Search

Kenneth Blum,1– 5 Bruce Steinberg,6 Marjorie C Gondre-Lewis,7 David Baron,1 Edward J Modestino,6 Rajendra D Badgaiyan,8– 10 B William Downs,11 Debasis Bagchi,11 Raymond Brewer,5 Thomas McLaughlin,12 Abdalla Bowirrat,13 Mark Gold14 1Center for Psychiatry, Medicine & Primary Care, Division of Addiction Research & Education, Graduate College, Western University Health Sciences, Pomona, CA, USA; 2Eötvös Loránd University, Institute of Psychology, Budapest, Hungary; 3Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Center, Dayton, OH (IE), USA; 4Department of Psychiatry, University of Vermont, Burlington, VT, USA; 5Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX, USA; 6Department of Psychology, Curry College, Milton, MA, USA; 7Developmental Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, USA; 8Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 9Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, USA; 10Long School of Medicine, University of Texas Medical Center, San Antonio, TX, USA; 11Division of Nutrigenomics, Victory Nutrition International, Inc., Harleysville, PA, USA; 12Department of Psychopharmacology, Center for Psychiatric Medicine, Lawrence, MA, USA; 13Adelson School of Medicine & Department of Molecular Biology, Ariel University, Ariel, Israel; 14Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USACorrespondence: Bruce SteinbergDepartment of Psychology, Curry College, Milton, MA, USATel +1 617-333-2226Fax +1 617-333-2316Email Bsteinbe4@gmail.comAbstract: This is a review of research on “Precision Behavioral Management” of substance use disorder (SUD). America is experiencing a high prevalence of substance use disorder, primarily involving legal and illegal opioid use. A 3000% increase in treatment for substance abuse has occurred between 2000 and 2016. Unfortunately, present day treatment of opioid abuse involves providing replacement therapy with powerful opioids to, at best, induce harm reduction, not prophylaxis. These interventions do not enhance gene expression and restore the balance of the brain reward system’s neurotransmitters. We are proposing a generalized approach called “Precision Behavioral Management”. This approach includes 1) using the Genetic Addiction Risk Severity (GARS, a 10 candidate polymorphic gene panel shown to predict ASI-alcohol and drug severity) to assess early pre-disposition to substance use disorder; 2) using a validated reward deficiency syndrome (RDS) questionnaire; 3) utilization of the Comprehensive Analysis of Reported Drugs (CARD™) to assess treatment compliance and abstinence from illicit drugs during treatment, and, importantly; 4) utilization of a “Pro-dopamine regulator (KB220)” (via IV or oral [KB220Z] delivery systems) to optimize gene expression, restore the balance of the Brain Reward Cascade’s neurotransmitter systems and prevent relapse by induction of dopamine homeostasis, and; 5) utilization of targeted DNA polymorphic reward genes to direct mRNA genetic expression profiling during the treatment process. Incorporation of these events can be applied to not only the under-considered African-American RDS community, but all victims of RDS, as a demonstration of a paradigm shift that uniquely provides a novel putative “standard of care” based on DNA guided precision nutrition therapy to induce “dopamine homeostasis” and rebalance neurotransmitters in the Brain Reward Cascade. We are also developing a Reward Deficiency Syndrome Diagnostic Criteria (RDSDC) to assist in potential tertiary treatment.Keywords: substance use disorder, SUD, genomic disparity, dopamine, pro-dopamine regulation, KB220, GARS, homeostasis

This study evaluated the effects of a putative activator of brain reward circuitry on outcomes in a 1-y prospective comprehensive outpatient clinical program. As part of the Gene Narcotic Attenuation Program, Haveos (Synaptamine)(TM) was administered for the treatment of substance use disorder. Seventy-six patients (45 males and 31 females; mean age, 33 y [standard deviation, 7.0]) who had been given a diagnosis of serious substance use disorder were recruited. After exclusion of 15 patients who dropped out before the end of the study, self-reported craving decreased from program entrance to 12 wk (visual analog scale whereby 0 represents no craving and 5, the strongest craving) for 61 compliant patients (mean decrease, 2.85, 95% confidence interval [CI], 2.65, 3.05); this improvement was significant (P<.001). Building up to relapse scores (each of 5 individual items and summary value) showed similar improvement after 1 y of treatment; the mean decrease in scores was significant for stress (t=3.3; P=.002), depression (t=4.0; P<.001), anger (t=4.4; P<.001), anxiety (t=4.5, P<.001), drug craving (t=5.4, P<.001), and summary building up to relapse (t=4.1; P<.001). Also, recovery score measures of energy level (t=8.4; P<.001) and ability to refrain from drug-seeking behavior (t=7.4; P<.001) showed significant mean increases from entry to 1 y. During the study, the alcoholic dropout rate was only 7% (4 of 57), which was significantly (Fisher's exact test, P<.001) lower than the 73% (11 of 15) dropout rate reported for psychostimulant users. Although these results are significant, any interpretation must await the performance of rigorous double-blind studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In a previous study, the H-Wave small-muscle fiber stimulator significantly reduced chronic pain and restored physical function among patients with pain in the lower and upper extremities and spine. In this extended population observational study, a cross-sectional,computer-administered 10-item survey was administered to 6774 patients (3367 men [49.7%], 3406 women [50.3%], and 1 sex not reported [<1%]; mean+/-SD age, 45.28+/-10.08 y; range, 18-65 y) with chronic soft-tissue injury or neuropathic pain to assess their therapeutic response. The mean+/-SE duration of self-administered H-Wave treatment before the survey was completed was 87.35+/-1.39 d. Sixty-five percent of study participants reported a reduced or eliminated need for pain medication; 79% reported improved functional capacity or activity; and 78% reported 25% or greater reduction of pain. This cross-sectional evaluation represents the largest outcome study on the benefits of the H-Wave device in patients with chronic soft-tissue injury or neuropathic pain. The results suggest that this nonpharmacologic approach may provide an important alternative to standard pharmacologic treatment. [ABSTRACT FROM AUTHOR]

