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

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complex [Kb220Z] shown to be beneficial in at least 20 human clinical trials and in a number of published and unpublished studies.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

Drug abuse relapse rates linked to level of education: can we repair hypodopaminergic-induced cognitive decline with nutrient therapy?

It is well known that athletes and other individuals who have suffered painful injuries are at increased risk for all reward deficiency syndrome (RDS) behaviors, including substance use disorder (SUD). Comparing patient demographics and relapse rates in chemical dependence programs is pertinent because demographics may affect outcomes. Increased risk for relapse and lower academic achievement were found to have a significant association in recent outcome data from a holistic treatment center (HTC) located in North Miami Beach, FL. Relapse outcomes from the Drug Addiction Treatment Outcome Study (DATOS; n = 1738) and HTC (n = 224) were compared for a 12-month period. Post-discharge relapse was reported by 26% of HTC patients and 58% of patients in DATOS. When broken out by education level-less than high school, high school diploma, college degree, and graduate degree-HTC patient relapse was 50%, 36%, 33%, and 16%, respectively, and demonstrated an inverse linear association (F = 5.702; P = 0.017). Looking at DATOS patient relapse rates broken down by educational grades/years completed, patients who attended school between 7th grade and 4 years of college also demonstrated an inverse linear association (F = 5.563; P = 0.018). Additionally, the lowest performers, patients who reported their academic performance as "not so good," had the highest relapse (F = 4.226; P = 0.04). Albeit certain limitations, compared with DATOS patients, HTC patients produced significantly larger net differences in relapse rates (X 2 = 84.09; P = 0.0001), suggesting that other variables, such as the treatment model may also affect patient relapse. Our results implicate the use of vitamin and mineral supplements coupled with a well-researched natural dopamine agonist nutrient therapy; both have been shown to improve cognition and behavior, and thus academic achievement. That relapse is highest among addicts who have less education and who report lower grades is a factor that can be useful when considering treatment type and controlled for when comparing treatment outcomes.

Summary Document Research on RDS Anti-addiction Modeling: Annotated Bibliography.

Annotated bibliography of genetic addiction risk severity (GARS) publications, pro-dopamine regulation in nutraceuticals (KB220 nutraceutical variants), and policy documents. Further research is required to encourage the field to consider "Reward Deficiency Syndrome (RDS) Anti-addiction Modeling" which involves early risk identification by means of genetic assessment similar to GARS, followed by induction of dopamine homeostasis by means of genetically guided pro-dopamine regulation similar to KB220. These results suggest that genetically based treatments may be a missing piece in the treatment of substance use disorder (SUD).

Addressing cortex dysregulation in youth through brain health check coaching and prophylactic brain development.

The Carter Center has estimated that the addiction crisis in the United States (US), if continues to worsen at the same rate, may cost the country approximately 16 trillion dollars by 2030. In recent years, the well-being of youth has been compromised by not only the coronavirus disease 2019 pandemic but also the alarming global opioid crisis, particularly in the US. Each year, deadly opioid drugs claim hundreds of thousands of lives, contributing to an ever-rising death toll. In addition, maternal usage of opioids and other drugs during pregnancy could compromise the neurodevelopment of children. A high rate of DNA polymorphic antecedents compounds the occurrence of epigenetic insults involving methylation of specific essential genes related to normal brain function. These genetic antecedent insults affect healthy DNA and mRNA transcription, leading to a loss of proteins required for normal brain development and function in youth. Myelination in the frontal cortex, a process known to extend until the late 20s, delays the development of proficient executive function and decision-making abilities. Understanding this delay in brain development, along with the presence of potential high-risk antecedent polymorphic variants or alleles and generational epigenetics, provides a clear rationale for embracing the Brain Research Commission's suggestion to mimic fitness programs with an adaptable brain health check (BHC). Implementing the BHC within the educational systems in the US and other countries could serve as an effective initiative for proactive therapies aimed at reducing juvenile mental health problems and eventually criminal activities, addiction, and other behaviors associated with reward deficiency syndrome.

Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences.

The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."

Psychostimulants for Children: Are We Over or Under Dosing?

