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

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.

Hypothesizing that a Pro-Dopaminergic Regulator (KB220z™ Liquid Variant) can Induce "Dopamine Homeostasis" and Provide Adjunctive Detoxification Benefits in Opiate/Opioid Dependence.

In order to explore the initiation of detoxification of addictive patients to opiates/opioids (along with some other anti-withdrawal agents), we developed a protocol to be utilized in treatment centers particularly with heavily dependent opiate/opioid subjects. Out of 17 subjects, only three received Buprenorphine/Naloxone (Bup/nx) along with KB220Z. In this pilot, we first used a dose of KB220Z of 2 oz twice daily before meals along with clonidine and benzodiazepines and other anti-nausea and sleep aids including Gabapentin. The dose of KB220Z was maintained for 6 days in five individuals. In a second scenario, we utilized a higher dose of 4 oz every 6 hours, over a 6-day period. The higher dose was employed in another 12 patients. It is noteworthy that only 3 people have relapsed utilizing these two protocols during the first two weeks of the study, allowing for the remaining 82% to be maintained on KB220Z. The patients have been maintained without any additional Bup/nx for a minimum of 120 days and in one subject, 214 days. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates utilizing data from the Clinical opiate Withdrawal Scale (COWS) pre and post KB220Z. We are in the process of testing this hypothesis in multiple treatment centers across the United Sates. While this does not constitute an acceptable controlled experiment, it does provide some preliminary evidence that agrees with an earlier study. Moreover, because of the utilization of standard detoxifying agents in this detoxification protocol, we cannot make any inference to KB220Z's effects. However, out of 17 subjects, only three required Bup/nx suggesting an interesting finding. If further confirmed in larger studies, the utilization for opiate/opioid detoxification may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification. This paradigm shift may translate to a reduction in utilizing powerful and addictive opioids like buprenorphine and methadone (especially in these patients at high genetic risk for addiction) as not only detoxifying agents, but also maintenance drugs. While extensive research is required, this pilot paves the way for future investigations that could assist in the reduction of addictive opiate/opioid use and mortalities amongst both the young and old in America.

Neurobiology of KB220Z-Glutaminergic-Dopaminergic Optimization Complex [GDOC] as a Liquid Nano: Clinical Activation of Brain in a Highly Functional Clinician Improving Focus, Motivation and Overall Sensory Input Following Chronic Intake.

BACKGROUND: With neurogenetic and epigenetic tools utilized in research and neuroimaging, we are unraveling the mysteries of brain function, especially as it relates to Reward Deficiency (RDS). We encourage the development of pharmaceuticals or nutraceuticals that promote a reduction in dopamine resistance and balance brain neurochemistry, leading to dopamine homeostasis. We disclose self-assessment of a highly functional professional under work-related stress following KB220Z use, a liquid (aqua) nano glutaminergic-dopaminergic optimization complex (GDOC). CASE PRESENTATION: Subject took GDOC for one month. Subject self-administered GDOC using one-half-ounce twice a day. During first three days, unique brain activation occurred; resembling white noise after 30 minutes and sensation was strong for 45 minutes and then dissipated. He described effect as if his eyesight improved slightly and pointed out that his sense of smell and sleep greatly improved. Subject experienced a calming effect similar to meditation that could be linked to dopamine release. He also reported control of going over the edge after a hard day's work, which was coupled with a slight increase in energy, increased motivation to work, increased focus and multi-tasking, with clearer purpose of task at hand. Subject felt less inhibited in a social setting and suggested Syndrome that GDOC increased his Behavior Activating System (reward), while having a decrease in the Behavior Inhibition System (caution). CONCLUSION: These results and other related studies reveal an improved mood, work-related focus, and sleep. These effects as a subjective feeling of brain activation maybe due to direct or indirect dopaminergic interaction. While this case is encouraging, we must await more research in a larger randomized placebo-controlled study to map the role of GDOC, especially in a nano-sized product, to determine the possible effects on circuit inhibitory control and memory banks and the induction of dopamine homeostasis independent of either hypo- or hyper-dopaminergic traits/states.