Delayed P300 latency identifies dementia better than the Mini-Mental Status Exam and, in some cases, the Wechsler Memory Scale (WMS-III). The purpose of this study was to determine whether the outcome of an objective Test of Variables of Attention (TOVA) correlates with the findings of an electrophysiologic test-P300 latency-in patients 40 y of age or older. Adult attention deficit disorder may be an important premorbid marker of memory dysfunction or dementia. In males, the means for P300 latency and age-adjusted P300 latency were significantly greater for patients classified as SD-BL (significantly deviant or borderline: TOVA<-1.0) than for those categorized as normal (TOVA(3)0) for attention failure (ie, omissions [P<.010] and commissions [P<.005]) but not for response time or for variability. Males with >2 SD-BL quarters had significantly delayed P300 latency and age-adjusted P300 latency compared with males who had 0 SD-BL quarters (P<.020) and 1 SD-BL quarter (P<.005). In females, the means for P300 latency and age-adjusted P300 latency were significantly delayed for those grouped as SD-BL than for those labeled normal for response time (P<.001) and variability (P<.010), but not for omissions or for commissions. Females with >2 SD-BL quarters had significantly delayed P300 latency and age-adjusted P300 latency compared with females who had 0 SD-BL quarters (P<.005) and 1 SD-BL quarter (P<.010). Results suggest that TOVA abnormalities may be an indicator of delayed P300 and attention disorder. Recent research correlates TOVA abnormalities with impaired WMS scores of early dementia. Coupling of TOVA assessment findings with results of P300, Mini-Mental Status Exam, and WMS-III may allow for enhanced accuracy in the diagnosis and evaluation of the complex pathway of failing attention, memory, and cognition that leads to dementia. [ABSTRACT FROM AUTHOR]

Background: Albeit other prospective randomized controlled clinical trials on H-Wave device stimulation (HWDS), this is the first randomized double-blind placebo controlled prospective study that assessed the effects of HWDS on range of motion and strength testing in patients who underwent rotator cuff reconstruction.Methods: Twenty-two patients were randomly assigned into one of two groups: 1) H-Wave device stimulation (HWDS); 2) sham-placebo device (PLACEBO). All groups received the same postoperative dressing and the same device treatment instructions. Group I was given HWDS which they were to utilize for one hour twice a day for 90 days postoperatively. Group II was given the same instructions with a Placebo device (PLACEBO). Range of motion was assessed by using one-way ANOVA with a Duncan Multiple Range Test for differences between the groups preoperatively, 45 days postoperatively, and 90 days postoperatively by using an active/passive scale for five basic ranges of motions: Forward Elevation, External Rotation (arm at side), External Rotation (arm at 90 degrees abduction), Internal Rotation (arm at side), and Internal Rotation (arm at 90 degrees abduction). The study also evaluated postoperative changes in strength by using the Medical Research Council (MRC) grade assessed strength testing.Results: Patients who received HWDS compared to PLACEBO demonstrated, on average, significantly improved range of motion. Results confirm a significant difference for external rotation at 45 and 90 days postoperatively; active range at 45 days postoperatively (p = 0.007), active at 90 days postoperatively (p = 0.007). Internal rotation also demonstrated significant improvement compared to PLACEBO at 45 and 90 days postoperatively; active range at 45 days postoperatively (p = 0.007), and active range at 90 days postoperatively (p = 0.006). There was no significant difference between the two groups for strength testing.Conclusion: HWDS compared to PLACEBO induces a significant increase in range of motion in positive management of rotator cuff reconstruction, supporting other previous research on HWDS and improvement in function. Interpretation of this preliminary investigation while suggestive of significant increases in Range of Motion of Post -Operative Rotator Cuff Reconstruction, warrants further confirmation in a larger double-blinded sham controlled randomized study. [ABSTRACT FROM AUTHOR]

