Precision Behavioral Management (PBM) a Novel Genetically Guided Therapy to Combat Reward Deficiency Syndrome (RDS)
K. Blum1-8, A K. Roy III9, A. Podesta9, E.J., Modestino,10 B. Steinberg, 10 M.C. Gondré -Lewis11, D. Baron3, P.K, Thanos12, L.Lott,8 J. ValdezPonce8, B. Boyett9, D. Siwicki8, M. Moran8, I. Elman13, D. Edwards14, T. McLaughlin15, E.R. Braverman4, T. Simpatico,5 M. Hauser6, B.W. Downs, 16R.D. Badgaiyan17
1Western University Health Sciences, Graduate School of Biomedical Sciences, Pomona, CA., USA; 2 Eotvos 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); 4Department of Clinical Neurology, Path Foundation NY, New York, NY, USA; 5Department of Psychiatry, University of Vermont, Burlington, VM, USA; 6Dominion Diagnostics, North Kingston, Rhode Island, USA; 7Division of Precision Addiction Management, Geneus Health, San Antonio, TX, USA; 8 Division of Neuroscience & Addiction Research, Pathway Healthcare, LLC., Birmingham, AL, USA; Department of Psychiatry, Tulane University School of Medicine, New Orleans, LA.., USA; 10Department of Psychology, Curry College, Milton, MA, USA; 11 National Human Genome Center and Departments of Anatomy & Psychiatry, Howard University School of Medicine, Washington, DC, USA; 12Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA; 13Department of Psychiatry, Cooper University School of Medicine, Camden, NJ, USA; 14Department of Clinical Medical Education, Lakeview Health in Jacksonville FL, Jacksonville, FL, USA; 15Center For Psychiatric Medicine, Lawrence MA, USA; 16 Division of Nutrigenomic Research, Victory Nutrition International, Lederach, PA.,USA; 17 Department of Psychiatry, Ichan School of Medicine, Mount Sinai, New York, NY., and Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, Long School of Medicine, University of Texas Medical Center, San Antonio, Tx, USA.
Contact: Kenneth Blum, Ph.D.; drd2gene@westernu.edu
Keywords: Dopamine Homeostasis, Precision Addiction Management, Precision Behavioral Management, GARStm, KB220PAM, KB220ZPBM, Pain, Reward Deficiency Syndrome (RDS).
“A rose by any other name is still a rose”-William Shakespeare
Introduction
It is crucial to realize that while we are cognizant that all drug and nondrug addictive behaviors are widespread globally and considered a problem for most countries, as American-based scientific and clinically experienced authors, we are compelled to respond to the worst opioid crisis ever in America with a message of hope. We must also point out that there is an increase in psychostimulant and benzodiazepine dependence and, as always, alcoholism in America [Scholl et al., 2018; Gressler et al., 2018].
The primary use of opioids, as analgesic pain treatment, is a momentous public health problem that costs at least $560-$635 billion annually, an amount that equals to about $2,000.00 for everyone living in the United States (U.S.). Health care cost due to pain ranges from $261 to $300 billion. That amount soars to $297-$336 billion with the addition of the cost of lost productivity; workdays missed, and work hours lost. Until now, the solution has been to prescribe opioid medications to reduce pain. However, the U.S. is experiencing an opioid overdose epidemic. Overdose deaths from prescription opioid increased significantly in parallel with the increased in opioid prescribing between 1999 and 2010, [Pergolizzi et al., 2018]. Of the 33,091 deaths drug overdoses in 2015, approximately half, involved prescription opioids [Rudd et al. 2016]. In the U.S., an estimated 2 million individuals have opioid use disorder (OUD) for an estimated $78.5 billion in economic costs annually [Florence et al., 2016]. Overall the cost of the opioid crisis has been estimated at north of one trillion dollars.
There are, however, several proven strategies have been developed to manage chronic pain effectively without opioids [Severino et al., 2018], they include “Reward Deficiency Solution System” (RDSS) and “Precision Behavioral Management“ (PBM) based on analytic evidence as presented here.
Understanding the neurogenetic and neurobiological correlates of all addictive behaviors can assist in changing prescribing practices, one step towards addressing the opioid overdose epidemic and its adverse effects on the US and global populations [Blum et al. 2015a, Blum et al. 2018a]. The challenge is to identify non- addicting and non-pharmacological alternatives to assist in pain and addiction attenuation [Blum et al., 2018b, Salling & Martinez, 2016]. Unfortunately, despite the well-known risk for opioid-induced hyperalgesia (OIH), which commonly results from long term use of opioids, in recent years the medical establishment has encouraged the expanded use of opioids for the treatment of chronic pain. The process of OIH involves an alteration of pain salience, determined in the periaqueductal gray matter and the rostroventral medulla through hypodopaminergia potentially via glutaminergic attenuation, resulting in increased pain sensitivity [Chen et al., 2009]. Notably, a recent JAMA report provides strong evidence that non-opioid treatment like NSAIDs is more effective than chronic opioids [Savannah et al., 2016; Krebs et al., 2018]. The brain reward center plays a central role in the modulation of nociception; the sensory nervous system’s response to certain harmful stimuli, like pain. Adaptations may effect several sensory and affective components of chronic pain syndromes in dopaminergic circuitry [Chen et al., 2009]. Analgesic tolerance, by itself, does not necessarily meet the diagnostic criteria for opioid use disorder (OUD), nor does the presence of somatic pain exclude the diagnosis of OUD.
This chapter provides research history and findings that pertain to the Reward Deficiency Syndrome (RDS) concept first generally described in an article in the American Scientist in 1996. Other names for RDS include “the dark side of emotion”; “anti-reward,” and “ dopamine deficiency syndrome,” to name a few. Currently, over 168 articles listed in
PUBMED (5-19-19 ) deal with RDS, 700 deal with “Reward Deficiency,” and 1,355 articles deal with “Dopamine Dysregulation.” RDS is defined in MS-Word and included in the SAGE Encyclopedia of Abnormal Psychology and Mental Illness [Blum, 2017]. There is also a body of literature that addresses the role of dopamine and reward deficiency in the derivative conceptualization of “wanting” and “liking.” These concepts dovetail onto the RDS model [Blum et al., 2012a].
Reward deficiency and the reward system concepts were adopted in ASAM’s new definition of Addiction in 2011 [Smith et al., 2012]. In this article we provide genetic and neurochemical evidence that could help addiction and pain specialists provide better care, by eliminating guessing, especially, as it relates to addiction risk and providing a paradigm shift by embracing PBM [Blum et al., 2018a] and the induction of “Dopamine Homeostasis” [Baron et al., 2018]. This proposed shift in treatment is the consequence of the RDS conceptualization.
Most researchers agree that, from a genetic point of view, both drug and non-drug addictive behaviors can best be explained by the formula P = G+E, where P= Phenotype (addiction); G = genetics and E = environment. Based on a literature search, the inheritable range of addiction varies between 30-50%. It is noteworthy that although E can take on many forms, for example, parental abuse, the resultant effect is an epigenetic phenomenon related to mRNA expression.
Analytics of Genetic Addiction Risk Score (GARS)
Over 30 years Blum’s group has developed a ten-gene panel, with several polymorphic variants of the functional genes that govern the brain reward circuit. This panel is called the Genetic
Addiction Risk Score (GARS). Knowing the result of the patient’s GARS, test, can provide an in-depth assessment of a patient’s brain reward functioning and assist in prophylaxis and early intervention for those at high risk for addiction.
The rationale for the development of the Genetic Addiction Risk Score (GARS) panel of reward gene polymorphisms [Blum et al., 2018c] and the prediction of clinical outcome, especially, for opioid dependence., is described here [Blum et al., 2018c].
The interaction of neurotransmitters and second messengers that control the release of dopamine the neurochemical that reduces stress and produces feelings of wellbeing is known as the Brain Reward Cascade (BRC) [Blum et al., 2014a]. Unfortunately, for many Americans, the pharmaceutical industry, possibly unintentionally, sold 298 million prescriptions for Oxycontin; a potent opioid to the American populace; in 2016. The neurochemical impact of chronic opioids on the BRC is the downregulation of several neurotransmitters, including dopamine, mainly, at the reward site of the brain located in the Nucleus Accumbens (NAc) [Figure 1].
