioid and alcohol consumption also actively block μ-receptors, but chronically down-regulate mesolimbic dopamine release. While studies show benefit especially in the short term, there is ongoing evidence that the retention and compliance with NTX are not sufficient to characterize adherence as high. However, extended-release NTX opioid treatment is associated with superior outcomes including less likely relapse (defined as daily use), and much longer time to relapse despite higher rates of concurrent non-opioid substance use like cocaine. Regarding long-term extended-release injectable (XR-NTX) for opioid dependence; there was higher compliance with Opioid Use Disorder (OUD) than for Alcohol Use Disorder (AUD.). Consideration of modalities in combination with XR-NTX is imperative. Research by Blum., et al. showed that a combination of Naltrexone and a pro-dopamine regulator neuro-nutrient (KB220) significantly prevented opioid relapse. Thus, early identification of addiction vulnerability with the Genetic Addiction Risk Score (GARS™) a panel of polymorphic risk alleles from ten reward circuitry genes will provide valuable information especially as it relates to genetically guided therapy with the KB220 neuro nutrient termed 'Precision Addiction Management".


Scientific Paper

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2018

Promoting Precision Addiction Management (PAM) to Combat the Global Opioid Crisis.

Blum K, Modestino EJ, Neary J, Gondré-Lewis MCSiwicki D, Moran M, Hauser M, Braverman ER, Baron D, Steinberg B, Laughlin TM, Badgaiyan RD.

Abstract:

 It is universally agreed that dopamine is a major neurotransmitter in terms of reward dependence, however, there remains controversy regarding how to modulate its role clinically to treat and prevent relapse for both substance and non-substance-related addictive behaviors. It is also agreed by most that there is a need to provide early genetic identification possibly through a novel researched technology referred to Genetic Addiction Risk Score(GARS).™ The existing FDA-approved medications promote blocking dopamine, however, we argue that a more prudent paradigm shift should be biphasic-short-term blockade and long-term upregulation, enhancing functional connectivity of brain reward. It is critical to understand that the real phenotype is not any specific drug or non -drug addictive behavior, but instead is Reward Deficiency Syndrome (RDS). Thus the true phenotype of all addictive behaviors is indeed RDS. Finally, we are suggesting that one way to combat the current out of control Opioid /Alcohol crisis worldwide is to seriously reconsider treating RDS by simply supplying powerful narcotic agents (e.g. Buprenorphine). This type of treatment will only keep people addicted. A more reasonable solution involving genetic testing, urine drug screens using Comprehensive Analysis of Reported Drugs (CARD) and dopamine homeostasis we call " Precision Addiction Management" ™ seems parsonomiuos.


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2017

Coupling Genetic Addiction Risk Score (GARS) and Pro Dopamine Regulation (KB220) to Combat Substance Use Disorder (SUD)

Blum K, Madigan MA, Fried L, Braverman ER, Giordano J, Badgaiyan RD.

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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2016

THE BENEFITS OF CUSTOMIZED DNA DIRECTED NUTRITION TO BALANCE THE BRAIN REWARD CIRCUITRY AND REDUCE ADDICTIVE BEHAVIORS.

Blum K, Downs BW, Dushaj K, Li M, Braverman ER, Fried L, Waite R, Demotrovics Z, Badgaiyan RD.

Abstract:

 DNA Customization of nutraceutical products is here. In the truest sense, "Gene Guided Precision Nutrition™" and KB220 variants (a complex mixture of amino-acids, trace metals, and herbals) are the pioneers and standard-bearers for a state of the art DNA customization. Findings by both, Kenneth Blum, Ph.D. and Ernest Noble, Ph.D. concerning the role of genes in shaping cravings and pleasure- seeking, opened the doors to comprehension of how genetics control our actions and effect our mental and physical health. Moreover, technology that is related to KB220 variants in order to reduce or eradicate excessive cravings by influencing gene expression is a cornerstone in the pioneering of the practical applications of nutrigenomics. Continuing discoveries have been an important catalyst for the evolution, expansion, and scientific recognition of the significance of nutrigenomics and its remarkable contributions to human health. Neuro-Nutrigenomics is now a very important field of scientific investigation that offers great promise to improving the human condition. In the forefront is the development of the Genetic Addiction Risk Score (GARS™), which unlike 23andMe, has predictive value for the severity of drug and alcohol abuse as well as other non-substance related addictive behaviors. While customization of neuronutrients has not yet been commercialized, there is emerging evidence that in the future, the concept will be developed and could have a significant impact in addiction medicine.


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2015

Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms.