Despite the advancement in wound care, the effective therapy of chronic diabetic ulcers continues to be a challenge. Wound healing is a highly controlled process, which involves a sequence of complex overlapping steps. This healing pathway comprises of hemostasis, inflammation, proliferative, and remodeling phases. Recent evidence suggests that phytomedicines can prevent or repair different kinds of destructive cellular damage, including chronic wounds. Several phytochemicals such as polyphenols, alkaloids, flavonoids, terpenoids, and glycosides have pleiotropic effects, including stimulation of fibroblast proliferation, the main step in wound healing. Besides, the mechanism involves induction of collagen synthesis, migration, and reepithelization and their antimicrobial, antioxidant, anti-inflammatory, and immunomodulatory actions. Similarly, the use of phytochemicals alone or as an adjuvant with standard therapy has demonstrated promising results in managing complications in the diabetic foot. For instance, the extract of Carica papaya has been shown antioxidant, antimicrobial, and anti-inflammatory, and immunomodulatory effects, which, together with proteolytic enzymatic activity, contributes to its wound healing property. It is generally believed that phytotherapy has no or minimal toxicity than synthetic therapeutic agents, favoring its use in diabetic foot ulcer management. The current review highlights the selected phytochemicals and their sources; and potential application in diabetic foot ulcer management.Key teaching points and nutritional relevanceCurrently, phytochemicals have been shown wide potential in disease. management including alleviating clinical manifestations, preventing degenerative disease, and curing illness.Increased evidence of phytochemical as anti-infective and anti-inflammatory suggests its role in the management of diabetic foot ulcer(DFU).Potential benefit along with minimal adverse effect favors its application as adjuvant therapy.Further research is needed to standardize its dose and formulation to enhance its clinical application in DFU management.

In this nonsystematic review and opinion, including articles primarily selected from PubMed, we examine the pharmacological and nonpharmacological treatments of neonatal abstinence syndrome (NAS) in order to craft a reasonable opinion to help forge a paradigm shift in the treatment and prevention of primarily opioid-induced NAS. Newborns of individuals who use illicit and licit substances during pregnancy are at risk for withdrawal, also known as NAS. In the US, the reported prevalence of NAS has increased from 4.0 per 1000 hospital births in 2010 to 7.3 per 1000 hospital births in 2017, which is an 82% increase. The management of NAS is varied and involves a combination of nonpharmacologic and pharmacologic therapy. The preferred first-line pharmacological treatment for NAS is opioid therapy, specifically morphine, and the goal is the short-term improvement in NAS symptomatology. Nonpharmacological therapies are individualized and typically focus on general care measures, the newborn-parent/caregiver relationship, the environment, and feeding. When used appropriately, nonpharmacologic therapies can help newborns with NAS avoid or reduce the amount of pharmacologic therapy required and the length of hospitalization. In addition, genetic polymorphisms of the catechol-o-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes appear to affect the length of stay and the need for pharmacotherapy in newborns with prenatal opioid exposure. Therefore, based on this extensive literature and additional research, this team of coauthors suggests that, in the future, in addition to the current nonpharmacological therapies, patients with opioid-induced NAS should undergo genetic assessment (i.e., the genetic addiction risk severity (GARS) test), which can subsequently be used to guide DNA-directed precision amino-acid enkephalinase inhibition (KB220) therapy as a frontline modality instead of potent opioids.

Scientific studies have provided evidence that there is a relationship between violent and aggressive behaviors and addictions. Genes involved with the reward system, specifically the brain reward cascade (BRC), appear to be associated with various addictions and impulsive, aggressive, and violent behaviors. In our previous research, we examined the Taq A1 allele (variant D2 dopamine receptor gene) and the DAT-40 base repeat (a variant of the dopamine transporter gene) in 11 Caucasian boys at the Brown School in San Marcus, Texas, diagnosed with intermittent explosive disorder. Thirty supernormal controls were screened to exclude several reward-deficit behaviors, including pathological violence, and genotyped for the DRD2 gene. Additionally, 91 controls were screened to exclude ADHD, pathological violence, alcoholism, drug dependence, and tobacco abuse, and their results were compared with DAT1 genotype results. In the schoolboys vs. supercontrols, there was a significant association with the D2 variant and a trend with the dopamine transporter variant. Results support our hypothesis and the involvement of at least two gene risk alleles with adolescent violent/aggressive behaviors. This study and the research presented in this paper suggest that violent/aggressive behaviors are associated with a greater risk of addiction, mediated via various genes linked to the BRC. This review provides a contributory analysis of how gene polymorphisms, especially those related to the brain reward circuitry, are associated with violent behaviors.

The current addiction crisis has destroyed a multitude of lives, leaving millions of fatalities worldwide in its wake. At the same time, various governmental agencies dedicated to solving this seemingly never-ending dilemma have not yet succeeded or delivered on their promises. We understand that addictive behavioral seeking is a multi-faceted neurobiological and spiritually complicated phenomenon. However, although the substitution replacement approach, especially to treat Opioid Use Disorder (OUD), has importance for harm reduction in the short term, it does not bring about a harm-free recovery or prevention. Instead, we propose a promising novel approach that uses genetic risk testing with induction of dopamine homeostasis and an objective Brain Health Check during youth. Our model involves a six-hit approach known as the "Reward Dysregulation Syndrome Solution System," which can identify addiction risk and target the root cause of addiction, dopamine dysregulation. While we applaud all past sophisticated neurogenetic and neuropharmacological research, our opinion is that in the long term, addiction scientists and clinicians might characterize preaddiction using tests; for example, administering the validated RDSQuestionarre29, genetic risk assessment, a modified brain health check, or diagnostic framing of mild to moderate Substance Use Disorder (SUD). The preaddiction concept could incentivize the development of interventions to prevent addiction from developing in the first place and target and treat neurotransmitter imbalances and other early indications of addiction. WC 222., Competing Interests: Declaration of Competing Interest KB owns the patents and pending related to GARS and KB220 variants. There are no other conflicts., (Copyright © 2022. Published by Elsevier B.V.)