Fig 1. The Brain Reward Cascade
Figure 1 illustrates the interaction of neurotransmitters within the mesolimbic reward system. Modified from [Erickson, C 2007],
America’s Opioid Crisis
Genetic and epigenetic variations within the BRC, predispose individuals to addictive behaviors and altered pain tolerance. A group of clinicians has utilized the GARS to accurately predict vulnerability to pain, addiction, and other compulsive behaviors, defined as RDS [Blum et al., 2018d]. Innovative strategies to combat the opioid epidemic have been proposed [Chen et al., 2009]. The predisposition to pain sensitivity; (tolerance or vulnerability) is moderated in the mesolimbic projection system by genetic polymorphisms [Taylor et al. 2016] that can be used to identify risk for subsequent addiction, involving RDS and anti -reward symptomatology [Upadhyay et al., 2010] and provide therapeutic targets for the treatment of pain [Taylor et al. 2016]. The initial studies that led to the development of Genetic Addiction Risk Score (GARS) test, which could assist in the early identification of RDS risk, including drug and alcohol
severity, will be explained. However, it is vital to understand complexities related to the neurogenetic basis of RDS. There is sufficient evidence to propose that there is a similarity of neurogenetic and neurochemical correlates between drug and non-drug, addictive-like behaviors. Although there are some differences in mechanisms of action, the so-called “common rubric” leads to an understanding of “addiction transfer.” Such transfers from one addiction to another addiction can be observed, for example, in bariatric medicine practice, where patients who had an eating disorder acquire Alcohol Use Disorder (AUD) after surgery. These potential transfers of “drug of choice” can also occur when a drug abused in a particular proband is eliminated in a control sample for research, the elimination of other common addictive behaviors, like gambling, gaming, excessive eating or out of control shopping or hoarding may not have been addressed (Blum et al., 2011a).
RDS-free controls
Counting several risk alleles in an individual’s GARS panel, as a measure of addiction risk severity seems quite acceptable as has been verified by other investigators with non-addicting gene panels [Chen et al., 2005]. However, the development of RDS free “super controls” would make it possible, to instead, weigh the effect of each gene based on Level of Detection (LOD) scores. Statistical analysis between RDS free controls and cases (RDS behaviors) will enable the accurate development of weighing the effect of each gene (LOD score provides power) and as such provide a “true” measurement of risk rather than a diagnostic assessment. [Blum et al. 2018e]
Follow-up genetic research in this area, resulting in confirmation of positive correlations with dopaminergic polymorphisms, and utilizing highly screened controls (eliminating any addictive, compulsive and impulsive behaviors in both proband and family), may have pertinent ramifications such as reducing spurious results and, thus, confusion. In this regard, the importance of using non-RDS controls has been demonstrated in earlier studies from Blum’s group [Chen et al., 2005].
While there may be concerns about many of the so-called controls, for example, blood donors, it is remarkable that there are a plethora of case-controlled studies, indicating a selective association of these risk alleles (measured in GARS), for the most part, indicating Hypodopaminergia (except for the D3 polymorphisms). Many but not all association studies are known currently as case-controlled trials, significant associations, however, were observed with a substantial cohort consisting of a total of 110,241 cases and 122,525 controls and a meta-analysis of this dataset is imminent. However, presently without RDS-free controls, there is sufficient evidence that each risk allele, displayed in GARS, relative to non-Substance Use Disorder (SUD) controls, associates as a risk for prediction for drug and alcohol severity and dependence.
With this caveat in mind, a neurology and family practice clinic in Princeton, NJ, eliminated every possible RDS behavior in 183 patients and family members of the proband, with a computerized program and found only 30 patients were free of any RDS behavior. When genotyped for the A1 allele (known to cause a 30-40% reduction in the number of DRD2 receptors), the A1 allele was found in about 33% of the unscreened patient population. However,
in the highly screened, non-RDS controls, the A1 allele was found in only one patient, 3.3% [Chen et al., 2005, 2012 ] (see Figure 2).
Fig 2 Prevalence of DRD2 A1 allele in unscreened AUD controls and screened RDS Free controls.
The systematic elimination of hidden RDS behaviors from control groups is required to avoid spurious study results. For example, a disputed study published in JAMA by Yale scientists concerning the role of DRD2 allele and alcoholism, whereby controls came from a French cohort of Tourette’s syndrome [Gelernter et al., 1991], an RDS subset. Over the years, following this negative report, there have been many studies including meta-analyses showing a positive association of the DRD2 A1 allele with opioid dependence and other addictions [Chen et al., 2011].
These studies raise the suspicion that, for example, neither alcoholism nor gambling behavior is the correct phenotype, but instead the DSM VI should consider the umbrella term, reflecting the
real root cause of the phenotype to be RDS. Hyman and other leading psychiatrists support this evidence-based concept. They correctly point out that neuroscience studies of psychiatric disorders rely on the narrow definitions of diagnoses from the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, the boundaries between disorders are often not as strict as the DSM-5 suggests. An alternative framework for research into psychiatric disorders was introduced by the Research Domain Criteria (RDoC) project from the US National Institute of Mental Health (NIMH). The five 'domains' of the RDoC, each reflect a brain system, with different degrees of impaired functioning in different psychiatric conditions. Without detailing this notable departure from DSM-5 thinking, one of the authors, Dr. Nick Craddock, had this to say: “Rather, it (RDoC) exemplifies the shortcomings of the current, descriptive method and highlights the need for different approaches in the future” [Casey et al., 2013].
RDS as Endophenotype
The proposition that RDS is the “true” phenotype may indeed change the recovery landscape. Rather than utilizing subtypes, like SUD or Behavioral Addictions (BA), which involve more measurement error due to crossover, abnormal behaviors, utilize dopaminergic gene polymorphisms that reflect an insufficiency of usual feelings of satisfaction or RDS. The pathology of RDS is a dysfunction in the “brain reward cascade,” (Figure 1) a complex interaction among neurotransmitters (primarily serotonergic, cannabinergic (not depicted) , endorphinergic, opioidergic and dopaminergic) in the brain reward circuitry [Blum et al., 2016a]. A family history of substance abuse may result in individuals who are born with a reduced ability to produce or use these neurotransmitters. In an ancient environment, this reduced ability may have provided a superior survival advantage, driving more aggressive a
intense survival induced reward-seeking behaviors. However, in our modern industrialized society of chronically overfed undernourished people, the suboptimal availability of nutritional resources necessary to fund reward satisfaction and survival, exposure to prolonged periods of stress and alcohol or other substances can induce a corruption of the brain reward cascade function [Elson et al, 1982] especially attenuation of endorphinergic synthesis.
Blum et al. [2011b] evaluated the potential association of four variants of dopaminergic candidate genes in RDS the dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; and dopamine beta-hydroxylase gene [DBH]). Blum et al., [2011b] tested for the DRD2 genetic alleles and collected data about RDS behaviors from up to five generations from two independent affected families, including from 13 deceased family members. Although no significant differences were found for the other genetic variants, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.01) more often found in the experimental RDS families N=55 vs. RDS free super controls N=30. The Taq A1 allele was found in all of Family A individuals 100% (N = 33), and 11 of 23 of Family B subjects 47.8% (see figure 3).
Fig 3. Family A
Figure 3 is a genogram of Genotype results of the Dopamine D2 receptor gene (DRD2) polymorphism of family A (n = 33) identified with multiple Reward Deficiency Syndrome (RDS) behaviors (Blum et al., 2011b).
Although their sample size was limited and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a non-specific RDS endophenotype, as Blum’s group suggested, along with Ernest Noble in their seminal findings of the association of the DRD2 A1 allele and severe alcoholism, [Blum et al., 1990]. The crucial finding here was that it is a reward gene and is associated with other RDS behaviors. This distinction informs our understanding of how evaluating single-subset
behaviors of RDS may lead to spurious results. For studies, involving polymorphisms and other neurotransmitter reward gene candidates the idea that RDS is a non-specific “reward,” phenotype may be a paradigm shift in association and linkage analysis [Blum et al., 2012a].
