Genetic Addiction Risk Score Research Articles

Genetic Addiction Risk Severity Assessment Identifies Polymorphic Reward Genes as Antecedents to Reward Deficiency Syndrome (RDS) Hypodopaminergia's Effect on Addictive and Non-Addictive Behaviors in a Nuclear Family.

This case series presents the novel genetic addiction risk score (GARS), which shows a high prevalence of polymorphic risk alleles of reward genes in a nuclear family with multiple reward deficiency syndrome (RDS) behavioral issues expressing a hypodopaminergic antecedent. The family consists of a mother, father, son, and daughter. The mother experienced issues with focus, memory, anger, and amotivational syndrome. The father experienced weight issues and depression. The son experienced heavy drinking, along with some drug abuse and anxiety. The daughter experienced depression, lethargy, brain fog, focus issues, and anxiety, among others. A major clinical outcome of the results presented to the family members helped reduce personal guilt and augment potential hope for future healing. Our laboratory's prior research established that carriers of four or more alleles measured by GARS (DRD1-DRD4, DAT1, MOR, GABABR3, COMT, MAOAA, and 5HTLPR) are predictive of the addiction severity index (ASI) for drug abuse, and carriers of seven or more alleles are predictive of severe alcoholism. This generational case series shows the impact that genetic information has on reducing stigma and guilt in a nuclear family struggling with RDS behaviors. The futuristic plan is to introduce an appropriate DNA-guided "pro-dopamine regulator" into the recovery and enhancement of life.

Researching Mitigation of Alcohol Binge Drinking in Polydrug Abuse: KCNK13 and RASGRF2 Gene(s) Risk Polymorphisms Coupled with Genetic Addiction Risk Severity (GARS) Guiding Precision Pro-Dopamine Regulation.

Excessive alcohol intake, e.g., binge drinking, is a serious and mounting public health problem in the United States and throughout the world. Hence the need for novel insights into the underlying neurobiology that may help improve prevention and therapeutic strategies. Therefore, our group employed a darkness-induced alcohol intake protocol to define the reward deficiency domains of alcohol and other substance use disorders in terms of reward pathways’ reduced dopamine signaling and its restoration via specifically-designed therapeutic compounds. It has been determined that KCNK13 and RASGRF2 genes, respectively, code for potassium two pore domain channel subfamily K member 13 and Ras-specific guanine nucleotide-releasing factor 2, and both genes have important dopamine-related functions pertaining to alcohol binge drinking. We present a hypothesis that identification of KCNK13 and RASGRF2 genes’ risk polymorphism, coupled with genetic addiction risk score (GARS)-guided precision pro-dopamine regulation, will mitigate binge alcohol drinking. Accordingly, we review published reports on the benefits of this unique approach and provide data on favorable outcomes for both binge-drinking animals and drunk drivers, including reductions in alcohol intake and prevention of relapse to drinking behavior. Since driving under the influence of alcohol often leads to incarceration rather than rehabilitation, there is converging evidence to support the utilization of GARS with or without KCNK13 and RASGRF2 risk polymorphism in the legal arena, whereby the argument that “determinism” overrides the “free will” account may be a plausible defense strategy. Obviously, this type of research is tantamount to helping resolve a major problem related to polydrug abuse.

Exploration of Epigenetic State Hyperdopaminergia (Surfeit) and Genetic Trait Hypodopaminergia (Deficit) During Adolescent Brain Development.

The risk for all addictive drug and non-drug behaviors, especially, in the unmyelinated Prefrontal Cortex (PFC) of adolescents, is important and complex. Many animal and human studies show the epigenetic impact on the developing brain in adolescents, compared to adults. Some reveal an underlying hyperdopaminergia that seems to set our youth up for risky behaviors by inducing high quanta pre-synaptic dopamine release at reward site neurons. In addition, altered reward gene expression in adolescents caused epigenetically by social defeat, like bullying, can continue into adulthood. In contrast, there is also evidence that epigenetic events can elicit adolescent hypodopaminergia. This complexity suggests that neuroscience cannot make a definitive claim that all adolescents carry a hyperdopaminergia trait. The primary issue involves the question of whether there exists a mixed hypo or hyper-dopaminergia in this population. Genetic Addiction Risk Score (GARS®) testing was carried out of 24 Caucasians of ages 12-19, derived from families with RDS. We have found that adolescents from this cohort, derived from RDS parents, displayed a high risk for any addictive behavior (a hypodopaminergia), especially, drug-seeking (95%) and alcohol-seeking (64%). The adolescents in our study, although more work is required, show a hypodopaminergic trait, derived from a family with Reward Deficiency Syndrome (RDS). Certainly, in future studies, we will analyze GARS in non-RDS Caucasians between the ages of 12-19. The suggestion is first to identify risk alleles with the GARS test and, then, use well-researched precision, pro-dopamine neutraceutical regulation. This "two-hit" approach might prevent tragic fatalities among adolescents, in the face of the American opioid/psychostimulant epidemic.