An estimated 3% to 10% of school children meet the DSM-V criteria for ADHD (Attention-Deficit/Hyperactivity Disorder), however, to be over-diagnosed, the rate of children inappropriately diagnosed with ADHD (false positives) would have to be larger than the number of children with ADHD who are under-identified and not diagnosed (false negatives). Accordingly, a number of investigators take the position that under-treatment with psychostimulants, especially in children and adolescence, will result in continued ADHD symptomatology including future Substance Use Disorder (SUD). However, other researchers and clinicians believe otherwise and espouse laudable arguments for caution and prolonged methamphetamine treatment. While there is ongoing controversy of the role of genetics and epigenetics linked to ADHD, it seems clear that a number of dopaminergic genes and their risk polymorphisms act as DNA antecedents impacted by epigenetic induced methylation. Our hypothesis and literature review suggest that one possible solution is to embrace non addictive interventions to induce global dopamine homeostasis.

Beyond Mor: Can Induction of Dopamine Homeostasis Along with Electrotherapy Attenuate the Opioid Crisis?

One important area for consideration especially in terms of combating the ongoing never ending opioid crisis, relates to novel newer assessments for all addictive behaviors both substance and non-substance behaviors (RDS). It is very important to identify early in one's life the possibility of, because of known DNA antecedents, the presence of pre-addiction. The development of the Genetic Addiction Risk Severity (GARS) test, Blum's group believes that this type of testing should be the "standard of care" following additional studies. Understandably that while polymorphisms in the Mu-Opioid receptor (MOR) is of real concern in terms of setting people up for predisposition to opioid dependence, the genetic and epigenetic status of dopaminergic function must be considered as well. While this sounds bold (which it is) the results should be protected by the G.I. N. A. law enacted in the USA in 2011. One avenue of further investigation, instead of providing powerful opioids for opioid dependence, is to seek out non-addictive alternatives. Accordingly, other non-addictive modalities including genetic guided KB220 (amino-acid-enkephalinase-N-acetylcysteine-NAD), non-invasive rTMS for psychiatry and pain, epigenetic remodeling, gene edits, non-invasive H-wave for pain management and enhanced functionality, brain spotting, cognitive behavioral therapy awarenesss integration therapy, NUCALM, trauma therapy, awareness tools, genograms, exercise, sports, fitness programs (one hour per day), light therapy and even laughing therapy as well as any other known modalities that can induce reward symmetry. While the short term use of opioids for opioid dependence to reduce harm is certainly acceptable, clinicians should consider a better long-term plan.

Futuristic Thinking about Engineering "Geneospirituality" to Help Prevent Relapse of Reward Deficiency Syndrome (RDS) Behaviors.

It is with a saddened heart that we are dedicating this article to the loving memory of our dear departed friend and associate B. William Downs. Bill was well known in the nutritional space worldwide for his major contributions to the health and welfare of millions around the globe. The founder of Victory Nutrition International (VNI) in conjunction with Kim Downs, as well as so many contributions to scientific literature, to those that knew him personally will forever be touched. Bill was a highly spirited human with a never ending love for caring and helping so many individuals. To know Bill is to walk in the face of a music lover playing drums, trained as a martial artist, and riding through the winds of a Beamer driven by an iconic man driven to victory. Our hearts may be saddened but Bills spirit to those that know him will be forever. In this article we discuss and review some potential futuristic concepts and technological advancements in terms of geneospirituality engineering to help prevent relapse and or even protect against an unwanted predisposition to RDS behaviors. Futuristic development may contribute to an attenuation of both DNA antecedents as well as epigenetic reward system insults leading to unwanted substance and non-substance addictive behaviors.

Are We Getting High Cause the Thrill is Gone?

In the USA alone, opioid use disorder (OUD) affects approximately 27 million people. While the number of prescriptions may be declining due to increased CDC guidance and prescriber education, fatalities due to fentanyl-laced street heroin are still rising. Our laboratory has extended the overall concept of both substance and non-substance addictive behaviors, calling it "Reward Deficiency Syndrome (RDS)." Who are its victims, and how do we get this unwanted disorder? Is RDS caused by genes (Nature), environment (Neuro-epigenetics, Nurture), or both? Recent research identifies resting-state functional connectivity in the brain reward circuitry as a crucial factor. Analogously, it is of importance to acknowledge that the cumulative discharge of dopamine, governed by the nucleus accumbens (NAc) and modulated by an array of additional neurotransmitters, constitutes a cornerstone of an individual's overall well-being. Neuroimaging reveals that high-risk individuals exhibit a blunted response to stimuli, potentially due to DNA polymorphisms or epigenetic alterations. This discovery has given rise to the idea of a diminished 'thrill,' though we must consider whether this 'thrill' may have been absent from birth due to high-risk genetic predispositions for addiction. This article reviews this issue and suggests the general concept of the importance of "induction of dopamine homeostasis." We suggest coupling a validated genetic assessment (e.g., GARS) with pro-dopamine regulation (KB220) as one possible frontline modality in place of prescribing potent addictive opioids for OUD except for short time harm reduction. Could gene editing offer a 'cure' for this undesirable genetic modification at birth, influenced by the environment and carried over generations, leading to impaired dopamine and other neurotransmitter imbalances, as seen in RDS? Through dedicated global scientific exploration, we hope for a future where individuals are liberated from pain and disease, achieving an optimal state of well-being akin to the proverbial 'Garden of Eden'.