NIDA-Drug Addiction Treatment Outcome Study (DATOS) Relapse as a Function of Spirituality/Religiosity.

BACKGROUND: The connection between religion/spirituality and deviance, like substance abuse, was first made by Durkheim who defined socially expected behaviors as norms. He explained that deviance is due in large part to their absence (called anomie), and concluded that spirituality lowers deviance by preserving norms and social bonds. Impairments in brain reward circuitry, as observed in Reward Deficiency Syndrome (RDS), may also result in deviance and as such we wondered if stronger belief in spirituality practice and religious belief could lower relapse from drugs of abuse. METHODS: The NIDA Drug Addiction Treatment Outcome Study data set was used to examine post hoc relapse rates among 2,947 clients who were interviewed at 12 months after intake broken down by five spirituality measures. RESULTS: Our main findings strongly indicate, that those with low spirituality have higher relapse rates and those with high spirituality have higher remission rates with crack use being the sole exception. We found significant differences in terms of cocaine, heroin, alcohol, and marijuana relapse as a function of strength of religious beliefs (x2 = 15.18, p = 0.028; logistic regression = 10.65, p = 0.006); frequency of attending religious services (x2 = 40.78, p < 0.0005; logistic regression = 30.45, p < 0.0005); frequency of reading religious books (x2 = 27.190, p < 0.0005; logistic regression = 17.31, p < 0.0005); frequency of watching religious programs (x2 = 19.02, p = 0.002; logistic regression = ns); and frequency of meditation/prayer (x2 = 11.33, p = 0.045; logistic regression = 9.650, p = 0.002). Across the five measures of spirituality, the spiritual participants reported between 7% and 21% less alcohol, cocaine, heroin, and marijuana use than the non-spiritual subjects. However, the crack users who reported that religion was not important reported significantly less crack use than the spiritual participants. The strongest association between remission and spirituality involves attending religious services weekly, the one marker of the five that involves the highest social interaction/social bonding consistent with Durkheim's social bond theory. CONCLUSIONS: Stronger spiritual/religious beliefs and practices are directly associated with remission from abused drugs except crack. Much like the value of having a sponsor, for clients who abuse drugs, regular spiritual practice, particularly weekly attendance at the religious services of their choice is associated with significantly higher remission. These results demonstrate the clinically significant role of spirituality and the social bonds it creates in drug treatment programs.

Quantitative Electroencephalography Analysis (qEEG) of Neuro-Electro-Adaptive Therapy 12™ [NEAT12] Up-Regulates Cortical Potentials in an Alcoholic during Protracted Abstinence: Putative Anti-Craving Implications.

INTRODUCTION: Cranial electrotherapy stimulation (CES) is a noninvasive therapy that has been used for decades in the United States to treat anxiety, depression, and insomnia in the general population. The effectiveness of CES has been questioned by many and its use is considered controversial. In this study we are presenting data on one alcoholic patient using a newly engineered device we call Neuro-Electro-Adaptive Therapy 12™ [NEAT12]. This hybrid device utilizes TENS current characteristics yielding CES effects. This device has been found to primarily target the excitation of the Cingulate Gyrus region of the brain. CASE PRESENTATION: This is a 42 year old male who has been abstinent from alcohol for approximately two months. The data presented herein represents the pre to post qEEG differences of an alcoholic in protracted abstinence. This subject was evaluated both before and after using the NEAT-12 device. The pre to post comparisons suggest that the cortical potentials especially at the Cingulate Gyrus are up regulated after using the device. The absolute power changes obtained shows a decrease of more than 2 SD as noted in the delta wave spectrum. Also noted is an overall cortical increase in the alpha spectrum. The resting alert state of a neuro typical population is most prominently marked by a regulation of 7.5-11 Hz alpha throughout the cortex. The decreased in delta and theta suggests an up regulation of the prefrontal cortex and the anterior Cingulate Gyrus a site involved in substance use disorder (SUD). CONCLUSION: A presence of dominant slow waves through the prefrontal cortex and the anterior Cingulate Gyrus is often associated with OCD, anxiety, impulsivity and cravings in addicted populations. It is conceivable that our initial finding of altered electrical activity of the brain using qEEG analysis suggests the NEAT-12 may induce a "normalization" of aberrant electrical activity of the cortical region of the brain known to occur during protracted abstinence of alcoholics. It may have utility as a putative anti-craving CES device and therefore warrants intensive investigation.

Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note.

BACKGROUND: While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. METHODS: We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded $50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. FINDINGS: At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.

Hypothesizing repetitive paraphilia behavior of a medication refractive Tourette's syndrome patient having rapid clinical attenuation with KB220Z-nutrigenomic amino-acid therapy (NAAT).

Background and aims Many patients presenting multiple behaviors including drug and food abuse as well as other pathological repetitive unwanted activities such as gambling, self-mutilation and paraphilias may not be appropriately diagnosed. Here we present a case of a male presenting many of these seemingly diverse behaviors and finally diagnosed with reward deficiency syndrome (RDS) by his attending physician. Methods The use of the dopamine agonist, ropinirole after two weeks showed improvement in terms of sexual behavior but tolerance set in and was discontinued especially when an infraction occurred with the patient's insurance. In this article, we carefully explore the potential of ropinirole to downregulate dopamine receptors causing adenylate cyclase receptor supersensitivity and tolerance a feature of neurotransmitter cross-talk. Based on previous scientific evidence showing KB220Znutrigenomic amino-acid therapy (NAAT) to rapidly (post one-hour) activate dopaminergic pathways in both the pre-frontal cortex cingulate gyrus (relapse loci) and ventral tegmental area-caudate-accumbens-putamen (craving and emotion loci) the patient was prescribed NAAT. Results and discussion Within one week of utilization the repetitive paraphilia was eliminated. There were also a number of other positive effects such as enhanced focus that persisted even after the patient stopped using KB220Z suggesting neuroplasticity (e.g. altruistic thoughts). However, these observed profound benefits require more in-depth study, especially in a large cohort against a placebo. While this report focused on a rapid response rather than long-term benefits previously associated with NAAT, it is somewhat encouraging and longer term required follow-up and larger placebo controlled studies are warranted before any definitive conclusions could be gleaned from this case report.

Neuropsychopharmacology and neurogenetic aspects of executive functioning: should reward gene polymorphisms constitute a diagnostic tool to identify individuals at risk for impaired judgment?

Executive functions are processes that act in harmony to control behaviors necessary for maintaining focus and achieving outcomes. Executive dysfunction in neuropsychiatric disorders is attributed to structural or functional pathology of brain networks involving prefrontal cortex (PFC) and its connections with other brain regions. The PFC receives innervations from different neurons associated with a number of neurotransmitters, especially dopamine (DA). Here we review findings on the contribution of PFC DA to higher-order cognitive and emotional behaviors. We suggest that examination of multifactorial interactions of an individual's genetic history, along with environmental risk factors, can assist in the characterization of executive functioning for that individual. Based upon the results of genetic studies, we also propose genetic mapping as a probable diagnostic tool serving as a therapeutic adjunct for augmenting executive functioning capabilities. We conclude that preservation of the neurological underpinnings of executive functions requires the integrity of complex neural systems including the influence of specific genes and associated polymorphisms to provide adequate neurotransmission.

Early intervention of intravenous KB220IV--neuroadaptagen amino-acid therapy (NAAT) improves behavioral outcomes in a residential addiction treatment program: a pilot study.