Epigenetic Repair of Terrifying Lucid Dreams by Enhanced Brain Reward Functional Connectivity and Induction of Dopaminergic Homeostatic Signaling.

During Lucid Dreams, the dreamer is aware, experiences the dream as if fully awake, and may control the dream content. The dreamer can start, stop, and restart dreaming, depending on the nature and pleasantness of the dream. For patients with Reward Deficiency Syndrome (RDS) behaviors, like Attention Deficit Hyperactivity Disorder (ADHD), Tourette's- Syndrome, and Posttraumatic Stress Disorder (PTSD), the dream content may be pleasant, unpleasant, or terrifying. A sample of psychiatric center patients identified as having RDS reported the effectiveness of a neuronutrient, dopamine agonist, KB200Z, in combating terrifying, lucid dreaming. These reports motivated the study of eight clinical cases with known histories of substance abuse, childhood abuse, and PTSD. The administration of KB200Z, associated with eliminating unpleasant or terrifying lucid dreams in 87.5% of the cases. Subsequently, other published cases have further established the possibility of the long-term elimination of terrifying dreams in PTSD and ADHD patients. Induction of dopamine homeostasis may mitigate the effects of neurogenetic and epigenetic changes in neuroplasticity, identified in the pathogenesis of PTSD and ADHD. The article explores how relief of terrifying lucid dreams may benefit from modulation of dopaminergic signaling activated by the administration of a neuronutrient. Recently, precision formulations of the KB220 neuronutrient guided by Genetic Addiction Risk Score (GARS) test results have been used to repair inheritable deficiencies within the brain reward circuitry. The proposition is that improved dopamine transmodulational signaling may stimulate positive cognitive recall and subsequently attenuate the harmful epigenetic insults from trauma.

High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial

Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30–600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence.

In Search of Reward Deficiency Syndrome (RDS)-Free Controls: The “Holy Grail” in Genetic Addiction Risk Testing

The search for an accurate, gene-based test to identify heritable risk factors for Reward Deficiency Syndrome (RDS) was conducted based on hundreds of published studies about the role of dopamine in addictive behaviors, including risk for drug dependence and compulsive/impulsive behavior disorders. The term RDS was first coined by Blum's group in 1995 to identify a group of behaviors with a common neurobiological mechanism associated with a polymorphic allelic propensity for hypodopaminergia. To outline the process used to select risk alleles of reward genes for the Genetic Addiction Risk Score (GARS) test. Consequently, to address the limitations caused by inconsistent results that occur in many case-control behavioral association studies. These limitations are perhaps due to the failure of investigators to adequately screen controls for drug and alcohol use disorder, and any of the many RDS behaviors, including nicotine dependence, obesity, pathological gambling, and internet gaming addiction. Review of the literature related to the function of risk alleles of reward genes associated with hypodopaminergia relevant case-control association studies for the selection of alleles to be measured by the Genetic Addiction Risk Score (GARS) test. The prevalence of the DRD2 A1 allele in unscreened controls (33.3%), compared to "Super-Controls" [highly screened RDS controls (3.3%) in proband and family] is used to exemplify a possible solution. Unlike one gene-one disease (OGOD), RDS is polygenetic, and very complex. In addition, any RDS-related behaviors must be eliminated from the control group in order to obtain the best possible statistical analysis instead of comparing the phenotype with disease-ridden controls.

Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum’s group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case –controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case –control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data –a work in progress.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Death by Opioids: Are there non-addictive scientific solutions?

