Mona Li

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

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

Genome wide sequencing compared to candidate gene association studies for predisposition to substance abuse a subset of Reward Deficiency Syndrome (RDS): are we throwing the baby out with the bathwater?

In 1990 Blum, Noble and associates utilized a candidate approach to associate the first genetic polymorphic association with severe alcoholism that was published in JAMA. This experiment was based on a “blue print” of the reward circuitry proposed as the “brain Reward Cascade”. Impairment of this system leads to aberrant substance seeking behavior. Over the last five years newer and more sophisticated techniques have been developed, including whole genome sequencing, as well as exome sequencing. While there are different schools of thought regarding appropriate approaches to dissecting a very complex disorder known as Reward Deficiency Syndrome (RDS) as an umbrella term for all addictions, future approaches may combine both genome sequencing with gene candidates. Importantly, GWAS/WES generally provides the most value for highly penetrant, rare alleles and as such may not currently be as informative as the candidate gene approach. However, since there is convergence of GWAS and neurotransmitter clusters including specific genes (e.g. DRD1, DRD2, DAt1, etc.) albeit small contributions for each gene, thousands of studies have elucidated risk alleles to RDS behaviors. Thus, we are proposing herein that we should not hasten to “throw out the baby with the bathwater”, because genetic addiction risk stratification depends upon the current candidate gene analysis.

Hypothesizing Music Intervention Enhances Brain Functional Connectivity Involving Dopaminergic Recruitment: Common Neuro-correlates to Abusable Drugs

The goal of this review is to explore the clinical significance of music listening on neuroplasticity and dopaminergic activation by understanding the role of music therapy in addictive behavior treatment. fMRI data has shown that music listening intensely modifies mesolimbic structural changes responsible for reward processing (e.g., nucleus accumbens [NAc]) and may control the emotional stimuli’s effect on autonomic and physiological responses (e.g., hypothalamus). Music listening has been proven to induce the endorphinergic response blocked by naloxone, a common opioid antagonist. NAc opioid transmission is linked to the ventral tegmental area (VTA) dopamine release. There are remarkable commonalities between listening to music and the effect of drugs on mesolimbic dopaminergic activation. It has been found that musical training before the age of 7 results in changes in white-matter connectivity, protecting carriers with low dopaminergic function (DRD2A1 allele, etc.) from poor decision-making, reward dependence, and impulsivity. In this article, we briefly review a few studies on the neurochemical effects of music and propose that these findings are relevant to the positive clinical findings observed in the literature. We hypothesize that music intervention enhances brain white matter plasticity through dopaminergic recruitment and that more research is needed to explore the efficacy of these therapies.

Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients

To our knowledge, this is the largest study evaluating relationships between 3T Magnetic Resonance Imaging (MRI) and P300 and memory/cognitive tests in the literature. The 3T MRI using NeuroQuant has an increased resolution 15 times that of 1.5T MRI. Utilizing NeuroQuant 3T MRI as a diagnostic tool in primary care, subjects (N=169; 19–90 years) displayed increased areas of anatomical atrophy: 34.62% hippocampal atrophy (N=54), 57.14% central atrophy (N=88), and 44.52% temporal atrophy (N=69). A majority of these patients exhibited overlap in measured areas of atrophy and were cognitively impaired. These results positively correlated with decreased P300 values and WMS-III (WMS-III) scores differentially across various brain loci. Delayed latency (p=0.0740) was marginally associated with temporal atrophy; reduced fractional anisotropy (FA) in frontal lobes correlated with aging, delayed P300 latency, and decreased visual and working memory (p=0.0115). Aging and delayed P300 latency correlated with lower FA. The correlation between working memory and reduced FA in frontal lobes is marginally significant (p=0.0787). In the centrum semiovale (CS), reduced FA correlated with visual memory (p=0.0622). Lower demyelination correlated with higher P300 amplitude (p=0.0002). Compared to males, females have higher demyelination (p=0.0064). Along these lines, the higher the P300 amplitude, the lower the bilateral atrophy (p=0.0165). Hippocampal atrophy correlated with increased auditory memory and gender, especially in males (p=0.0087). In considering temporal lobe atrophy correlations: delayed P300 latency and high temporal atrophy (p=0.0740); high auditory memory and low temporal atrophy (p=0.0417); and high working memory and low temporal atrophy (p=0.0166). Central atrophy correlated with aging and immediate memory (p=0.0294): the higher the immediate memory, the lower the central atrophy. Generally, the validation of brain atrophy by P300 and WMS-III could lead to cost-effective methods utilizable in primary care medicine following further confirmation.