Blum K, Simpatico T, Badgaiyan RD, Demetrovics Z, Fratantonio J, Agan G, Febo M, Gold MS.

Abstract:

 Earlier work from our laboratory, showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2]) to associate with severe alcoholism serves as a blue-print for the development of "Personalized Medicine" in addiction. Prior to the later genetic finding, we developed the concept of Brain Reward Cascade, which continues to act as an important component for stratification of addiction risk through neurogenetics. In 1996 our laboratory also coined the term "Reward Deficiency Syndrome (RDS)" to define a common genetic rubric for both substance and non-substance related addictive behaviors. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroadaptogen- amino-acid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220Z formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds. Following these experiments, we have been successfully developing a panel of genes known as "Genetic Addiction Risk Score" (GARSpDX)™. Selection of 10 genes with appropriate variants, a statistically significant association between the ASI-Media Version-alcohol and drug severity scores and GARSpDx was found A variant of KB220Z in abstinent heroin addicts increased resting state functional connectivity in a putative network including: dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In addition, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior thalamic nuclei, hippocampus, pre-limbic and infra-limbic loci. KB220Z demonstrates significant functional connectivity, increased brain volume recruitment and enhanced dopaminergic functionality across the brain reward circuitry. We propose a Reward Deficiency System Solution that promotes early identification and stratification of risk alleles by utilizing GARSDx, allowing for customized nutrigenomic targeting of these risk alleles by altering KB220Z ingredients as an algorithmic function of carrying these polymorphic DNA-SNPS, potentially yielding the first ever nutrigenomic solution for addiction and pain.


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2013

Neurogenetic impairments of brain reward circuitry links to reward deficiency syndrome (RDS) as evidenced by genetic addiction risk score (GARS): A Case Study

Blum K, Han D, Hauser M, Downs B.

Abstract:

 Importantly, research from our laboratory in both in-patient and outpatient facilities utilizing the Comprehensive Analysis of Reported Drugs (CARD)™ found a significant lack of compliance to prescribed treatment medications and a lack of abstinence from drugs of abuse during active recovery. This unpublished, ongoing research provides an impetus to develop accurate genetic diagnosis and holistic approaches that will safely activate brain reward circuitry in the mesolimbic dopamine system. Our laboratory has extensively published the neurogentics of brain reward systems with particular reference to genes related to dopaminergic function. In 1996, we coined “Reward Deficiency Syndrome” (RDS), used to describe behaviors found to have an association with gene-based hypodopaminergic function. Many subsequent studies have embraced RDS as a useful concept to help expand our understanding of Substance Use Disorder (SUD), process addictions, and other obsessive, compulsive and impulsive behaviors. Here, we illustrate the usefulness of the genetic testing of a panel of reward-related genes, the Genetic Addiction Risk Score (GARS) in only one case study. Interestingly, we were able to describe lifetime RDS behaviors in a recovery addict (17 years sober) blindly by just assessing resultant GARS data. We encourage further required studies in this important emerging field.


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2012

Neurogenetic Impairments of Brain Reward Circuitry Links to Reward Deficiency Syndrome (RDS): Potential Nutrigenomic Induced Dopaminergic Activation

K Blum, M Oscar-Berman, J Giordano, BW Downs, T Simpatico, D Han, and John Femino.

Abstract:

 Work from our laboratory in both in-patient and outpatient facilities utilizing the Comprehensive Analysis of Reported Drugs (CARD)TM found a significant lack of compliance to prescribed treatment medications and a lack of abstinence from drugs of abuse during active recovery. This unpublished, ongoing research provides an impetus to develop accurate genetic diagnosis and holistic approaches that will safely activate brain reward circuitry in the mesolimbic dopamine system. This editorial focuses on the neurogenetics of brain reward systems with particular reference to genes related to dopaminergic function. The terminology “Reward Deficiency Syndrome” (RDS), used to describe behaviors found to have an association with gene-based hypodopaminergic function, is a useful concept to help expand our understanding of Substance Use Disorder (SUD), process addictions, and other obsessive, compulsive and impulsive behaviors. This editorial covers the neurological basis of pleasure and the role of natural and unnatural reward in motivating and reinforcing behaviors. Additionally, it briefly describes the concept of natural dopamine D2 receptor agonist therapy coupled with genetic testing of a panel of reward genes, the Genetic Addiction Risk Score (GARS). It serves as a spring-board for this combination of novel approaches to the prevention and treatment of RDS that was developed from fundamental genomic research. We encourage further required studies.