In the face of the current Opioid crisis in America killing close to 800,000 people since 2004, we are proposing a novel approach to assist in at least attenuating these unwanted premature deaths. While we applaud the wonderful efforts of our governmental institutes and professional societies (NIDA, NIAAA, ASAM, ABAM ) in their extraordinary efforts in combating this continued dilemma, the current approach is failing, and other alternative approaches should at least be tested. These truths present a serious ethical dilemma to scientists, clinicians and counselors in the Reward Deficiency Syndrome (RDS) treatment community. It is important to realize that the current DSM-5 does not actually accurately display the natural brain reward process. The human brain has not been designed to carve out specific drugs like opioids, alcohol, nicotine, cocaine, benzodiazepines or cannabis and process addictions such as gambling as distinct endophenotypes. This is true in spite of natural ligands for cannabinoids, endorphins, or even benzodiazepines. The most accurate endophenotype is indeed reward dysfunction (e.g hypodopaminergic or hyperdopaminergic). With this mind, we are hereby proposing that the current Medication Assisted Treatment (i.e. 'MAT') expands to needed individuals as an initial "Band-Aid" to reduce harm avoidance, with the long-term goal of prophylaxis. So, to be clear, there may be other promising modalities other than MAT such as repetitive transcranial magnetic stimulation (rTMS), exercise and even new medications with positive allosteric modulators of GABA-A receptors, as well as the highly researched Genetic Addiction Risk Score (GARS) coupled with precision KB220Z. This will induce "dopamine homeostasis" to effectively rebalance and restore healthier brain function by promoting the cross talk between various brain regions (e.g. Nucleus accumbens, cingulate gyrus, hippocampus etc.) resulting in dopamine homeostasis. Our laudable goal is to not only save lives, but to redeem joy and improve the quality of life in the recovery community through scientifically sound natural non-addicting alternatives.

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

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.

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

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

Genetic addiction risk score (GARS) ™, a predictor of vulnerability to opioid dependence.

The interaction of neurotransmitters and genes that control the release of dopamine is the Brain Reward Cascade (BRC). Variations within the BRC, whether genetic or epigenetic, may predispose individuals to addictive behaviors and altered pain tolerance. This discussion authored by a group of concerned scientists and clinicians examines the Genetic Addiction Risk Score (GARS), the first test to accurately predict vulnerability to pain, addiction, and other compulsive behaviors, defined as Reward Deficiency Syndrome (RDS). Innovative strategies to combat epidemic opioid, iatrogenic prescription drug 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. They provide unique therapeutic targets that could assist in the treatment of pain, and identify risk for subsequent addiction. Pharmacogenomic testing of candidate genes like CB1, mu receptors, and PENK might result in pharmacogenomic, personalized solutions, and improved clinical outcomes. Genetically identifying risk for all RDS behaviors, especially in compromised populations, may be a frontline tool to assist municipalities to provide better resource allocation.

Would induction of dopamine homeostasis via coupling genetic addiction risk score (GARS®) and pro-dopamine regulation benefit benzodiazepine use disorder (BUD)?

Prescriptions for Benzodiazepines (BZDs) have risen continually. According to national statistics, the combination of BZDs with opioids has increased since 1999. BZDs (sometimes called “benzos”) work to calm or sedate a person by raising the level of the inhibitory neurotransmitter GABA in the brain. In terms of neurochemistry, BZDs act at the GABAA receptors to inhibit excitatory neurons, reducing VTA glutaminergic drive to reduce dopamine release at the Nucleus accumbens. Benzodiazepine Use Disorder (BUD) is very difficult to treat, partly because BZDs are used to reduce anxiety which paradoxically induces hypodopaminergia. Considering this, we are proposing a paradigm shift. Instead of simply targeting chloride channel direct GABAA receptors for replacement or substitution therapy, we propose the induction of dopamine homeostasis. Our rationale is supported by the well-established notion that the root cause of drug and non-drug addictions (i.e. Reward Deficiency Syndrome [RDS]), at least in adults, involve dopaminergic dysfunction and heightened stress. This proposition involves coupling the Genetic Addiction Risk Score (GARS) with a subsequent polymorphic matched genetic customized Pro-Dopamine Regulator known as KB220ZPBM (Precision Behavioral Management). Induction of dopamine homeostasis will be clinically beneficial in attempts to combat BUD for at least three reasons: 1) During detoxification of alcoholism, the potential induction of dopamine regulation reduces the need for BZDs; 2) A major reason for BZD abuse is because people want to achieve stress reduction and subsequently, the potential induction of dopamine regulation acts as an anti-stress factor; and 3) BUD and OUD are known to reduce resting state functional connectivity, and as such, potential induction of dopamine regulation enhances resting state functional connectivity. Future randomized placebo-controlled studies will investigate this forward thinking proposed novel modality.