Menopause Analytical Hormonal Correlate Outcome Study (MAHCOS) and the Association to Brain Electrophysiology (P300) in a Clinical Setting

Various studies have demonstrated that increased leptin levels and obesity are inversely related to cognitive decline in menopausal women. It is hypothesized that adiposity is inversely correlated with cognitive decline, as women with increased weight are less vulnerable to diminishing cognition. However, it is increasingly observed that menopausal women, even with increased adiposity, experience significant cognitive decline. Positron emission tomography (PET) has been used to analyze cognitive function and processing in menopausal women. Evoked potentials (P300) and neurophysiologic tests have validated brain metabolism in cognitively impaired patients. Post-hoc analyses of 796 female patients entering PATH Medical Clinic, between January 4, 2009 and February 24, 2013, were performed as part of the “Menopause Analytical Hormonal Correlate Outcome Study” (MAHCOS). Patient age range was 39–76 years (46.7±0.2). P300 latency and amplitude correlated with a number of hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, estrone, estriol, DHEA, pregnenolone, progesterone, free and total testosterone, thyroid stimulating hormone (TSH), Vitamins D 1.25 and D 25OH, leptin, and insulin-like growth factor-binding protein 3 (IGF-BP3). Corrected statistics did not reveal significant associations with P300 latency or amplitude for these hormones except for leptin plasma levels. However, factor analysis showed that FSH and LH clustered together with Vitamin D1.25 and Vitamin D25OH, P300 latency (not amplitude), and log leptin were found to be associated in the same cluster. Utilizing regression analysis, once age adjusted, leptin was the only significant predictor for latency or speed (p = 0.03) with an effect size of 0.23. Higher plasma leptin levels were associated with abnormal P300 speed (OR = 0.98). Our findings show a significant relationship of higher plasma leptin levels, potentially due to leptin resistance, and prolonged P300 latency. This suggests leptin resistance may delay electrophysiological processing of memory and attention, which appears to be the first of such an association.

A Multi-Locus Approach to Treating Fibromyalgia by Boosting Dopaminergic Activity in the Meso-Limbic System of the Brain

Fibromyalgia (FM), is associated with fatigue, chronic diffuse pain, and cognitive/mood disturbances [1,2]. FM patients have greater healthcare costs and reduced workplace productivity. Stress and the neurotransmitter dopamine may interact, and this interaction may induce FM. Interestingly, FM has been called a ‘stress-related disorder’ presenting an exacerbation of symptoms on the context of stressful events [3].Certainly, many genes are involved in FM causation and potential predisposition. However, it is important to realize that epigenetics may also be involved in the progression of this disorder. Specifically, Menzies

KB220Z™ a Pro-Dopamine Regulator Associated with the Protracted, Alleviation of Terrifying Lucid Dreams. Can We Infer Neuroplasticity-induced Changes in the Reward Circuit?