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.

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including genome-wide association studies (GWAS). To develop an accurate test to help identify those at risk for at least alcohol use disorder (AUD), a subset of reward deficiency syndrome (RDS), Blum's group developed the genetic addiction risk severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions, including pain and even bariatric surgery, as a predictor of severe vulnerability to unwanted addictive behaviors, published since 1990 until now. This analysis calculated the Hardy-Weinberg Equilibrium of each polymorphism in cases and controls. Pearson's χ 2 test or Fisher's exact test was applied to compare the gender, genotype, and allele distribution if available. The statistical analyses found the OR, 95% CI for OR, and the post risk for 8% estimation of the population's alcoholism prevalence revealed a significant detection. Prior to these results, the United States and European patents on a ten gene panel and eleven risk alleles have been issued. In the face of the new construct of the "preaddiction" model, similar to "prediabetes", the genetic addiction risk analysis might provide one solution missing in the treatment and prevention of the neurological disorder known as RDS.

Reward Deficiency Syndrome (RDS) is defined as a breakdown of reward neurotransmission that results in a wide range of addictive, compulsive, and impulsive behaviors. RDS is caused by a combination of environmental (epigenetic) influences and DNA-based (genetic) neurotransmission deficits that interfere with the normal satisfaction of human physiological drives (i.e., food, water, and sex). An essential feature of RDS is the lack of integration between perception, cognition, and emotions that occurs because of (1) significant dopaminergic surges in motivation, reward, and learning centers causing neuroplasticity in the striato-thalamic-frontal cortical loop; (2) hypo-functionality of the excitatory glutamatergic afferents from the amygdala-hippocampus complex. A large volume of literature regarding the known neurogenetic and psychological underpinnings of RDS has revealed a significant risk of dopaminergic gene polymorphic allele overlap between cohorts of depression and subsets of schizophrenia. The suggestion is that instead of alcohol, opioids, gambling disorders, etc. being endophenotypes, the true phenotype is RDS. Additionally, reward deficiency can result from depleted or hereditary hypodopaminergia, which can manifest as a variety of personality traits and mental/medical disorders that have been linked to genetic studies with dopamine-depleting alleles. The carrying of known DNA antecedents, including epigenetic insults, results in a life-long vulnerability to RDS conditions and addictive behaviors. Epigenetic repair of hypodopaminergia, the causative basis of addictive behaviors, may involve precision DNA-guided therapy achieved by combining the Genetic Addiction Risk Severity (GARS) test with a researched neutraceutical having a number of variant names, including KB220Z. This nutraceutical formulation with pro-dopamine regulatory capabilities has been studied and published in peer-reviewed journals, mostly from our laboratory. Finally, it is our opinion that RDS should be given an ICD code and deserves to be included in the DSM-VI because while the DSM features symptomology, it is equally important to feature etiological roots as portrayed in the RDS model.

Pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) is a concept that is used to characterize a subset of children with neuropsychiatric symptoms, tic disorders, or obsessive-compulsive disorder (OCD), whose symptoms are exacerbated by group A streptococcal (GAS) infection. PANDAS has been known to cause a sudden onset of reward deficiency syndrome (RDS). RDS includes multiple disorders that are characterized by dopaminergic signaling dysfunction in the brain reward cascade (BRC), which may result in addiction, depression, avoidant behaviors, anxiety, tic disorders, and/or OCD. According to research by Blum et al ., the dopamine receptor D2 (DRD2) gene polymorphisms are important prevalent genetic determinants of RDS. The literature demonstrates that infections like Borrelia and Lyme, as well as other infections like group A beta-hemolytic streptococcal (GABHS), can cause an autoimmune reaction and associated antibodies target dopaminergic loci in the mesolimbic region of the brain, which interferes with brain function and potentially causes RDS-like symptoms/behaviors. The treatment of PANDAS remains controversial, especially since there have been limited efficacy studies to date. We propose an innovative potential treatment for PANDAS based on previous clinical trials using a pro-dopamine regulator known as KB220 variants. Our ongoing research suggests that achieving "dopamine homeostasis" by precision-guided DNA testing and pro-dopamine modulation could result in improved therapeutic outcomes., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest regarding the publication of this paper.

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA , there has been an explosion of genetic candidate association studies, including GWAS. To develop an accurate test to help identify those at risk for at least Alcohol Use Disorder (AUD), Blum's group developed the Genetic Addiction Risk Severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions published from 1990 until 2021. This analysis calculated the Hardy-Weinberg Equilibrium of each polymorphism in cases and controls. If available, the Pearson's χ 2 test or Fisher's exact test was applied to comparisons of the gender, genotype, and allele distribution. The statistical analyses found the OR, 95% CI for OR, and a post-risk for 8% estimation of the population's alcoholism prevalence revealed a significant detection. The OR results showed significance for DRD2, DRD3, DRD4, DAT1, COMT, OPRM1, and 5HTT at 5%. While most of the research related to GARS is derived from our laboratory, we are encouraging more independent research to confirm our findings., Competing Interests: K.B. is the inventor of GARS and is credited with domestic and foreign patents. D.H. was a paid consultant for Ivitalize Inc. The other authors declare no conflict of interest.