Scientific Paper


2010

GENETIC ADDICTION RISK SCORE (GARS) ANALYSIS: EXPLORATORY DEVELOPMENT OF POLYMORPHIC RISK ALLELES IN POLY-DRUG ADDICTED MALES

Kenneth Blum, John Giordano, Stearns A. Morse, Yiyun Liu, Jai Tan, Abdalla Bowirrat, Andrew Smolen, Roger L. Waite, Margaret A. Madigan, Mallory M Kerner, G Holistic, Weil Cornell

Abstract:

 There is a need to classify patients at genetic risk for drug seeking behavior prior to or upon entry to residential and or non-residential chemical dependency programs. We have determined based on a literature review, that there are seven risk alleles associated with six candidate genes that were studied in this patient population of recovering poly-drug abusers. To determine risk severity of these 26 patients we calculated the percentage of prevalence of the risk alleles and provided a severity score based on percentage of these alleles. Subjects carry the following risk alleles: DRD2=A1; SLC6A3 (DAT) =10R; DRD4=3R or 7R; 5HTTlRP = L or LA; MAO= 3R; and COMT=G. As depicted in table 2 low severity (LS) = 1-36%; Moderate Severity =37-50%, and High severity = 51- 100%. We studied two distinct ethnic populations group 1 consisted of 16 male Caucasian psycho stimulant addicts and group 2 consisted of 10 Chinese heroin addicted males. Based on this model the 16 subjects tested have at least one risk allele or 100%. Out of the 16 subjects we found 50% (8) HS; 31% (5) MS; and 19% LS (3 subjects). These scores are then converted to a fraction and then represented as a Genetic Addiction Risk Score (GARS) whereby we found the average GARS to be: 0.28 low severity, 0.44 moderate severity and 0.58 high severity respectively. Therefore, using this GARS we found that 81% of the patients were at moderate to high risk for addictive behavior. Of particular interest we found that 56% of the subjects carried the DRD2 A1 allele (9/16). Out of the 9 Chinese heroin addicts [one patient not genotyped] (group 2) we found 11% (1) HS; 56% (5) MS; and 33% LS (3 subjects). These scores are then converted to a fraction and then represented as GARS whereby we found the average GARS to be: 0.28 Low Severity; 0.43 moderate severity and 0.54 high severity respectively. Therefore, using GARS we found that 67% of the patients were at moderate to high risk for addictive behavior. Of particular interest we found that 56% of the subjects carried the DRD2 A1 allele (5/9) similar to group 1. Statistical analysis revealed that the groups did not differ in terms of overall severity (67 vs. 81%) in these two distinct populations. Combining these two independent study populations reveal that subjects entering a residential treatment facility for poly-drug abuse carry at least one risk allele (100%). We found 74% of the combined 25 subjects (Caucasian and Chinese) had a moderate to high GARS. Confirmation of these exploratory results and development of mathematical predictive values of these risk alleles are necessary before any meaningful interpretation of these results are to be considered.


Scientific Paper

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2010

Acute intravenous synaptamine complex variant KB220™ "normalizes" 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.

Miller DK, Bowirrat A, Manka M, Miller M, Stokes S, Manka D, Allen C, Gant C, Downs BW, Smolen A, Stevens E, Yeldandi S, Blum K.

Abstract:

 It is well established that in both food- and drug-addicted individuals, there is dopamine resistance due to an association with the DRD2 gene A1 allele. Evidence is emerging whereby the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may find its place in recovery from reward deficiency syndrome (RDS) in patients addicted to psychoactive chemicals. Utilizing quantitative electroencephalography (qEEG) as an imaging tool, we show the impact of Synaptamine Complex Variant KB220™ as a putative activator of the mesolimbic system. We demonstrate for the first time that its intravenous administration reduces or "normalizes" aberrant electrophysiological parameters of the reward circuitry site. For this pilot study, we report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (ie, widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™. Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively. The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR, locus symbol SLC6A4). We emphasize that these are case studies, and it would be unlikely for all individuals to carry all putative risk alleles. Based on previous research and our qEEG studies (parts 1 and 2 of this study), we cautiously suggest that long-term activation of dopaminergic receptors (ie, DRD2 receptors) will result in their proliferation and lead to enhanced "dopamine sensitivity" and an increased sense of happiness, particularly in carriers of the DRD2 A1 allele. This is supported by a clinical trial on Synaptamine Complex Variant KB220™ using intravenous administration in > 600 alcoholic patients, resulting in significant reductions in RDS behaviors. It is also confirmed by the expanded oral study on Synaptose Complex KB220Z™, published as part 2 of this study. Future studies must await both functional magnetic resonance imaging and positron emission tomography scanning to determine the acute and chronic effects of oral KB220™ on numbers of D2 receptors and direct interaction at the nucleus accumbens. Confirmation of these results in large, population-based, case-controlled experiments is necessary. These studies would provide important information that could ultimately lead to significant improvement in recovery for those with RDS and dopamine deficiency as a result of a multiple neurotransmitter signal transduction breakdown in the brain reward cascade.