Background Recent reports by our laboratory have indicated that lucid dreams may be linked to psychiatric conditions, including Attention Deficit Hyperactivity Disorder (ADHD) and other Reward Deficiency Syndrome-related diagnoses. In the latter case, it has been our observation that such lucid dreams can be unpleasant and frequently terrifying. Case presentations We present four cases of a dramatic and persistent alleviation of terrifying, lucid dreams in patients diagnosed with ADHD/PTSD and/or opiate/opioid addiction. The amelioration of such dreams could well be permanent, since the patients had stopped taking the nutraceutical for between 10 to 12 months, without their recollection or recurrence. In the first case, the patient is a 47-year-old, married male who required continued Buprenorphine/ Naloxone (Suboxone) treatment. The second case involved a 32-year-old female with the sole diagnosis of ADHD. The third case involves a 38-year-old male who carried the diagnoses of Substance Use Dependence and ADHD. The fourth case involved a 50-year-old female with the diagnoses of Alcohol Abuse, ADHD and Posttraumatic Stress Disorder. Results In order to attempt to understand the possibility of neuroplasticity, we evaluated the effect of KB220Z in non-opioid-addicted rats utilizing functional Magnetic Resonance Imaging methodology. While we cannot make a definitive claim because rat brain functional connectivity may not be exactly the same as humans, it does provide some interesting clues. We did find following seeding of the dorsal hippocampus, enhanced connectivity volume across several Regions of Interest (ROI), with the exception of the pre- frontal cortex. Interestingly, the latter region is only infrequently activated in lucid human dreaming, when the dreamer reports that he/she had the thought that they were dreaming during the lucid dream. Conclusions The four patients initially reported a gradual but, then, complete amelioration of their long-term, terrifying, lucid dreams, while taking KB220Z. The persistent amelioration of these dreams continued for up to 12 months, after a self-initiated, cessation of use of KB220Z. These particular cases raise the scientific possibility that KB200Z increases both dopamine stability as well as functional connectivity between networks of brain reward circuitry in both rodents and humans. The increase in connectivity volume in rodents suggest the induction of neuroplasticity changes, which may be analogous to those involved in human lucid dreaming as well as Rapid Eye Movement sleep. The possibility that the complex induces long-term, neuroplasticity changes must await more intensive investigations, involving large-population, double-blinded studies.

Common Neurogenetic Diagnosis and Meso-Limbic Manipulation of Hypodopaminergic Function in Reward Deficiency Syndrome (RDS): Changing the Recovery Landscape

Abstract: Background: In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed “Brain Reward Cascade.” These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed “Reward Deficiency Syndrome” (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic. Objective: In this review article, we attempt to clarify these terms and provide a working model to accurately diagnose and treat these unwanted behaviors. Method: We are hereby proposing the development of a translational model we term “Reward Deficiency Solution System™” that incorporates neurogenetic testing and meso-limbic manipulation of a “hypodopaminergic” trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced “dopamine resistance,” while embracing “dopamine homeostasis.” Result: The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184.

Hypothesizing that Putative Dopaminergic, Melatonin, BenzodiazepineReward Circuitry Receptor(s) Activator Provides Sleep Induction Benefits

The issue of insomnia is a global phenomenon which requires additional in-depth research. Insomnia especially in alcohol-dependent patients, for example, may lead to suicide. It is noteworthy that childhood sleep problems predict the onset of drinking in boys. We now know that while there are multi-faceted reasons for sleep problems and disturbances (e.g. sleep drive homeostasis, circadian rhythm physiology, and genetic influences), the scientific community has not been able to deliver an appropriate solution. Some benefit has been noted with cognitive behavioral therapy, but it has minimal effects in patients relapsing from drugs especially alcohol, cocaine and opiates. While there are a number of pharmaceutical drugs developed to treat insomnia, most have associated side effects and even addiction liability. We do know that benzodiazepines hijack the midbrain dopamine system leading to addiction. Finally, it has been proposed that dopamine D2 receptors are involved in rapid eye movement sleep, suggesting as proposed herein that dopaminergic activation is a worthwhile mechanism to explore in the future. The concepts presented herein on potential nutrigenomic therapy warrants further in-depth analysis. In this regard we hypothesize based on both literature review and empirical data that a putative dopaminergic, melatonin, benzodiazepine reward circuitry receptor(s) activator provides sleep induction benefits.

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

ABSTRACT 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.