Introduction: Polymorphic gene variants, particularly the genetic determinants of low dopamine function (hypodopaminergia), are known to associate with Substance Use Disorder (SUD) and a predisposition to PTSD. Addiction research and molecular genetic applied technologies supported by the National Institutes of Health (NIH) have revealed the complex functions of brain reward circuitry and its crucial role in addiction and PTSD symptomatology., Discussion: It is noteworthy that Israeli researchers compared mice with a normal immune system with mice lacking adaptive immunity and found that the incidence of PTSD increased several-fold. It is well established that raising endorphinergic function increases immune response significantly. Along these lines, Blum's work has shown that D-Phenylalanine (DPA), an enkephalinase inhibitor, increases brain endorphins in animal models and reduces stress in humans. Enkephalinase inhibition with DPA treats Post Traumatic Stress Disorder (PTSD) by restoring endorphin function. The Genetic Addiction Risk Severity (GARS) can characterize relevant phenotypes, genetic risk for stress vulnerability vs . resilience. GARS could be used to pre-test military enlistees for adaptive immunity or as part of PTSD management with customized neuronutrient supplementation upon return from deployment., Conclusion: Based on GARS values, with particular emphasis on enhancing immunological function, pro-dopamine regulation may restore dopamine homeostasis. Recognition of the immune system as a "sixth sense" and assisting adaptive immunity with Precision Behavioral Management (PBM), accompanied by other supportive interventions and therapies, may shift the paradigm in treating stress disorders., Competing Interests: CONFLICT OF INTEREST Dr. Kenneth Blum is the Editor-in-Chief of Current Psychopharmacology (CPSP). Dr. Blum has percent ownership in Geneus Health, LLC. Drs. Blum and Raymond Brewer are officers of Geneus Health, LLC. Drs. Baron, Thanos, Elman, Modestino, McLaughlin, Badgaiyan are members of the Scientific Advisory Board of Geneus Health, LLC. B. William Downs is President of Victory Nutrition International, LLC., a company promoting GARS and Pro-Dopamine regulators licensed from Geneus Health, LLC. Victory Nutrition International, LLC, employs Dr. Bagchi.

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.

This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of the addiction risk severity (GARS) test. Based on both neurogenetic and epigenetic evidence, the test evaluates the presence of reward genes and risk alleles. Existing evidence demonstrates that the novel genetic risk testing system can successfully stratify the potential for developing opioid use disorder (OUD) related risks or before initiating opioid analgesic therapy and RDS risk for people in recovery. In the case of opioid use disorders, long-term maintenance agonist treatments like methadone and buprenorphine may create RDS, or RDS may have been in existence, but not recognized. The test will also assess the potential for benefit from medication-assisted treatment with dopamine augmentation. RDS methodology holds a strong promise for reducing the burden of addictive disorders for individuals, their families, and society as a whole by guiding the restoration of dopamine homeostasisthrough anti-reward allostatic neuroadaptations. WC 175.

In 2019, the US Center for Disease Control and Prevention provided vital statistics related to drug overdoses in the United State1. They concluded that in the USA the number of deaths at almost 72,000 was due to 66.6% of opioid overdoses. In fact, the rate is alarming and increasing yearly. To make 2021 even more scary is the daunting effect on increased drug usage due to COVID 19 as a pandemic, albeit the new vaccines. Specifically, in 2020, the death rate from opioid overdoses rose to 13% nationally and in some sates 30%. The common neuromodulating aspects of neurotransmission, and its disruption via chronic exposure of drugs and behavioral addictions, requires further intense research focus on developing novel strategies to combat these unwanted genetic and epigenic infractions as accomplished with heroin addiction by our group. The take home message is the plausible acceptance of the well-established evidence for hypodopaminergia, a blunted reward processing system, reduced resting state functional connectivity, genetic antecedents, anti- reward symptomatology, poor compliance with MAT, and generalized RDS. With this evidence it is conceivable that pursuit through intensive future research should involve an approach that incorporates "dopamine homeostasis". This required paradigm shift may consist of many beneficial modalities including but not limited to: exercise, pro-dopamine regulation, nutrigenomics, cognitive behavioral therapy, hedonic hot spot targets brain, rTMRS, deep brain stimulation, diet, genetic edits, genetic guided therapeutics, epigenetic repair, amongst others. It is our opinion that nutrigenomics may assist the millions of people of getting out of a" hypodopaminergic ditch" WC 250., Competing Interests: Conflict of Interest KB is the inventor of GARS and Pro-dopamine regulator (KB220) either owned and or licensed to his various companies (Geneus Health LLC, Synaptamine, Ivitalize). BWD and DB are employed by Victory Nutrition International (VNI) and the recipient GARS and KB220Z license AR, TS, RH, RG, RB are supported in part by Ivitalize. Vis employment, or consultation services.AR is a member of Ivitalize Board of Directors. There are no other conflicts to report.

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.