Substance use disorders (SUD) are inheritable and the culprit is hypodopaminergic function regulated by reward genes. We evaluated a natural dopaminergic agonist; KB220 intravenous (IV) and oral variants, to improve dopaminergic function in SUD. Our pilot experiment found a significant reduction of chronic symptoms, measured by the Chronic Abstinence Symptom Severity (CASS) Scale. The combined group (IV and oral) did significantly better than the oral-only group over the first week and 30-day follow-up period. Next, the combination was given to 129 subjects and three factors; Emotion, Somatic, and Impaired Cognition, with eigenvalues greater than one were extracted for baseline CASS-Revised (CASS-R) variables. Paired sample t-tests for pre and post-treatment scales showed significant declines (p = .00001) from pre- to post-treatment: t = 19.1 for Emotion, t = 16.1 for Somatic, and t = 14.9 for Impaired Cognition. In a two-year follow-up of 23 subjects who underwent KB220IV therapy (at least five IV treatments over seven days) plus orals for 30+ days: 21 (91%) were sober at six months, 19 (82%) having no relapse; 19 (82%) were sober at one year, 18 (78%) having no relapse; and 21 (91%) were sober two-years post-treatment, 16(70%) having no relapse. We await additional research and advise caution in interpreting these encouraging results.

Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms.

In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the "Brain Reward Cascade" (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications.

Neurogenetics and clinical evidence for the putative activation of the brain reward circuitry by a neuroadaptagen: proposing an addiction candidate gene panel map.

This document presents evidence supporting the role of the KB220/KB220Z neuroadaptagens consisting of amino-acid neurotransmitter precursors and enkephalinase-catecholamine-methyl-transferase (COMT) inhibition therapy called Neuroadaptagen Amino Acid Therapy (NAAT) in brain reward function. It is becoming increasingly clear that this novel formulation is the first neuroadaptagen known to activate the brain reward circuitry. Ongoing research repeatedly confirms the numerous clinical effects that ultimately result in significant benefits for victims having genetic antecedents for all addictive, compulsive and impulsive behaviors. These behaviors are correctly classified under the rubric of"Reward Deficiency Syndrome" (RDS). We are proposing a novel addiction candidate gene map. We present preliminary findings in the United States using qEGG and in China using Functional Magnetic Resonance Imaging (fMRI) regarding the effects of oral NAAT on the activation of brain reward circuitry in victims of SUD. In unpublished data utilizing an fMRI 2X2 design at resting state, NAAT in comparison to placebo shows activation of the caudate brain region and potentially a smoothing out of heroin-induced putamen (a site for emotionality) abnormal connectivity. Although awaiting final analysis, if confirmed by ongoing studies in China coupled with published qEEG results in America, showing an increase in alpha and low beta, NAAT may be shown to impact treatment outcomes.

Generational association studies of dopaminergic genes in reward deficiency syndrome (RDS) subjects: selecting appropriate phenotypes for reward dependence behaviors.

UNLABELLED: Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). METHODOLOGY: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. RESULTS: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. CONCLUSIONS: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

H-Wave® effects on blood flow and angiogenesis in longitudinal studies in rats.

Effects of repeated H-Wave® device stimulation (HWDS) on blood flow and angiogenesis in the rat hind limb were studied. The hypothesis tested was that HWDS acutely increases hind limb blood flow, and that repeated HWDS would elicit angiogenesis. Animals were HWDS-conditioned (``Conditioned'') or sham-stimulated (``Sham'') (n = 5/group) daily for 3 weeks. The contralateral limb in both groups served as the control. Each animal was injected with bromodeoxyuridine (BrDU). After 3 weeks, rats were anesthetized and iliac artery blood flow was measured bilaterally before, during, and after acute HWDS. HWDS of the Conditioned limbs elicited a 247% increase in blood flow above resting conditions compared to a 200% increase in control legs. Sham animals did not demonstrate between-leg differences in flow. Hindlimb musculature staining for BrDU revealed angiogenesis in Conditioned versus Sham groups. Flow changes accompanying HWDS corroborated earlier microvascular findings demonstrating a significant striated muscle arteriolar dilation with HWDS.

Test of variables of attention (TOVA) as a predictor of early attention complaints, an antecedent to dementia.