Bayes Theorem and At Birth Predictability of RDS
Bayes Theorem named after Reverend Thomas Bayes (1701-1761), describes an event probability. He was the first to use conditional probability to provide an algorithm (his Proposition 9) that uses evidence, based on prior knowledge of conditions that might be related to the event, to calculate the limits on an unknown parameter, from An Essay towards solving a Problem in the Doctrine of Chances (1763) [Bellhouse, 2004]. Blum’s laboratory used this mathematically based theorem to determine the Predictive Value (PV)] that the individual who carries the DRD2 A1 allele would potentially indulge in drug and non- drug addictive behaviors (RDS).
Decades of research indicate that the genetics of the dopaminergic system profoundly implicated in reward mechanisms in the mesolimbic circuitry of the brain, and dysfunction, has an essential role in vulnerability to severe substance-seeking behavior. Blum et al. [1995a] and Archer et al. [2012] proposed that variants of the D2 dopamine receptor gene are important common genetic determinants in predicting impulsive disease. Blum et al., [1995b] determined, through the Bayes approach, that for the A1 variant of the DRD2 gene, the total Predictive Value (PV) for RDS behaviors, is 74.4%. Thus, people who carry this A1 allele will have a 74 % chance that in the future they will engage in excessive reward-seeking behaviors.
In this regard, the full GARS panel (explained below) has not as yet been analyzed using Bayes Theorem, but the authors hypothesize that the PV would possibly be higher.
The risk for future abuse of alcohol, for example, has been highlighted by earlier work by Blum’s group [Blum et al., 1982] in genetically bred rodent models. Specially, three strains of mice, ICR Swiss, DBA/2J, and C57Bl/6J were compared for initial sensitivity and recovery from intoxication, and acute development of tolerance to ethanol. The alcohol loving C57Bl/6J mice were less sensitive and to recover comparatively quickly the same dose of ethanol as given to the other two, less loving or hating alcohol strains. In humans, Blum, Nobel, and associates showed that more Children of Alcoholics (COAs) had a significantly greater association with the DRD2 A1 allele than children of non-alcoholics [Blum et al., 1991]. In support of this result, Schuckit’s group assessed the risk for alcoholism among sons of alcoholics by measuring tolerance to a single dose of ethanol using a sway machine. Similar to the results of the rodent study by Elston et al., [1982], these authors also found that the sons of alcoholics had higher innate tolerance to a single dose of ethanol, compared to sons of non-alcoholics. They concluded that a low level of response (LR) to alcohol had been shown to predict a high future risk fo alcoholism. Their robust findings suggested that future research on the relationship between LR and the risk for alcoholism in Family History Positive (FHPs) can be carried out with a single intoxicating dose of alcohol and without Family history, negative (FHN) controls [Schuckit & Smith, 1997]. These data support the concept that family history of SUD or behavioral addictions (like overeating) load onto a high risk for substance misuse in children who may like their parents need treatment. Early intervention and genetic identification may help young adults avoid dangerous substance use and as such have a prophylaxis effect.
Understanding GARS
Blum’s group and others, in particular [Barh et al., 2017; Blum et al., 2014b, 2012a ], have published extensively on brain reward systems concerning the genes related to dopaminergic function and reward. In the mid-1990s, Blum coined the term, “Reward Deficiency Syndrome” (RDS) to portray behaviors found to have a gene-based association with hypo-dopaminergic function [Blum et al. 2017b]. RDS has been embraced in many subsequent studies to increase our understanding of addictions and other obsessive, compulsive, and impulsive behaviors. Interestingly, in one published study, Blum’s group was able to describe lifetime RDS behaviors in a recovering addict (17 years sober) by assessing only the resultant Genetic Addiction Risk Score (GARS) data [Blum et al., 2013a ]. It was hypothesized that based on early genetic testing that found high risk an effective strategy, like environmental manipulation might prevent, reduce, or eliminate pathological substance and behavioral seeking activity [Loth et al., 2011].
As discussed earlier in this chapter, here we consider a select number of genes, their polymorphisms, and associated risks for RDS. Genome-Wide Association Studies (GWAS), have found evidence for convergence on reward candidate genes [Olfson & Bierut, 2012]. The evidence presented in many studies provides a brain-print of relevant genetic information that will guide targeted therapies on an individualized basis to improve recovery and prevent relapse [Haile et al., 2012].
Reward Deficiency Syndrome (RDS) driven by a hypodopaminergic genetic trait is initiated by epigenetic states (methylation and deacetylation on chromatin structure) related to trans-generational effects like maternal depression and addiction [Han & Nestler, 2017]. As David
E. Smith [2017] points out this new era in addiction medicine, is based on the neuroscience of addiction. Addiction is part of RDS a pathological condition that calls for appropriate, evidence-based therapy, including early genetic risk assessment.
Genomic testing of candidate genes like dopaminergic, endorphinergic, cannabinoidergic, glutaminergic, and GABAergic receptors; serotonergic and dopamine transporters; and catabolic enzymes of Mono-Amine–Oxidase A (MAO-A) and Catecholamine–Methyl-Transferase (COMT) and many others seems reasonable albeit still a source of some controversy [Samek et al.,2016]. However, Koob’s group [Reilly et al., 2017] at National Institute on Alcohol Abuse and Alcoholism (NIAAA) has provided evidence from multiple reward gene association studies, which show significant associations with alcohol use disorder (figure 4).
Fig4.
In Figure 4, candidate genes for alcohol dependence characterized into stages of the addiction cycle. This schematic shows the three stages of the addiction cycle: (1): binge-intoxication (above), (2): withdrawal-negative affect (right) and (3): preoccupation-anticipation (left); also shown are behavioral domains linked to each stage of the cycle: incentive salience, negative emotionality, and executive function, respectively. Candidate functional genes identified by non-GWAS approaches are shown in ovals and shaded according to the relevant addiction stage the gene is hypothesized to function. GWAS candidates are shown in rectangles and shaded according to the relevant addiction stage the gene is hypothesized to function. The general biological function of each gene in the figure is in black highlight. Overlapping ovals indicate functional gene relationships that are Non-GWAS. Overlapping ovals and rectangles indicate hypothesized non-GWAS genes and GWAS candidate functional relationship. GWAS candidates in each stage are grouped according to potential biological functional similarities where possible. Finally, one example of pleiotropy is shown in the preoccupation-anticipation stage. BDNF-COMT functional variants have pleiotropic effects in both the preoccupation-anticipation stage and the withdrawal-negative affect stage. This pleiotropic relationship is shown by dual shading of the BDNF-COMT ovals reflecting both addiction stages (need Permission Reilly et al. 2017).
Understanding these concepts will advance pharmacogenomics advance personalized solutions and improve clinical outcomes. Identifying genetic risk for all RDS behaviors may be a frontline tool to assist municipalities in providing better resource allocation in underserved communities [Levran et al., 2015; Simpatico, 2015].