Background: A common neurological condition worldwide is Reward Deficiency Syndrome (RDS) leading to both substance and non-substance addictive behaviors, that must be combatted by integrating both central nervous system and peripheral nervous system biological approaches. Integrity of hemoglobin is a crucial determining factor for the overall health functions. Nutrient repletion therapy should be a fundamental strategy to restore the healthy properties of blood. A unique patent-pending iron-free VMP35 formulation was engineered by our laboratory to restore iron-dependent hemoglobin in anemic cells using a proprietary Prodosome ® absorption technology. This formulation, containing an array of nano-emulsified botanical ingredients rich in bioflavonoids, strengthens the structural integrity of connective tissues, and potentiates immune competence, cellular aerobic metabolism, and enhances efficient regulation of inflammatory events. We discuss the intricate aspects of strong vs. fragile immunity and consequential inflammatory responses to convey a deeper understanding of the varied and overly complex sequela of immunological behaviors and events. The effect of the VMP35 is mediated through highly absorbable nutritional/nutrigenomic repletion enabling improvements in the systemic set of functional behaviors. In fact, the iron-free VMP35 facilitates a "Systems Biology Approach" which restores hemoglobin status, reverses anaerobic hypoxia, improves competent immune responsivity, and regulates appropriate and controlled activation of general and neuro-inflammatory sequela. Under these pathogenic circumstances, iron-deficiency anemia has been misconceptualized, and a new nosological term, Chronic Anemia Syndrome, is proposed. The comparative therapeutic rationale of Reductionist vs. Systems Biology approaches is also explained in detail., Methods: The efficacy of the novel therapeutic iron-free VMP35 liquid nutraceutical is detailed in restoring iron-dependent hemoglobin to RBCs and boosting cellular morphology, viability, and immune competence, thereby reducing the need for prolonging inflammatory sequela., Results: This was demonstrated in a previous IRB approved multi-subject human study. In addition, two recent case studies report dramatic restorative benefits of nutrient repletion therapy of the VMP35 on subjects having experienced near-fatal events, which confirmed the findings explained in this manuscript., Conclusions: This novel iron-free VMP35 modulates an array of homeostatic biological parameters such as enhanced hemoglobinization, aerobic metabolism, viral immuno-competence, and inflammatory regulation. Further research, examining mechanistic and beneficial effects in athletic performance, is in progress. Importantly, during these troubled immune challenging times, modulating an array of homeostatic immunological and inflammatory dysfunctions are tantamount to improved population outcomes., Trial Registration: The Clinical investigation in a total of 38 subjects was conducted under an Institutional Review Board (IRB) from the Path Foundation in New York, NY (#13-009 April 25, 2013). The two case studies were done at Lancaster General Hospital, Lancaster, PA, and Jefferson University Hospital, Philadelphia, PA, USA. Both studies were retrospectively registered., Competing Interests: Competing interests Both Drs. Bruce S. Morrison, DO and Jeffrey Galvin, MD are highly respected board-certified practicing physicians whose clinical experience with the VMP35 confirmed the concept and hypothesis of this article and guided the writing of the manuscript. Bernard W. Downs is employed by Victory Nutrition International, Inc. (VNI), Lederach, PA, Debasis Bagchi, a professor in the Department of Pharmacological & Pharmaceutical Sciences, University of Houston college of Pharmacy and Steve Kushner of ALM R&D, are both scientific consultants to VNI, all of whom contributed to the concept of the manuscript respectively. Dr. Manashi Bagchi is an independent consultant, who compiled the data, wrote, and routed the manuscript to all concerned. Kourtney Randsdorp, and Justin Randsdorp are certified Occupational Therapists who were involved in the recovery treatment of DH in Case Study #1 and provided valuable suggestions and criticisms while drafting the manuscript.

In the face of the global pandemic of COVID 19, approaching 1.75 Million infected worldwide (4/12/2020) and associated mortality (over 108, 000 as of 4/12/2020) as well-as other catastrophic events including the opioid crisis, a focus on brain health seems prudent [1] (https://www.coronavirus.gov). This manuscript reports on the systemic benefits of restoring and achieving dopamine homeostasis to reverse and normalize thoughts and behaviors of Reward Deficiency Syndrome (RDS) dysfunctional conditions and their effects on behavioral physiology; function of reward genes; and focuses on digestive, immune, eye health, and the constellation of symptomatic behaviors. The role of nutrigenomic interventions on restoring normal brain functions and its benefits on these systems will be discussed. We demonstrate that modulation of dopamine homeostasis using nutrigenomic dopamine agonists, instead of pharmaceutical interventions, is achievable. The allied interlinking with diverse chronic diseases and disorders, roles of free radicals and incidence of anaerobic events have been extensively highlighted. In conjunction, the role of dopamine in aspects of sleep, rapid eye movement and waking are extensively discussed. The integral aspects of food indulgence, the influence of taste sensations, and gut-brain signaling are also discussed along with a special emphasis on ocular health. The detailed mechanistic insight of dopamine, immune competence and the allied aspects of autoimmune disorders are also highlighted. Finally, the integration of dopamine homeostasis utilizing a patented gene test and a research-validated nutrigenomic intervention are presented. Overall, a cutting-edge nutrigenomic intervention could prove to be a technological paradigm shift in our understanding of the extent to which achieving dopamine homeostasis will benefit overall health., Competing Interests: Conflicts of interest Kenneth Blum, PhD assigned his IP to GARS IP, LLC., Hollywood Florida. Drs. Blum and Brewer are paid employees of GARS IP, LLC., and Geneus Health, LLC.