The goal of this study was to determine if impairments detected by the test of variables of attention (TOVA) may be used to predict early attention complaints and memory impairments accurately in a clinical setting. We performed a statistical analysis of outcomes in a patient population screened for attention deficit hyperactivity disorder or attention complaints, processing errors as measured by TOVA and the Wechsler Memory Scale (WMS-III) results. Attention deficit disorder (ADD) checklists, constructed using the Diagnostic and Statistical Manual of Mental Disorders 4th Edition criteria, which were completed by patients at PATH Medical, revealed that 72.8% of the patients had more than one attention complaint out of a total of 16 complaints, and 41.5% had more than five complaints. For the 128 males with a significant number of ADD complaints, individuals whose scores were significantly deviant or borderline (SDB) on TOVA, had a significantly greater number of attention complaints compared with normals for omissions (P < 0.02), response time (P < 0.015), and variability (P < 0.005), but not commissions (P > 0.50). For males, the mean scores for auditory, visual, immediate, and working memory scores as measured by the WMS-III were significantly greater for normals versus SDBs on the TOVA subtest, ie, omission (P < 0.01) and response time (P < 0.05), but not variability or commissions. The means for auditory, visual, and immediate memory scores were significantly greater for normals versus SDBs for variability (P < 0.045) only. In females, the mean scores for visual and working memory scores were significantly greater for normals versus SDBs for omissions (P < 0.025). The number of SDB TOVA quarters was a significant predictor for "impaired" or "normal" group membership for visual memory (P < 0.015), but not for the other three WMS-III components. For males, the partial correlation between the number of attention complaints and the number of SDB TOVA quarters was also significant (r = 0.251, P < 0.005). For the 152 females with a significant number of attention complaints, no significant differences between SDBs and normals were observed (P > 0.15). This is the first report, to our knowledge, which provides evidence that TOVA is an accurate predictor of early attention complaints and memory impairments in a clinical setting. This finding is more robust for males than for females between the ages of 40 and 90 years.

Overcoming qEEG abnormalities and reward gene deficits during protracted abstinence in male psychostimulant and polydrug abusers utilizing putative dopamine D2 agonist therapy: part 2.

BACKGROUND: It is well established that in both food- and drug-addicted individuals there is "dopamine resistance" associated with the DRD2 gene A1 allele. Based on earlier studies, evidence is emerging wherein the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may play a significant role in the recovery of individuals with reward deficiency syndrome, including those addicted to psychoactive chemicals. FINDINGS: Positive outcomes demonstrated by quantitative electroencephalographic (qEEG) imaging in a randomized, triple-blind, placebo-controlled, crossover study involving oral Synaptose Complex KB220Z™ showed an increase of alpha waves and low beta wave activity in the parietal brain region. Using t statistics, significant differences observed between placebo and Synaptose Complex KB220Z™ consistently occurred in the frontal regions after week 1 and then again after week 2 of analyses (P = 0.03). This is the first report to demonstrate involvement of the prefrontal cortex in the qEEG response to a natural putative D2 agonist (Synaptose Complex KB220Z™), especially evident in dopamine D2 A1 allele subjects. Independently, we have further supported this finding with an additional study of 3 serious polydrug abusers undergoing protracted abstinence who carried the DRD2 A1 allele. Significant qEEG differences were found between those who received 1 dose of placebo compared with those who were administered Synaptose Complex KB220Z™. Synaptose Complex KB220Z™ induced positive regulation of the dysregulated electrical activity of the brain in these addicts. The results are indicative of a phase change from low amplitude or low power in the brain to a more regulated state by increasing an average of 6.169 mV(2) across the prefrontal cortical region. In the first experiment we found that while 50% of the subjects carried the DRD2 A1 allele, 100% carried ≥ 1 risk allele. Specifically, based on the proposed addiction risk score for these 14 subjects, 72% had moderate-to-severe addiction risk. Similar findings were obtained by repeating the experiment in 3 additional currently abstinent polydrug abusers carrying the DRD2 A1 allele. CONCLUSION: This seminal work will provide important information that may ultimately lead to significant improvement in the recovery of individuals with psychostimulant and polydrug abuse problems, specifically those with genetically induced dopamine deficiency. Based on this small sample size, we are proposing that with necessary large populations supporting these initial results, and possibly even additional candidate genes and single nucleotide polymorphisms, we may eventually have the clinical ability to classify severity according to genotype and possession of risk alleles, along with offering a safe, nonaddicting, natural dopaminergic receptor agonist that potentially upregulates instead of downregulates dopaminergic receptors, preferably the D2 subtype.