Scientific Paper


2006

Reward deficiency syndrome in obesity: a preliminary cross-sectional trial with a Genotrim variant.

Blum K, Chen T, Meshkin B, Downs BW, Gordon CA, Blum S, Mengucci JF, Braverman ER, Arcuri V, Varshavskiy M, Deutsch R, Martinez-Pons M.

Abstract:

 Obesity is the second largest preventable cause of death in the United States. Even though it was classified as a disease in 1985, traditionally, obesity has been treated primarily as a behavioral problem that requires only modifications in diet and exercise. Similar to research on obesity, clinical studies have elucidated the role of biologic and genetic factors in alcoholism and other conditions previously classified as behavioral. These studies showed that behavioral adjustments alone may not address underlying genetic causes. We hypothesize that biologic and genetic factors must be addressed synergistically while behavioral modifications are implemented to adequately treat obese patients. We hypothesize that a predisposition to glucose craving and obesity is due to inadequate dopaminergic activity in the reward center of the brain. This defect drives individuals to engage in activities of behavioral excess, which, in turn, enhance brain dopamine function. Consumption of large quantities of alcohol or carbohydrates (carbohydrate bingeing) stimulates production and usage of dopamine within the brain; the term reward deficiency syndrome (RDS) may be used to categorize such biologic influences on behavior. We propose that a novel approach to nutritional supplementation may be required to target the role of RDS in obesity. In this regard, GenoTrim, a DNA-customized nutritional solution, has been developed and is currently under investigation in several clinical studies. Through its mechanism of action, GenoTrim addresses the genetic influence of RDS on obesity. In this cross-sectional study, 24 subjects were studied after they had completed a case report format questionnaire. For this assessment, we used a novel assessment tool-a path analysis. This statistical regression model is used to (1) examine the effectual relationships between various systems within a multisystem matrix, and (2) measure the contributory roles of those relationships in obesity, enabling the development of targeted and effective therapeutic interventions.


Scientific Paper


2010

Acute intravenous synaptamine complex variant KB220™ "normalizes" 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.

Miller DK, Bowirrat A, Manka M, Miller M, Stokes S, Manka D, Allen C, Gant C, Downs BW, Smolen A, Stevens E, Yeldandi S, Blum K.

Abstract:

 It is well established that in both food- and drug-addicted individuals, there is dopamine resistance due to an association with the DRD2 gene A1 allele. Evidence is emerging whereby the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may find its place in recovery from reward deficiency syndrome (RDS) in patients addicted to psychoactive chemicals. Utilizing quantitative electroencephalography (qEEG) as an imaging tool, we show the impact of Synaptamine Complex Variant KB220™ as a putative activator of the mesolimbic system. We demonstrate for the first time that its intravenous administration reduces or "normalizes" aberrant electrophysiological parameters of the reward circuitry site. For this pilot study, we report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (ie, widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™. Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively. The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR, locus symbol SLC6A4). We emphasize that these are case studies, and it would be unlikely for all individuals to carry all putative risk alleles. Based on previous research and our qEEG studies (parts 1 and 2 of this study), we cautiously suggest that long-term activation of dopaminergic receptors (ie, DRD2 receptors) will result in their proliferation and lead to enhanced "dopamine sensitivity" and an increased sense of happiness, particularly in carriers of the DRD2 A1 allele. This is supported by a clinical trial on Synaptamine Complex Variant KB220™ using intravenous administration in > 600 alcoholic patients, resulting in significant reductions in RDS behaviors. It is also confirmed by the expanded oral study on Synaptose Complex KB220Z™, published as part 2 of this study. Future studies must await both functional magnetic resonance imaging and positron emission tomography scanning to determine the acute and chronic effects of oral KB220™ on numbers of D2 receptors and direct interaction at the nucleus accumbens. Confirmation of these results in large, population-based, case-controlled experiments is necessary. These studies would provide important information that could ultimately lead to significant improvement in recovery for those with RDS and dopamine deficiency as a result of a multiple neurotransmitter signal transduction breakdown in the brain reward cascade.


Scientific Paper