Background: 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., Objectives: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: CONFLICT OF INTEREST Dr. Blum is the inventor of GARS and along with Dr. Siwicki own Geneus Health. Lisa Lott and Jessica Ponce are paid by Geneus Health.

Competing Interests: Conflicts of interest Kenneth Blum, PhD is the holder of a number of US and Foreign patents issued and pending related to Nutrigenomics and Nutraceuticals. Together with Geneus Health, LLC a developmental commercialization of the Genetic Addiction Risk Score (GARS)® with a sales license to Dominion Diagnostics, LLC. Kenneth Blum is a paid consultant (Chief Scientific Advisor) of Dominion Diagnostics, LLC, and is Chairman of The Board and CSO of Geneus Health, LLC. Dr. Blum is a member of the scientific advisory board of Dominion Diagnostics, LLC and is their Chief Scientific Advisor. Drs. Blum (Chairman), Badgaiyan, Thanos, Siwicki, Baron and Badgaiyan are members of Geneus Health Scientific Advisory Board. B.W Downs is the founder and owns stock in Victory International Nutrition, Inc., and that company is a licensed distributor of GARS and Restoregen products. The authors state that there are no other conflicts of interest.

Background: Enzymes are crucial for all aspects of metabolic function. Digestive enzymes from natural sources have been credited with beneficial effects in the digestion and absorption of food. N-SORB is a novel KD120 multienzyme complex (MEC) of metabolically activated enzymes composed of proteases, amylases, lipases, alpha-galactosidase, and glucoamylase from natural sources. These enzymes are encapsulated in a SK713 SLP (non-GMO soy lecithin phospholipid) absorption technology (Prodosome ® ). Objective: This randomized, double-blind placebo-controlled investigation assessed the safety and efficacy of N-SORB KD120 MEC in healthy male and female volunteers on various parameters of the blood, immunity, body composition, physical health, and quality of life following a 90-day intervention. Methods: Forty-six male and female (mean age: 25.8 ± 12.1 years) healthy volunteers were randomly assigned to receive either N-SORB (1 mL, twice daily) or placebo for 90 consecutive days. Complete blood count, as well as blood glucose, liver enzymes, and lipid profile were assessed pre- and post-intervention. Serum cytokine levels were determined by using a Bio-Plex Pro Human Cytokine 8-plex assay and enzyme linked immunosorbent assay (ELISA). Whole body composition analysis was performed by dual-energy x-ray absorptiometry (DEXA) to determine body fat mass, lean mass, and android and gynoid fat. Body weight, blood pressure, and physical health were assessed. Changes in quality of life were examined using the World Health Organization Quality of Life-abbreviated version and sleep quality was assessed using the 24-item Pittsburgh Sleep Quality Index (PSQI) questionnaire. Adverse events were monitored before, during, and after completion of the study. Results: Of the 46 subjects enrolled, a total of 40 subjects successfully completed the study. Compared to placebo, changes in blood cell counts including hematocrit, hemoglobin, mean corpuscular volume, platelets, and lymphocytes provide evidence of some improvement. Quality of life (QOL) parameters showed a small but significant improvement in the N-SORB group. A significant increase was observed in aspartate aminotransferase level in the placebo group at the end of 90 days of treatment; however, no increase was observed in the N-SORB group. No significant changes in blood urea nitrogen, serum creatinine, alkaline phosphatase, alanine aminotransferase, and lipid profile were observed between the placebo and treatment groups before and following intervention. No adverse effects were reported. Conclusions: This randomized, double blind, placebo-controlled clinical study demonstrates that short-term intervention with N-SORB improves the QOL and PSQI in healthy volunteers and did not significantly alter cardiometabolic parameters, lipid profile, or body composition.

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., Competing Interests: Conflicts of interest Kenneth Blum, PhD through his companies and patents related to Pro-dopamine regulation (Kb220 and variants) have been worldwide exclusively licensed to Geneus Health, LLC. Moreover, genetic patents related to GARS are owned by Geneus Health, LLC. Kenneth Blum and David Siwicki through their company IGENE, LLC have percent ownership in Geneus Health. B.W. Downs is founder and CEO of Victory Nutrition International, a licensee of Geneus Health. Dr. Blum is on their Scientific Advisory Board. Drs. Lisa Lott and Raymond Brewer are paid consultants of Geneus Health. Drs. Blum (Chair), Baron, Siwicki, Brewer, Roy, and Badgaiyan are members of Geneus Health, Scientific Board. Dr. Blum is paid consultant of Pathway Healthcare. There are no other conflicts of interest.