Neuro-psychopharmacogenetics and Neurological Antecedents of Posttraumatic Stress Disorder: Unlocking the Mysteries of Resilience and Vulnerability.

BACKGROUND AND HYPOTHESIS: Although the biological underpinnings of immediate and protracted trauma-related responses are extremely complex, 40 years of research on humans and other mammals have demonstrated that trauma (particularly trauma early in the life cycle) has long-term effects on neurochemical responses to stressful events. These effects include the magnitude of the catecholamine response and the duration and extent of the cortisol response. In addition, a number of other biological systems are involved, including mesolimbic brain structures and various neurotransmitters. An understanding of the many genetic and environmental interactions contributing to stress-related responses will provide a diagnostic and treatment map, which will illuminate the vulnerability and resilience of individuals to Posttraumatic Stress Disorder (PTSD). PROPOSAL AND CONCLUSIONS: We propose that successful treatment of PTSD will involve preliminary genetic testing for specific polymorphisms. Early detection is especially important, because early treatment can improve outcome. When genetic testing reveals deficiencies, vulnerable individuals can be recommended for treatment with "body friendly" pharmacologic substances and/or nutrients. Results of our research suggest the following genes should be tested: serotoninergic, dopaminergic (DRD2, DAT, DBH), glucocorticoid, GABAergic (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor, Monamine B, CNR1, Myo6, CRF-1 and CRF-2 receptors, and neuropeptide Y (NPY). Treatment in part should be developed that would up-regulate the expression of these genes to bring about a feeling of well being as well as a reduction in the frequency and intensity of the symptoms of PTSD.

Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS).

Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual's D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. [18] found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction.

Neurogenetics of dopaminergic receptor supersensitivity in activation of brain reward circuitry and relapse: proposing "deprivation-amplification relapse therapy" (DART).

BACKGROUND AND HYPOTHESIS: It is well known that after prolonged abstinence, individuals who use their drug of choice experience a powerful euphoria that often precipitates relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed "supersensitivity" might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared with DRD2 A2 allele carriers. Because carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine D2 agonist bromocriptine. Moreover, under chronic or long-term therapy with D2 agonists, such as bromocriptine, it has been shown in vitro that there is a proliferation of D2 receptors. One explanation for this relates to the demonstration that the A1 allele of the DRD2 gene is associated with increased striatal activity of L-amino acid decarboxylase, the final step in the biosynthesis of dopamine. This appears to be a protective mechanism against low receptor density and would favor the utilization of an amino acid neurotransmitter precursor like L-tyrosine for preferential synthesis of dopamine. This seems to lead to receptor proliferation to normal levels and results in significantly better treatment compliance only in A1 carriers. PROPOSAL AND CONCLUSION: We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse, including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: "denervation supersensitivity." Rats with unilateral depletions of neostriatal dopamine display increased sensitivity to dopamine agonists estimated to be 30 to 100 x in the 6-hydroxydopamine (6-OHDA) rotational model. Given that mild striatal dopamine D2 receptor proliferation occurs (20%-40%), it is difficult to explain the extent of behavioral supersensitivity by a simple increase in receptor density. Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing amino acid neurotransmitter precursors, enkephalinase, and catechol-O-methyltransferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in reward deficiency syndrome (RDS) probands. If future translational research reveals that dopamine agonist therapy reduces relapse in RDS, it would support the proposed concept, which we term "deprivation-amplification relapse therapy" (DART). This term couples the mechanism for relapse, which is "deprivation-amplification," especially in DRD2 A1 allele carriers with natural D2 agonist therapy utilizing amino acid precursors and COMT and enkepalinase inhibition therapy.