Neurogenetics and Epigenetics of Loneliness.

Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.

The addictive brain: all roads lead to dopamine.

This article will touch on theories, scientific research and conjecture about the evolutionary genetics of the brain function and the impact of genetic variants called polymorphisms on drug-seeking behavior. It will cover the neurological basis of pleasure-seeking and addiction, which affects multitudes in a global atmosphere where people are seeking "pleasure states".

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.

Proposing a "Brain Health Checkup (BHC)" as a Global Potential "Standard of Care" to Overcome Reward Dysregulation in Primary Care Medicine: Coupling Genetic Risk Testing and Induction of "Dopamine Homeostasis".

In 2021, over 100,000 people died prematurely from opioid overdoses. Neuropsychiatric and cognitive impairments are underreported comorbidities of reward dysregulation due to genetic antecedents and epigenetic insults. Recent genome-wide association studies involving millions of subjects revealed frequent comorbidity with substance use disorder (SUD) in a sizeable meta-analysis of depression. It found significant associations with the expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. However, despite the rise in SUD and neuropsychiatric illness, there are currently no standard objective brain assessments being performed on a routine basis. The rationale for encouraging a standard objective Brain Health Check (BHC) is to have extensive data available to treat clinical syndromes in psychiatric patients. The BHC would consist of a group of reliable, accurate, cost-effective, objective assessments involving the following domains: Memory, Attention, Neuropsychiatry, and Neurological Imaging. Utilizing primarily PUBMED, over 36 years of virtually all the computerized and written-based assessments of Memory, Attention, Psychiatric, and Neurological imaging were reviewed, and the following assessments are recommended for use in the BHC: Central Nervous System Vital Signs (Memory), Test of Variables of Attention (Attention), Millon Clinical Multiaxial Inventory III (Neuropsychiatric), and Quantitative Electroencephalogram/P300/Evoked Potential (Neurological Imaging). Finally, we suggest continuing research into incorporating a new standard BHC coupled with qEEG/P300/Evoked Potentials and genetically guided precision induction of "dopamine homeostasis" to diagnose and treat reward dysregulation to prevent the consequences of dopamine dysregulation from being epigenetically passed on to generations of our children.

Precision Behavioral Management (PBM) and Cognitive Control as a Potential Therapeutic and Prophylactic Modality for Reward Deficiency Syndrome (RDS): Is There Enough Evidence?

This brief commentary aims to provide an overview of the available and relatively new precision management of reward deficiencies manifested as substance and behavioral disorders. Current and future advances, concepts, and the substantial evidential basis of this potential therapeutic and prophylactic treatment modality are presented. Precision Behavioral Management (PBM), conceptualized initially as Precision Addiction Management (PAM), certainly deserves consideration as an important modality for the treatment of impaired cognitive control in reward processing as manifested in people with neurobiologically expressed Reward Deficiency Syndrome (RDS).

Hypothesizing in the Face of the Opioid Crisis Coupling Genetic Addiction Risk Severity (GARS) Testing with Electrotherapeutic Nonopioid Modalities Such as H-Wave Could Attenuate Both Pain and Hedonic Addictive Behaviors.

In the United States, amid the opioid overdose epidemic, nonaddicting/nonpharmacological proven strategies are available to treat pain and manage chronic pain effectively without opioids. Evidence supporting the long-term use of opioids for pain is lacking, as is the will to alter the drug-embracing culture in American chronic pain management. Some pain clinicians seem to prefer classical analgesic agents that promote unwanted tolerance to analgesics and subsequent biological induction of the "addictive brain". Reward genes play a vital part in modulation of nociception and adaptations in the dopaminergic circuitry. They may affect various sensory and affective components of the chronic pain syndromes. The Genetic Addiction Risk Severity (GARS) test coupled with the H-Wave at entry in pain clinics could attenuate pain and help prevent addiction. The GARS test results identify high-risk for both drug and alcohol, and H-Wave can be initiated to treat pain instead of opioids. The utilization of H-Wave to aid in pain reduction and mitigation of hedonic addictive behaviors is recommended, notwithstanding required randomized control studies. This frontline approach would reduce the possibility of long-term neurobiological deficits and fatalities associated with potent opioid analgesics.