Importance: Erich arch bars, 4-point fixation, and bone-supported arch bars are currently used in maxillomandibular fixation, although to what extent they differ in terms of overall charges and clinical outcomes has yet to be reported., Objective: To determine the association of Erich arch bars, 4-point fixation, and bone-supported arch bars in maxillomandibular fixation with hospital charges and clinical outcomes., Design, Setting, and Participants: This historical cohort included 93 patients with mandible fracture who underwent maxillomandibular fixation from January 1, 2005, to June 30, 2015, at a tertiary care center. Statistical analysis was conducted from October 4, 2015, to September 8, 2017., Main Outcomes and Measures: Charge analysis from an institutional perspective, operative time, necessity for a secondary procedure, and postoperative complications., Results: Of the 93 patients in the study (18 women and 75 men; median age, 28.0 years [interquartile range, 23.0-40.0 years]), 27 (29%) received Erich arch bars, 51 (55%) received 4-point fixation, and 15 (16%) received bone-supported arch bars. The mean operative time for Erich arch bars (98.7 minutes; 95% CI, 89.2-108.2 minutes) was significantly longer than for 4-point fixation (48.8 minutes; 95% CI, 41.8-55.7 minutes) and bone-supported arch bars (55.9 minutes; 95% CI, 43.1-68.6 minutes). A total of 17 patients who received Erich arch bars (63%), 37 patients who received 4-point fixation (72%), and 1 patient who received bone-supported arch bars (7%) needed to return to the operating room for hardware removal. Patients who received Erich arch bars and those who received 4-point fixation had significantly higher odds of requiring a secondary procedure than did patients who received bone-supported arch bars (Erich arch bars: odds ratio, 27.1; 95% CI, 2.7-274.6; and 4-point fixation: odds ratio, 42.8; 95% CI, 4.4-420.7). Mean total operative charges for application of the hardware alone were significantly less for 4-point fixation ($5290; 95% CI, $4846-$5733) and bone-supported arch bars ($6751; 95% CI, $5936-$7566) than for Erich arch bars ($7919; 95% CI, $7311-$8527). When secondary procedure charges were included, the mean total charge for Erich arch bars ($9585; 95% CI, $8927-$10 243) remained significantly more expensive than the mean total for 4-point fixation ($7204; 95% CI, $6724-$7684) and bone-supported arch bars ($6924; 95% CI, $6042-$7807). No clinically meaningful difference in complications between groups was found (Erich arch bars, 3 [11%]; 4-point fixation, 5 [10%]; and bone-supported arch bars, 2 [13%])., Conclusions and Relevance: Bone-supported arch bars have comparable complication outcomes, operative time for placement, and overall charges when compared with Erich arch bars and 4-point fixation, and have a lower likelihood of requiring removal in an operative setting.

Background: The American Society of Hematology reported that according to the National Heart, Lung, and Blood Institute (NHLBI) anemia is the most common blood disorder, which affects more than 3 million Americans, while the Global Burden of Disease 2016 (GBD 2016) reported that iron deficiency anemia (IDA) is the leading cause of anemia, which affects 1.93 billion people worldwide. Anemia is intricately linked to chronic inflammation, chronic kidney disease, gastrointestinal and gynecological malignancies, and autoimmune disorders. Hemorrhagic anemia results in substantial loss of blood, which causes significant alterations in all blood parameters, including reduced iron. The other type of anemia is chronic anemia syndrome (CAS), which is a constellation of disorders and chronic inflammatory events caused by an increasing anaerobic/acidic environment (promoting the growth of anaerobic organisms), inducing a defensive expenditure of alkalinizing buffers in hemoglobin (i.e. histidine), to prevent a dangerous lowering of blood pH. In this process, iron is cleaved from heme groups and transferred out of blood circulation into other organs, like the liver, appearing to be IDA, where excessive accumulation can lead to hemochromatosis, also known as 'iron overload anemia'., Design: A pilot clinical study was conducted in 38 subjects (men = 10; women = 28; age = 22-82 years) to evaluate the rate of absorption and effects on blood of VMP35 multi-nutrient complex (MNC), a non-iron containing liquid nutraceutical supplement. Subjects consumed either placebo or VMP35 (30 mL) over a period of 0, 5, or 30 min., Methods: Changes in peripheral blood smears from 38 subjects were observed using live blood cell imaging (LBCI) with phase contrast microscopy. Adverse events were rigorously monitored., Results: VMP35 caused positive changes in the blood, including morphological, hematological (including restoration of hemoglobin), and rheological changes following 5 min of administration, which were sustained for at least 30 min., Conclusion: Overall, the non-iron containing VMP35 can induce improvements in blood properties and potential benefits for subjects even with compromised digestive systems. No adverse events were reported. Further research studies are in progress to explore the mechanistic insight., Competing Interests: JRC is a highly respected board-certified practicing medical doctor whose clinical experience with the VMP35 confirmed the concept and hypothesis of this article and guided the writing of the manuscript. BWD, DB and SK contributed to the concept of the manuscript and are engaged with Victory Nutrition International, Inc., Lederach, PA, and ALM R&D, Oldsmar, FL, respectively. TA is an integral part of Veritas Health Inc., Woodbridge, ON, who organized the live cell imaging procedures. MB (Dr. Herbs LLC, Concord, CA) is an independent consultant, who compiled the data and routed the manuscript to all concerned.

Competing Interests: Conflict of Interest Statement KB and DS through Igene LLC, and own stock in Geneus Health, LLC., and in some companies holding patents on genetic testing and KB220PAM. KB is Chairman of the Genus Health LLC Board of Directors and Scientific Advisory board and CSO, DS is a member of the Genus Health Scientific Advisory board and President. DB, MG-L, and RDB are members of the Genus Health LLC scientific advisory board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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.