During a five-year sojourn, Blum’s group and Colorado University sought to address genetic risk for alcohol/drug-seeking by evaluating the combined effect of reward gene polymorphisms that primarily contribute to a hypodopaminergic-trait. This trait profile was associated with RDS-related substance and non-substance addictive behaviors. The patient population included 393 poly-drug SUD patients, attending eight independent treatment centers in the United States. The Addiction Severity Index- Media Version (ASI-MV) was used to assess the clinical severity of alcohol and drug use behaviors. The GARS test was carried out on DNA from saliva samples from n = 273 subjects with ASI phenotype, from seven centers. The analysis sample comprised of 57.8% (n = 160) male; the average age was 35.3 years (S.D. = 13.1, Range: 18-70) and 88.1% (n = 244) reported their race as White. Of the total patient population (n = 393), 17.6% scored
low, 80.7%, moderate and 1.5% high severity ranges. The number of GARS alleles ranged between 3 and 17; the mean was 7.97 (S.D. = 2.34). All genotypes were within Hardy-Weinberg Equilibrium (HWE). Preliminary examination of the relationship between the GARS genotype panel and the Alcohol Risk Severity Score using the Fisher’s Exact Test revealed a significant, predictive relationship (Χ2 = 8.84, df = 1, p < 0.004, 2-tailed) that after controlling for age remained significant (p < 0.01). Although less robust a Chi-square analysis of the ASI Drug Severity Risk Score obtained (p <0.05) significance with a linear regression (b = -0.122, t = -1.91, p = 0.10, 2-tailed). When corrected along a priori lines, the GARS panel associated with the ASI Drug Severity Risk score; p-value < 0.05 (1-tailed). Since this result, albeit significant, is less robust for drugs, compared to alcohol, it is notable that we are comparing a paper and pencil, self-report test with an objective genetic test. Since psychoactive drugs are illegal, there could be several patients lying about its use. It is known that carriers of the DRD2 A1 allele, as measured by GARS, show an association with higher Defense Style Questionnaire scores (lying) than non-carriers, as reported by Comings et al. [1995].
The test results show that if a patient carries any combination of 4 GARS risk alleles, this result is predictive of drug addiction severity (p<.05) or any combination of 7 GARS risk alleles is predictive of alcohol severity (p<.004). Notably, 100% of these patients from chemical dependency treatment programs carried at least one risk allele. The GARS test measures a panel of gene polymorphisms to predict alcohol and drug severity as a cluster and therefore, cannot display false positives [Vitali et al., 2016]. Also, each subject’s DNA was genotyped, and the data analyzed at the Institute for Behavioral Genetics (IBG) at the University of Colorado Boulder. The associations with psychological issues, medicalization, and family problems were significantly correlated with higher numbers of risk alleles, and stronger risk for drug and
alcohol misuse severity. Notably, if any specific SNP was changed, the significance was lost. Also, with the utilization of any arbitrary multiplier for any allele-based gene, the significance is lost. That the ideal would be to employ a known odds ratio determined by comparisons with cases and RDS free controls speaks to the question of counting alleles vs. odds ratios and real non-RDS Super-controls and emphasizes that the selection of the alleles in the GARS panel is crucial. False results may also occur with other tests that have little to no clinical research to validate their outcomes, particularly if the test is based on spurious controls that are not RDS free [Blum et al. 2011b]. Most association studies, of course, analyze both case controls and disease phenotype. The selection of the reward genes in the GARS panel, involved scrutiny of the association studies listed in PUBMED as of 11-12-17 [see figure 5]. The development of the current GARS panel was based on these and other data, from which Cyt P450, dopamine–b-hydroxylase, and serotonin receptor 2a/c were eliminated.
Fig 5. GARS panel association studies PUBMED as of 11-12-17
The GARS panel consists of a precise cluster of gene sequence variations (polymorphisms). The ASI predicts both drug and alcohol use severity; however, the GARS test is not restricted to any drug per se but predicts the entire array of RDS behaviors. These include substance and non-
substance addictive thoughts and behaviors like overeating, pathological gambling, gaming, internet addiction, shopping, hoarding, sex addiction. The rubric common to all RDS behaviors is allele based hypodopaminergia that predisposes individuals to all addictive thoughts and behaviors, including “liking and wanting” [Blum et al., 2012b].
In an attempt to resolve the controversy regarding the causal contributions of mesolimbic dopamine (DA) systems to reward, we evaluated the three main competing, explanatory categories: “wanting,” “liking,” and “learning." That is, dopamine may mediate the pursuit of rewards by attributing incentive salience to reward-related stimuli (wanting); the hedonic impact of reward (liking); and learned predictions about rewarding effects (learning). Blum et al., evaluated these hypotheses, especially as they relate to the RDS, and found that a majority of the evidence supported the incentive salience or "wanting" hypothesis of dopamine function. Neuro-imaging studies have shown that anticipated behaviors; psychoactive substances, palatable foods, and, behaviors such as gaming and gambling affect brain regions involving reward circuitry, and may not be unidirectional [Blum et al., 2012b]. Drugs of abuse enhance dopamine signaling and sensitize mesolimbic mechanisms that evolved to attribute incentive salience to rewards essential aspects of survival like food and sex. Addictive substances have in common that they are self-administered, used voluntarily and enhance (directly or indirectly) dopaminergic synaptic function in the NAc. They stimulate the functioning of brain reward circuitry (producing the "high" that drug users seek). In a study by Vanderbilt scientists [Treadway et al., 2012] utilizing dual-scan PET imaging protocol found that “go-getters” willing to work hard for rewards, showed a higher release of dopamine in the striatum and VTA cortex. However, possibly as a compensatory mechanism in other parts of the brain (for example, the Anterior Insula) high. dopamine induces reduced desire to work. We could argue that 20 minutes of an animal’s
behavior hardly corresponds to a human’s long-term, however, with objective measures across the brain reward circuitry (like the GARS test) we could treat the underlying conditions instead of symptoms [Hyman, 2007].
Although initially believed to encode the set point of hedonic tone, these circuits are now believed to be functionally more complex. They encode attention, incentive motivation; reward expectancy and disconfirmation of reward expectancy [Hyman, 2007]. Elevated stress levels an epigenetic insult, together with polymorphisms of dopaminergic and genetic variants of other neurotransmitters may have a cumulative effect on vulnerability to addiction and other RDS behaviors. The RDS model of etiology holds up very well for a variety of substance and non-substance behavioral addictions.
The reduction in the net release of dopamine in the reward center of the brain the NAc is indeed the principal culprit in RDS. Many metabolic/pathophysiology studies from both National Institute on Drug Abuse (NIDA) and NIAAA support the laudable goal “Dopamine Homeostasis” the combined result of genetics (DNA) and epigenetics (RNA) environmental components interacting with genetics) [Blum et al., 2017a,b; Febo et al., 2017].
The Benefits of GARS Testing in Substance Use Disorder (SUD)
The benefit of GARS™ testing in known addicts already in treatment programs [Blum et al., 2016b, Blum et al., 2018f] are listed below:
Denial - It is well-known that many patients in treatment programs deny that they have a problem and believe that they can control their addiction. The GARS test predicts risk for both substance and non-substance severity; this helps to remove denial by providing evidence of hereditary biological disease and help to promote recovery-oriented approaches to reduce misconceptions, labeling, and stigmatization [Corrigan et al., 2017]. The 12-step recovery movement has been the leading approach to SUDs, emphasizing first confession/admission (to remove denial), abstinence, and spiritual connection with a higher power [Blum et al., 2015a].
Guilt/Shame- A widespread response from people already addicted is a profound sense of shame and guilt [Matthews et al., 2017]. Addiction is a lonely person-level phenomenon. Guilt and shame are part of the nature of addiction, part of the standard phenomenology of addiction and often motivate the healing process. Recently Addiction literature has attempted to return to normative concepts, including choice and drinking goal responsibility, in understanding how to treat addiction [Kelly et al., 2013]. In many cases, people with RDS behaviors are unable to exert self-control and feel ashamed of their lack of self-control capacity and of failing to live a good human life [Vonasch et al., 2017]. Many with RDS addictions, experience their behaviors as ego dystonic [Joseph et al., 2011]. Patients realize that “Just Say No,” to stop normally, is not enough and is based on a is a false premise. The goal of work in genetics is to yield simple interventions that adjust the genes of those with a predisposition to RDS thoughts and behaviors. In the future, novel interventions might work to arrest addiction and, by acknowledging the possibility of a positive epigenetic impact on reward gene expression. It is conceivable, that providing biological and genetic (GARS) evidence to predict risk for both substance and non-substance addiction severity may help remove both guilt and shame in patients [Blum et al., 2015d].