The benefits of genetic addiction risk score (GARS™) and pro-dopamine regulation in combating suicide in the American Indian population.

It is well-known that Native Americans (NA) clinically present with a very high rate of alcoholism and other drugs of abuse. It is also known that NA also display a very high rate of suicide compared to other ethnic groups. Furthermore, individuals with various psychiatric disorders (e.g., depression) also have higher rates of suicide that are frequently alcohol related. Males are as much as four times more likely to die from suicide than females. Studies comparing Native to other populations within the same geographic regions in North America divulged, almost universally, that alcohol involvement is higher among Native suicides than among the local, non-Native people. Unfortunately, suicide is the eighth leading cause of death in the U.S. and is the third cause of death in those ages 15-24. With these disappointing statistics, we are hereby proposing that because of such a high genetic risk as supported by the work of Barr and Kidd showing that NA carriers the DRD2 A1 allele at the rate of 86%, compared to a highly screened reward deficiency free control of only 3%. It seems reasonable that early identification, especially in children, be tested with the Genetic Addiction Risk Score (GARS) and concomitantly be offered the precision pro-dopamine regulator (KB220PAM), one that matches their unique brain polymorphisms involving serotonergic, endorphinergic, glutaminergic, gabaergic and dopaminergic pathways among others. We believe that using the Precision Addiction Management (PAM) platform at an early age may be prophylactic, while in adults PAM may reduce substance craving affecting tertiary treatment and even relapse and mortality prevention.

Invited Commentary: In a Genomic Era, Should We Promote Dopamine Homeostasis to Treat Opiate/ Opioid Abuse, Instead of Blocking Brain Dopamine Function?

We are currently in a genomics era with important implications for the field of psychiatry. An understanding of DNA, as well as polymorphic changes affecting the brain’s reward circuitry, has provided a new way of approaching and thinking about addictive behaviors. Our current goal is to provide a foundation for more accurate genetic diagnoses as well, as the application of dopamine agonist therapy (pro-dopamine regulation), in order to balance dopaminergic activation. Based upon our extensive research, we are proposing a novel approach which challenges the Addiction recovery field to utilize these tools by introducing them into inpatient/outpatient addiction treatment programs The following tools, we hope, will change the recovery landscape: The Genetic Addiction Risk Score (GARS™) for Reward Deficiency Syndrome (RDS) diagnoses; the Comprehensive Analysis Of Reported Drugs (CARD™) to establish compliance of prescribed medications and abstinence during treatment; natural Dopamine agonistic therapy (KB220™); mRNA (patent pending) to resolve pre-and post-candidate gene expressions in Reward Deficiency Syndrome (RDS). As a result we have dubbed, this paradigm shift as: “The Reward Deficiency Solutions System (RDSS™).”Wc 180Keywords: Genome, Genetic Addiction Risk Score (GARS), KB220 variants, Pro-Dopamine Regulation, Pain, Opiate/opioid epidemic

Hypothesizing That Neuropharmacological and Neuroimaging Studies of Glutaminergic-Dopaminergic Optimization Complex (KB220Z) Are Associated With “Dopamine Homeostasis” in Reward Deficiency Syndrome (RDS)