Hypothesizing That Pediatric Autoimmune Neuropsychiatric Associated Streptococcal (PANDAS) Causes Rapid Onset of Reward Deficiency Syndrome (RDS) Behaviors and May Require Induction of "Dopamine Homeostasis".

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.

Theorizing the Role of Dopaminergic Polymorphic Risk Alleles with Intermittent Explosive Disorder (IED), Violent/Aggressive Behavior and Addiction: Justification of Genetic Addiction Risk Severity (GARS) Testing.

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.

Should Reward Deficiency Syndrome (RDS) Be Considered an Umbrella Disorder for Mental Illness and Associated Genetic and Epigenetic Induced Dysregulation of Brain Reward Circuitry?

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.

Nicotinamide Adenine Dinucleotide (NAD+) and Enkephalinase Inhibition (IV1114589NAD) Infusions Significantly Attenuate Psychiatric Burden Sequalae in Substance Use Disorder (SUD) in Fifty Cases.

Background: There is a shortage of clinical studies examining the efficacy of Nicotinamide Adenine Dinucleotide and Enkephalinase infusions (IV1114589NAD) in treating Substance Use Disorder (SUD). Objective: This study aims to provide evidence that IV1114589NAD infusions significantly attenuate substance craving behavior. Methods: The study cohort consisted of addicted poly-drug, mixed gender, multi-ethnic individuals resistant to standard treatment. The investigation utilized Likert-Scales to assess behavioral outcomes. Results: Using Wilcoxon signed-rank tests and sign tests, our team detected significant results by comparing baseline to post outcome scores after IV1114589NAD injections: craving scores (P=1.063E-9); anxiety (P=5.487E-7); and depression (P=1.763E-4). A significant reduction in cravings, anxiety, and depression followed a dose-dependent linear trend. Linear trend analyses showed a significant relationship between NAD infusions and decreasing scores for cravings (P=0.015), anxiety (P=0.003), and depression (P=8.74E-5). A urine analysis was conducted on a subset of 40 patients midway through the study to assess relapse; 100% of the urine samples analyzed failed to detect illicit substance use. Discussion: The opioid crisis in America has claimed close to 800,000 lives since 2004; daily deaths are estimated to stand at 127, and in 2021, over 107,000 deaths were due to overdose. There is an urgency to find safe, side-effect-free solutions. Current interventions, such as Naltrexone implants, are invasive and may interfere with dopamine homeostasis leading to an anti-reward phenomenon. Larger randomized double-blinded placebo-controlled studies are needed to elucidate further the significance of the results presented in this study. The current pilot study provides useful preliminary data regarding the effectiveness of IV1114589NAD infusions in SUD treatment. Conclusion: This pilot study provides significant evidence that NAD infusions are beneficial in the treatment of SUD. This investigation serves as a rationale to extend these findings onto future research investigating the use of NAD/NADH as a stand-alone treatment, especially in patients showing high genetic risk as measured in the Genetic Addiction Risk Severity (GARS) test. Utilizing GARS will help provide a real personalized therapeutic approach to treat Reward Deficiency Syndrome (RDS).

Neurogenetic and Epigenetic Aspects of Cannabinoids.

Cannabis is one of the most commonly used and abused illicit drugs in the world today. The United States (US) currently has the highest annual prevalence rate of cannabis consumption in the world, 17.9% in individuals aged 12 or older, and it is on the rise. With increasing cannabis use comes the potential for an increase in abuse, and according to the Substance Abuse and Mental Health Services Administration (SAMHSA), approximately 5.1% of Americans had Cannabis Use Disorder (CUD) in 2020. Research has shown that genetics and epigenetics play a significant role in cannabis use and CUD. In fact, approximately 50-70% of liability to CUD and 40-48% of cannabis use initiation have been found to be the result of genetic factors. Cannabis usage and CUD have also been linked to an increased risk of psychiatric disorders and Reward Deficiency Syndrome (RDS) subsets like schizophrenia, depression, anxiety, and substance use disorder. Comprehension of the genetic and epigenetic aspects of cannabinoids is necessary for future research, treatment plans, and the production of pure cannabinoid compounds, which will be essential for FDA approval. In conclusion, having a better understanding of the epigenetic and genetic underpinnings of cannabis use, CUD, and the endocannabinoid system as a whole will aid in the development of effective FDA-approved treatment therapies and the advancement of personalized medicine.