Genogram Confirmation- Patients enrolled in treatment programs are usually asked to provide a Genogram; a family history of all kinds of RDS behaviors, including addictions, in the form of a family tree. [Raheb et al., 2016]. A genogram is a pictorial configuration of an individual's family and medical history; it allows the treatment professionals and families to visualize hereditary patterns and psychological factors that highlight relationships. This approach is a simple way to view various relationship dynamics and to review and identify a variety of trends and developmental influences. Within the genogram, representation of individuals and relationships illustrated by the unique placement of each symbol, and the lines illuminate dynamic patterns and individual qualities. Health professionals, including doctors, researchers, psychiatrists, counselors, and psychologists, use genograms. Multiple genograms are conglomerated by medical and behavioral researchers to uncover recurring patterns in the data, such as violence and aberrant sexual behaviors within family groups. Multigenerational interviewing and subsequent coding of multi-level data may suggest causal elements, like generational learning, genetics, and how factors, such as the environment and socioeconomic status, influence family functioning and personal development. Offering the GARS test to a person in treatment and their family may be the best way to confirm addiction risk within the family and identify the genetic basis of the Genogram.
Medication-Assisted Treatment (MAT) Dosing- The amount of scientific research that shows successful treatment of opioid dependence with buprenorphine or the buprenorphine-naloxone combination (Suboxone®) is overwhelming. However, the use of these agents for long-term maintenance requires caution. There may often be severe withdrawal symptoms that are often the consequence of tapering the dosage. Additionally, Hill et al. [2013] have shown a long-term flat affect with chronic Suboxone® use, and other unwanted side effects, including diversion and anhedonia-related suicide attempts. Comprehending the interaction of reward circuitry and
genotypes in treatment to augment a patient's clinical experience, such as with buprenorphine, provides a novel framework and benefits during opioid replacement therapy. In patients with SUD, including AUD, recognize that clinical outcome may be contingent upon dopaminergic genes and their associated polymorphisms [Patriquin et al., 2015]. For example, Lawford et al., [1995] in a double-blind, placebo-controlled study, demonstrated that bromocriptine (a DRD2 agonist) administered to alcoholics, some with either the A1/A1 and A1/A2 genotypes, others only with the A2/A2 genotype allele of the DRD2 gene, produced the most significant improvement in anxiety and craving in the A1 alcoholics. Importantly, the placebo-treated A1 alcoholics had the highest attrition rate suggesting that treatment outcome is a function of genotype.
Further, Blum et al., [2008a] underscored by the feasibility of treating RDS based upon pharmacogenetics. Pearson correlation with the days within treatment (r = .42) was significant for the DRD2 gene variant (A1 allele vs. A2 allele). The number of days within treatment for the DRD2 A1 negative carriers, with the dopamine-promoting compound KB220, was 51.9 ± 9.9 SE (95% CI, 30.8 to 73.0) versus 110.6 ± 31.1 (95% CI, 38.9 to 182.3) days within treatment for the DRD2 A1positive carriers. As expected, the attrition rate was highest in the A1 negative genotype group. Thus, the suggestion was that genotype might predict compliance and treatment persistence and that a relapse might depend upon treatment response effected by the DRD2 A1 allele.
The first reported association between the TaqI A1 allele and a substantially increased relapse rate in AUD patients was from Dahlgren et al. [2011]. Along similar lines, Ritchie and Noble [1996] measured postmortem [3H] Naloxone binding in AUD and non-AUD brain tissue. They found that [3H] naloxone binding was less in all brain regions examined of subjects with the A1
allele rather than in those without this allele; however, the difference was significant in the caudate nucleus. They suggested that in subjects with the A1 allele, the decreased [3H] naloxone binding might be compensation for decreased dopaminergic modulation of opiate receptor activity. This result is crucial for VivitrolÒ (naltrexone) therapy for the treatment of Opioid Use Disorder (OUD).
Interestingly, Gerra et al., [2014] provided clear evidence that buprenorphine treatment response in heroin-addicted humans has an influential relationship to the dopaminergic system. Unexpectedly, the frequency of the kappa opioid receptor (OPRK1), 36G>T SNP was not significantly different between responders and non-responders to buprenorphine. However, for the dopamine transporter (DAT) in "non-responders," the frequency polymorphism (SLC6A3/DAT1), allele 10 was slightly higher (64%) than in "responder" individuals (55.93%), and frequencies in of other alleles category was higher in “responder” (11.02%) than in non-responder individuals (2.13%). It appears that hypodopaminergic traits mediate a better response during treatment. It is noted that the 9 allele transports dopamine out of the synapse back to the pre-synaptic neuron 4 times faster than the 10 allele, supporting the view that response is a function of need. One may hypothesize that nine allele of the DAT1 carriers would have a hypodopaminergic trait due to its faster transport activity, and better treatment response with buprenorphine. Finally, Barratt et al. [2006] while not showing significant differences in methadone or buprenorphine maintenance outcomes regarding TaqI A1 allele carriers, did show in successful methadone patients that significantly fewer A(1) allele carriers had withdrawal than A2 carriers (P = 0.04).
Moreover, Blum et al., [2013b] found in a patient with genetically determined hypodopaminergic trait at 432 days post-Suboxone® withdrawal, abstinence was maintained on the dopamine
agonist KB220Z, as verified by opiate-free urine testing. Genotypes data revealed a moderate risk of addiction with a hypodopaminergic trait. Another case of buprenorphine withdrawal syndrome was observed and treated by Makhinson and Gomez-Makhinson [2014]. The symptoms, including restlessness, had been resistant to benzodiazepines and clonidine were treated successfully with a D2 agonist, pramipexole.
Willuhn et al. [2014] addressed the dopamine antagonists versus agonists or dopaminergic surfeit or deficit, in a paper published in Nature Neuroscience. They revealed that when phasic dopamine release is decreased in the ventromedial striatum (VMS) of rats their rate of self-administered cocaine intake increased. They reported the reversal of increased cocaine use by the administration of L-DOPA, which increased dopamine release in the VMS. This result provides evidence for the dopamine "deficit" explanation of addiction and treatment with a dopamine agonist.
As proposed previously by Blum et al., [2008b] activation rather than blocking mesolimbic dopaminergic reward circuitry is the preferred modality in the long-term treatment of RDS. Acute treatment consisting of antagonism of postsynaptic NAc dopamine receptors (D1-D5), in long-term treatment should consist of activation of the DA system, by the release and activation of DA in the NAc. This hypothesis attributes excessive craving behavior to the effect of the DRD2 A1 allele; a reduced number of D2 receptors, in contrast to a sufficient density of D2 receptors, which results in reducing craving. A primary goal of treatment and prevention of substance use and misuse, as well as non-substance addictive behaviors (i.e. obesity, pathological gambling, sex addiction, Attention-Deficit Hyperactivity Disorder [ADHD], shopping and hoarding etc.) [Blum et al. 2018g] might be to restore neuroplasticity and induce a proliferation of D2 receptors in individuals with the A1 genotype making them genetically less vulnerable.
Experiments in vivo used a typical D2 receptor agonist to induce down-regulation, however, in vitro experimental results have shown that genetic antecedents notwithstanding, constant stimulation by a D2 agonist, for example, bromocriptine, results in significant acute D2 receptors proliferation of in the Dopamine system [Boundy et al., 1995]. However, down-regulation, instead of up-regulation is the product of chronic treatment. That effect is a reason for failure in treatment with potent D2 agonists like bromocriptine. Dopaminergic balance is the goal of proposed treatment with the neuronutrient KB220Z [Febo et al., 2017].
Resource Allocation- Stepped care models focus on matching treatment defined by the needs of the patient. Avoiding misplacements may be a way to make the best use of available treatment resources. Step care models introduced in the medical field, including psychiatry, starts with the least intensive care, progressing to more intensive regimes for non-responders. Stepwise patient placement models within addiction treatment are well known from North America [Andrews et al., 2015 ] and employed in both adolescents and adults, and concerning patients with dual diagnoses [Schoenthaler et al., 2017]. Another model developed in Europe is the Dutch model Measurements in the Addictions for Triage and Evaluation (MATE), a model ideal for judicial patients [Simpatico, 2015].
Placement decisions about placement intensity require feasibility, validity, reliability, effectiveness, and cost-effectiveness, GARS testing will provide a genetically based method to support effective resource allocation methodology.