ABSTRACTBackground: There is need for better treatments of addictive behaviors, both substance and non-substance related, termed Reward Deficiency Syndrome (RDS). While the FDA has approved pharmaceuticals under the umbrella term Medication Assisted Treatment (MAT), these drugs are not optimal. Objectives: It is our contention that these drugs work well in the short-term by blocking dopamine function leading to psychological extinction. However, use of buprenorphine/Naloxone over a long period of time results in unwanted addiction liability, reduced emotional affect, and mood changes including suicidal ideation. Methods: We are thus proposing a paradigm shift in addiction treatment, with the long-term goal of achieving “Dopamine Homeostasis.” While this may be a laudable goal, it is very difficult to achieve. Nevertheless, this commentary briefly reviews past history of developing and subsequently, utilizing a glutaminergic-dopaminergic optimization complex [Kb220Z] shown to be beneficial in at least 20 human clinical trials and in a number of published and unpublished studies. Results: It is our opinion that, while additional required studies could confirm these findings to date, the cited studies are indicative of achieving enhanced resting state functional connectivity, connectivity volume, and possibly, neuroplasticity. Conclusions/Importance: We are proposing a Reward Deficiency Solution System (RDSS) that includes: Genetic Addiction Risk Score (GARS); Comprehensive Analysis of Reported Drugs (CARD); and a glutaminergic-dopaminergic optimization complex (Kb220Z). Continued investigation of this novel strategy may lead to a better-targeted approach in the long-term, causing dopamine regulation by balancing the glutaminergic-dopaminergic pathways. This may potentially change the landscape of treating all addictions leading us to the promised land.

Molecular Genetic Testing in Pain and Addiction: Facts, Fiction and Clinical Utility.

The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors as well as altered pain tolerance. While there are many studies claiming a genetic association with addiction and other behavioral infractions, defined as Reward Deficiency Syndrome (RDS), not all are scientifically accurate and in some case just wrong. Albeit our bias, we discuss herein the facts and fictions behind molecular genetic testing in RDS (including pain and addiction) and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one's genetic risk for RDS.

Can Genetic Testing Provide Information to Develop Customized Nutrigenomic Solutions for Reward Deficiency Syndrome?

We are entering the era of genomic medicine and neuroimaging as it relates to addiction a subset of Reward Deficiency Syndrome (RDS) [1-3]. In 2005 our laboratory received the first USA patent on Nutrigenomics and RDS treatment. This was awarded on the basis of our earlier work 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 sever alcoholism [4-7]. Prior to the later genetic finding we developed the concept of Brain Reward Cascade which continues to act as blue-print for stratification of addiction risk through neurogentics [8]. 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 [9,10]. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroaaptogen- aminoacid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220 formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds [11]. This was followed up in the USA with similar significant effects [12,13]. Following these experiments we have been successfully developing a panel of genes known as “Genetic Addiction Risk Score [14,15] (GARSDX).™ In unpublished work, we found that when we selected 10 genes with appropriate variants, a statistically significant association between the ASI- Media Version -alcohol and drug severity scores and GARSDx provided the first validated genetic panel for RDS. This observation was found in 273 patients attending seven diverse treatment centers. This now validated panel could be utilized to provide a personalized approach by coupling gene polymorphisms with potential nutrigenomic solutions. Independently, a variant of NAAT –KB220Z in abstinent heroin addicts, increased resting state functional connectivity. Specifically we observed enhanced rs functional connectivity in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum [16].In other unpublished rat work using a novel segmented rat atlas, 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. This response induced by KB220Z demonstrates significant functional connectivity, increased brain volume recruitment and enhanced dopaminergic functionality across the brain reward circuitry. This robust yet selective response implies clinical relevance. These results and other quantitative electroencephalogy (qEEG) experiments results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction [17]. We are now paused to 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 NAAT ingredients as an algorithmic function of carrying these polymorphic DNA –SNPS potentially yielding the first ever nutrigenomic solution for addiction and pain[18]. The concept of dopaminergic activation in the long term is supported by the recent work of Willuhn et al. showing that a deficiency of phasic dopamine causes escalation of cocaine intake in animals. This suggests dopamine agonistic therapy rather than dopamine antagonistic therapy in the long-term treatment with patients presenting with RDS [19]. Certainly, we encourage others to also develop similar addiction algorithms based on reward gene polymorphisms and as therapeutic targets to improve clinical outcomes and long term remission for all RDS addictive behaviors.

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

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.

Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction.

BackgroundThe Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components.MethodsTo carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS.ResultsWhile there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate.ConclusionAlbeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one’s genetic risk for RDS.