Opioid Pain Compound Avoidance - The role of neuro-genetics of opioids and pain mechanisms studied extensively has indicated that both sensitivity and tolerance to morphine are dependent on genotype, with inheritance characterized by dominance or partial-dominance as seen in many published works [Gold et al., 2018]. That human responses to opioids differ. For
example, individuals respond better to a particular type of opioids. There are differences in individual responses to analgesic and other effects, toxicities, side effects, and interactions. Some of the differences unraveled by research into various genetic receptor interactions, and biochemical differences of opioid responses in humans may be exploited to provide better care. Genetic testing has become more readily available and cost-effective instead of relying solely on patient feedback and trial and error. Individualized selection and dosing for opioid analgesic therapy and optimal opioid rotation strategies can be devised and supported by genetic information available to clinicians.
Although not obvious at present, candidate genes for gene-directed opioid therapy have been studied. Associations of specific candidate genes, some included genes in the GARS test with pain sensitivity and analgesic requirements for both acute and chronic pain were found [Blum et al., 2014c]. Stamer and Stüber [2007] found an association with analgesia for chronic pain and variants of the mu-opioid receptor, guanosine triphosphate glycohydrolase, melanocortin-1 receptor catechol-O-methyl-transferase, candidate genes.
In contrast, the genetic variants of drug-metabolizing enzymes that influence the effect of pharmacotherapies are well-known. Polymorphisms of the cytochrome P450 enzymes influence responses to tramadol, nonsteroidal anti-inflammatory drugs, codeine, and tricyclic antidepressants. An example is the cytochrome P450 (CYP) 2D6. It results in inactivity that decreases the clearance of methadone slightly, decreases the efficacy of tramadol by lack of formation of the active O-desmethyl-tramadol, and it also renders codeine ineffective due to lack of morphine formation [Lötsch et al., 2004]. In an animal genetic experiment, Mogil and Wilson [1997], found that sensitivity and tolerance to morphine were dependent on genotype. They used two strains of mice BALB/cByand C57BL/6By, as well as, seven recombinant, inbred strains of
their reciprocal F1 hybrids, and measured sensitivity using a locomotive activity; the ‘hot plate’ method, and tolerance following administration of single or repeated of 20 mg/kg of morphine hydrochloride or saline.
Other candidate gene polymorphisms and drug-metabolizing enzyme genetic variants will be targeted in ongoing research (GARS testing). In the search for associations between drug response and an individual’s genetic profile is pharmacogenetics. The mu-opioid receptor gene encodes the receptor targets for some endogenous opioids. The genetic influences on cocaine and opiate addiction (including morphine, heroin, and synthetic opioids) have benefited from studies of mu-opioid receptor polymorphisms [Hall et al., 2004 ]. López-Moreno et al., [2010] have investigated genes of the monoaminergic system, the endogenous opioid system, and other genes encoding the dopamine, serotonin, and norepinephrine transporters, and dopamine β-hydroxylase, have also been studied
The primary legal gateway to opioid addiction and abuse starts in many cases with iatrogenic prescribing of powerful analgesics (like OxyContin®). The GARS test prevents this legal dilemma by revealing opioid dependence risk and supporting the use of other non-opioid pain relievers like electrotherapies [Johnson et al., 2015] and non -steroid analgesics [Bershad et al., 2018] or, possibly, customized neuro-nutrients [Blum et al., 2007a].
Pro-Dopamine Regulation and Precision Personalized Therapy -Gene-guided precision neuronutrients; KB220 variants, a complex mixture of amino acids, herbals, and trace metals, are pioneers and standard-bearers for a state-of-the-art DNA customization [Blum et al., 2007a]. Research findings demonstrated the role of genetics in shaping our cravings and pleasure-seeking and have opened the doors to the comprehension of how genetics control behavior and affect physical and mental health. Moreover, the technology that is related to the ability of KB220
variants to influence based on genetics amelioration of extreme cravings may be the cornerstone of the practical applications of neurogenetics/nutrigenomics [Blum et al., 2015d]. Continuing research discoveries are a principal catalyst for the expansion, evolution, and the scientific recognition of the significance of nutrigenomics, which provides potentially remarkable contributions to medicine and human health.
Neuro-Nutrigenomics is now a vital field of scientific investigation that offers great promise to improve the human condition. Individual customization of neuronutrients has now been commercialized for RDS behaviors, known as ‘Precision Addiction Management’ (PAM) and ‘Precision Behavioral Management’ (PBM) and is already having impact on addiction treatment programs and modalities [Blum et al., 2018g].
These benefits of the GARS test in SUD are carefully reviewed in a recent paper [Blum et al., 2018f].
Reductionist vs. Systems Biology Therapeutic Interventions
Up to this point, the discussion has been about how RDS thoughts and behaviors result from an impairment in dopamine tone and functionality (synthesis, transport, reception, and degradation/reuptake), with a focus on the influence of, for example, the Dopamine Receptor D2 TaqI A1 allele. We have also discussed different types of interventions that have been used to reduce RDS behaviors. An essential distinction of therapeutic interventions is that most of them employ a reductionist approach, whether as dopamine antagonists or agonist therapies. In general, a reductionist approach (or ‘Paradigm’) is an intervention: reduced to a single active substance; relies on a single mechanism of action; targets a single biological site; and has the objective of achieving a single beneficial outcome. There are some creative mechanistic
exceptions like with Suboxone and Wellbutrin, for example. However, even these are employing a targeted pharmacological effect. However, with pharmaceuticals, the outcome can be accompanied by a plethora of undesirable side effects from the pharmacological imposition. These and other consequences, like the development of tolerance from feedback signaling and compensatory homeostatic ‘adjustments’ are characteristic of biphasic actions; the drug exerts its pharmacological effect (phase 1), and the body mounts a retaliatory/adversarial response to the pharmacological effect (phase 2). An example of a biphasic action is with Bromocriptine, which results in down-regulation, instead of up-regulation or balance as is proposed for KB220Z [Febo et al., 2017]. That effect is a reason for failure in treatment with potent D2 agonists.”
The other paradigm is a ‘systems biology’ therapeutic approach. In this approach, the objective is to positively influence the functional relationships and mechanistic interactions of an entire ‘suite’ (or ‘system’) of biomolecules; in this case, targeting the neurotransmitters in the brain reward cascade (BRC) from serotonin down to dopamine. The goal is to epigenetically optimize the expression of genes involved in regulating the synthesis, transport, reception, and degradation/reuptake of each of the BRC neurotransmitters. It involves optimizing the interconnective signaling of neurotransmitters downstream, upstream (via feedback) and cross-stream (collateral effects). This effect achieved through nutrigenomic mechanisms whereby a selection of vitamins, minerals, and botanicals, have been shown, to restore BRC normalization and functional competence. The restoration of functional competence is analogous to the ‘orchestra of nutrition going in and enabling the symphony of neurochemistry.’ The KB220 variants have been shown in over 41 published clinical studies to promote BRC neurotransmitter function; interconnectivity; and brain reward processing and satisfaction.
Evidence-Based Studies on KB220 Variants
Substance - Seeking
Neurotransmitters, along with other chemical messengers like dopamine, cannabinoids, endorphins, and glutamine, play significant roles in brain reward processing. Most recently, the cholinergic system seems to load onto Cannabis Use Disorder [Demontis et al., 2019].
As mentioned earlier, there is a devastating opiate/opioid/psychostimulant/benzodiazepine epidemic in the United States. The Centers for Disease Control and Prevention (CDC) say over one hundred people are dying every day due to narcotic overdose, and heroin overdoses are increasing. Some MAT has been approved by the Food and Drug Administration (FDA) for alcoholism, opiate, and nicotine dependence but nothing for psycho-stimulant and cannabis abuse. These MAT pharmaceuticals are essential for the short-term induction of "psychological extinction,” however, in the long-term caution is necessary because MAT favors blocking dopaminergic function, which is indispensable for achieving usual satisfaction in life. The problem here is the biphasic process of MATs. Two institutions devoted to alcoholism NIAAA and drug dependence NIDA realize that MAT is not optimal and continue to seek better treatment options. Blum’s group have over the last 50 years developed a glutaminergic-dopaminergic optimization complex, called KB220 and its improved evolutionary variants, to provide for the possible eventual balancing of the brain reward system and the induction of "dopamine homeostasis" [Blum et al., 2016a]. The complexity of the neurotransmitter activity of various brain regions may be bi-directional and as such, opposite in function. This conundrum makes it challenging to assume that one agent fits all. However, we propose that under normal conditions all the neurological functional parts work in concert to, for example, present the
correct amount of dopamine to be released at the NAc. Thus, in the face of either aberrant surfeit or deficit, balancing the activities of the entire brain reward system seems most prudent. With this in mind as thinking clinicians, our goal must be to potentially reach homeostasis of the neurochemistry of the brain reward circuitry.
The KB220 complex may provide substantial clinical benefit to the victims of RDS and assist in recovery from iatrogenically-induced addiction to unwanted opioids and other addictive behaviors. Inducing "dopamine homeostasis” (balance) across the brain reward circuitry has been the best way to treat all addictive-like behaviors. Moreover, utilizing fMRI in abstinent heroin addicts in China (see figure 6), one hour after administration of KB220Z (the ‘Z’ represents the addition of some botanicals rich in various saccharides), compared to placebo, showed profound activation of dopamine pathways of the caudate-accumbens region of the brain and reduction in dopaminergic activation of cerebellum [Blum et al., 2015b]. This experiment demonstrates that through this mechanism, activation of dopamine pathways, craving behavior, as well as stress, will be reduced.
Fig 6.
Figure 6 is rsfMRI of caudate –accumbens and cerebellum one hour after administration of KB220Z in heroin use disordered (HUD) brains following sixteen-months of abstinence. Taken from Blum et al., with permission (Blum et al., 2015b).
Understanding Precision Addiction or Behavioral Management (PAM/PBM)
GARS testing of dependent persons in treatment provides a map of the brain's chemical messenger function (receptor number and neurotransmitter production) and can lead to personalized addiction medicine, based on Pro–dopamine regulation.
Iatrogenic prescription drug abuse is the fastest-growing problem in the United States. About unintentional drug overdose deaths reached 64,000 in the United States, back in 2017. The two main US populations at risk for prescription drug overdose are the approximately 9 million individuals, who report long-term medical use of opioids, and about the 5 million individuals who report non-medical use, no prescription or medical need. Of the patients prescribed high
daily doses, twenty percent seek care from multiple clinicians. This group account for 80% of opioid overdoses and are likely to be diverting drugs to others, who use them without prescription. In addition to the principal pain pathways that ascend from the dorsal horn of the spinal cord to the medulla, many gene polymorphisms in the BRC; the mesolimbic reward center of the brain, are involved in the moderation of pain sensitivity and tolerance [Yao et al., 2015].
The Genetic Addiction Risk Score (GARS ) test for reward genes, such as DRD2, for risk for narcotic addiction predisposition, together with P450 genotyping for narcotic metabolism and can identify patients in the early stages of treatment with a predisposition to addiction [Blum et al., 2017a,b,c,d,e; Bousman et al., 2019]. These unique identified gene polymorphisms can provide therapeutic targets for non-narcotic pharmacogenomic solutions and other non-addictive alternative treatment that can be used to treat pain.
One such alternative is a natural dopaminergic agonist KN220Z that was tested utilizing neuroimaging tools including fMRI, and QEEG in both humans and, most recently, rodent models. The rodent fMRI’s showed Blood Oxygen Level Dependent (BOLD) regulation of PFC– cingulate gyrus activity and activation of dopaminergic pathways [Febo et al., 2017c], and in abstinent heroin [Blum et al., 2015b] and psycho-stimulant abusers using qEEG [Blum et al., 2010]. Finally, the Comprehensive Analysis of Reported Drugs (CARD) analysis on thousands of specimens reveals a significant difference in both compliance and abstinence rates. Opioid substitution programs show the best compliance with a range of 88% to 92% with Methadone and Buprenorphine/naloxone, respectively, but also show high drug abuse rates during treatment; approximately 47% [Blum et al., 2014c, 2018h; Blum et al., 2018i].
We continue to propose “Precision Behavioral Management” that includes genetic testing, assessing both metabolism and narcotic risk before opioid prescription; electrotherapy, a non-addicting alternative to opioid prescription; dopaminergic activation with KB220PBM; medical monitoring with CARD and 12 step self–help programs [Blum et al., 2015d].
It is noteworthy that any pain specialist should/would welcome a non-addicting way to achieve attenuation of acute and chronic pain in their patients. The proposal is that alternative approaches that could include both electrotherapy and pro-dopamine regulation to induce dopamine balance (homeostasis) are indicated for patients with a history of chronic pain and a high genetic risk for addiction.
Non-Substance seeking behavioral addictions
Reward Deficiency Syndrome is a brain disorder characterized by a clinically significant reduction of the essential neurotransmitter dopamine in the brain's reward Center; specifically, the midbrain and prefrontal cortex. This syndrome can primarily be acquired genetically, but can also be the consequence of and exacerbated by prolonged stress. The experience of pleasure, reward, joy, and contentment is mediated by dopamine. Dopamine ascribes "salience" to behaviors directly connected to species-centered survival drives, e.g., eating, hydration, and copulation, to name a few [Berridge & Robinson, 2016]. Recent research shows that perhaps as many as 30% of the US population have a genetically acquired “dopamine deficiency”, and thus, are at increased "risk" for developing addictive-type disease or other debilitating brain disorders including: depression, anxiety disorder, ADHD, stress-related disorders, sexual compulsions, pathological gambling, hedonic overeating and obesity [Blum et al., 1996a]. It is noteworthy that as a result of genotyping over 1000 people of all nationalities living in the United States,
unpublished results from Blum’s laboratory found a very high genetic risk for drugs (< 90%) and risk for alcoholism (< 60%).
All psychoactive drugs induce an acute release of dopamine at the NAc (reward site). Carriers of inherited genetic antecedents that produce dopamine deficiency, experience enhanced well-being when exposed to a substance or when they engaged in behavior that elevates dopamine levels, particularly, during a time of stress or sadness. Many people believe the false assumption that substance use is the solution to stress, boredom, bad feelings, bad days, and social ineptness. People engaged in substance use may conclude that the relief is only temporary (due to high release of dopamine at NAc), but learning how to change your mood artificially, even for a short time, is a tell-tale sign of RDS [DiChiara & Imperato, 1988]. Self-medication with a behavior or substance is an attempt at ”normalcy.” This step can set up an individual for disaster. The persistent use of substances can upset neurotransmitter balance and functional connectivity and may induce neurological reward deficits. All psychoactive artificially spike the brain’s dopamine level, which results in a chemically induced "high" that far exceeds a naturally attained high [DiChiara & Imperato, 1988] However, what goes up--must come down. Unlike natural rewards, after a drug-induced high, dopamine levels become significantly reduced to unhealthy deficit levels. So, the more mood-altering substance or addictive behaviors used by an individual to feel better, the worse they feel; which is the ‘biphasic’ neurobiological result [Niikura et al., 2010].
Sustained abstinence is usually necessary before the individual’s brain to replenish dopamine levels and function properly. However, a deficit in dopamine creates "anhedonia," or the inability to feel happy, feel contented, appreciate natural rewards and beauty, no small thing. For many, depending on their circumstances, such as stress, poor social support, and numerous
other social and environmental variants, abstinence alone may not be enough and relapse is more common than not [Gardner, 2011]. Deprivation alone can lead to a slingshot rebound phenomenon described in another paper from Blum et al., and called “Deprivation Amplification Relapse” [Blum et al., 2009].
RDS encompasses addictive, impulsive and compulsive behaviors, and is an advance, in how we conceptualize and treat SUD, depression, anxiety, stress disorders, problems with attention and focus, overeating, obesity, Internet Gaming Disorder, to name a few behaviors. The RDS conceptualization has also opened the door to new and novel treatments by reframing the question much more broadly. What do all the disorders mentioned above have in common? While the brain neurotransmitter systems are very complex, one prominent answer is crucially, dopamine deficits in brain reward areas. Whereas traditional treatment modalities, including medication, psychotherapy, and social support remain the mainstay for most people are by design, symptom reduction strategies not addressing the root cause. While addressing the cause a hypodopaminergic RDS has allowed for numerous new and novel treatment approaches such as gentle BRC system biological neuronutrient-dopamine agonist therapy [Blum et al., 2016c]. Clinical trials of the neuro-nutrient over the past decade have produced a significant reduction of symptoms associated with RDS. There is, also emerging evidence that in some cases, over time, dopamine reward once attained can be permanently stabilized. Obtaining the genetic profile of the individual, which until now, has been unattainable for the general population, is crucial for understanding, who will benefit from specific guided gene therapy, and potentially achieve “dopamine homeostasis.”
We should point out that the word “Addiction” in the GARS name can also refer to addictive behaviors not related to substances of abuse; they are excessive reward-seeking thoughts and
behaviors. All RDS linked disorders share common etiological roots and psychopathology (biological abnormalities). The GARS test can identify many aberrant, seemingly diverse behaviors that have common neurochemical and neurogenetic antecedents that impair genetic expression and subsequently foster the development of unwanted discomfort and disease. While the DSM 5 artificially carves out brain-related disorders based on symptom severity, many in the field have argued that targeting symptoms and not biological pathology seems to be counter-intuitive. While it is still the favored approach, targeting symptoms for the diagnosis of illness with neurochemistry requires serious reconsideration. Accordingly, future editions of the DSM might be better if the actual and more accurate etiology of psychiatric disorders, are articulated by adding the neurobiological aspects of structure and function for context [Hyman, 2007]. In that regard, future diagnostic manuals should strongly consider Reward Deficiency as an entry to help explain the neurobiological basis of all addictions.
An alternative approach to treat and possibly prevent RDS is the utilization of a well-researched neuro-nutrient, called KB220 and its advanced variants, investigated in at least 41 studies. They have shown evident effects of KB220 including reduced Against Medical Advice (AMA) rate, attenuation of craving behavior, reward system activation, (including BOLD dopamine signaling), relapse prevention, as well as reduction in stress, anger, and aggressive behaviors, elimination of nightmares, improved cognition, attenuated shopping, paraphilia, hoarding, glucose craving, gaming behavior, and ADHD symptoms, among others. This research is continuing, to potentially combat not only the opioid/psycho-stimulant epidemic but the full range of other RDS-type addictive behaviors [Blum et al., 2007b; Blum et al., 2018h].
Based on animal research and clinical trials to date, the Pro-Dopamine Regulator known as KB220 and variants shows promise in treating addiction and pain. Other neurobiological and genetic studies are required to help understand the mechanism of action of this neuro-nutrient formulation. The evidence to date, however, points to induction of "dopamine homeostasis" enabling an asymptotic approach for epigenetic induced "normalization" of brain neurotransmitter signaling and associated improved function in the face of either genetic or epigenetic impairment of the BRC [Blum et al., 2007b].
With that said, we are encouraged about these results published over the last 50 years and look forward to continued advancements related to appropriate nutrigenomic solutions for the millions of victims of all addictions. These addictions include drugs to food to smoking to gambling and gaming, especially in our next generation — Reward Surfeit Syndrome (RSS) in adolescents and Reward Deficiency Syndrome (RDS) in adulthood.
Genetic Testing and Screening and Ethical Issues
Human medical genetics deals with the role of genes in illness. Traditional analysis of the genetic contribution to human characteristics and illness and has involved three types of disorders: 1) disorders due to changes in single genes; 2) polygenic disorders influenced by > 1 gene; 3) chromosomal disorders.
Genetic screening differs from genetic testing. Although the terms are interchangeable, genetic screening is carried out on a defined (by age, sex, or other risk factors) section or a subgroup of the population, in which specific disabilities may be the result of genetic factors. Genetic screening: “… a search in a population to identify individuals who may have, or be susceptible to, a serious genetic disease, or who, though not at risk themselves, as gene carriers may be at risk of having children with that genetic disease.” On the other hand, genetic testing: “… the analysis of a specific gene, its product or function, or other DNA and chromosome analysis, to detect or exclude an alteration likely to be associated with a genetic disorder,” and results in a definitive assessment that measures the potential risk to develop a disorder for the individual involved.
Screening programs are crucial in public health care systems, where they can identify individuals at severe risk and prevent morbidity by timely treatment. In this regard, the goals are 1) to improve the health of persons with genetic disorders; 2) to facilitate informed choices regarding reproduction for the carriers of abnormal genes; 3) to alleviate the concerns of families and communities about the severe genetic disease; 4) reduce public health costs. For those institutions seeking to reduce cost and better manage their public health exposure, genetic screening is a good option.
There are some concerns that genetic testing of the human population could slide into eugenics. Eugenics was a social movement that sought to improve the genetic features of human populations through sterilization and selective breeding (for example, sterilization of the mentally “unfit” practiced in some states until the 1970s). However, this is far from the case for genetic screening or testing for the RDS-phenotype, suggested in order to facilitate early and accurate genetic assessments and preventive treatments. Nonetheless, it is noteworthy that the negative impact of genetic screenings has ethical implications, both personal and societal categories of harm.
Personal harm concerns the psychological well-being of the individual and may include increased personal anxiety about labeling, health, and decisions related to infant and prenatal testing. Societal harm, perhaps with more powerful ethical considerations, involves the interaction of society with the individual, concerning employment prospects, access to health insurance, life insurance, and other benefits as well as harm stemming from eugenics. For example, societal harm may involve our current opioid epidemic. The primary benefit of opioids to treat opioid use disorder is nothing more than harm reduction while waiting for prophylactic solutions [Blum & Baron, 2019].
The advent of psychiatric genetics has mandated the confrontation of various ethical issues. As knowledge grows regarding the genetic basis of psychiatric disorders, the accepted etiology of most psychiatric disorders will be that environmental factors interact with multiple predisposing genes. As tests for the genes involved in psychiatric disorders become more readily available for prenatal testing and screening in children and adults, pressures to use such testing for premarital screening and selection of potential adoptees may develop aside from using genetic screening to diagnose the predisposition for illness and design treatment and preventative programs for those illnesses.
Challenges of genetic testing include the impact that such knowledge can have on the individual, on one’s sense of self; misunderstanding of the consequences of genetic predisposition and discrimination; and using genetic information to deny a person access to, for example, employment and insurance. Most states have some legislation aimed at preventing discrimination. However, coverage by most state law is spotty. Now with the US Genetic
Information Non-Discrimination Act (GINA) of 2008 in place, individuals are protected by federal law. Physicians may find that they have new duties created by reports of genetic test results, including addressing common misunderstandings of the consequences of possessing an affected allele and alerting third parties, who may share the patient’s genetic endowment.
Some questions about appropriate disclosure of information to individuals and their family members during the process of genetic research have arisen. Germane information about the genes studied, how the subjects of the research are defined, and how the collection of information from the proband’s family members should be addressed. Medical professionals will need to attend to and resolve these dilemmas soon, as neglecting them will leave others to make rules to control psychiatric medical practice, including psychiatric genetic research.
Ethical concerns arise over the genetic testing of children, such as disclosure to the child and informed consent. Even if future research confirms the need to test preschoolers, for RDS-ADHD risk behaviors, specific laws now in place will govern the subsequent testing in children. If the provider’s view is that the potential for harm would outweigh the potential benefit of the test, or if no benefit from medical intervention would be possible until adulthood, the test would be deferred until adulthood. Only when it is in the child’s best interest can he test be conducted, the justification being that the test should be timely and medically beneficial to the child. Dr. John Nurnberger recently on October 4th suggested “ In child onset disorders, particularly autism spectrum disorders and intellectual disability, genetic testing is not only useful but also regarded as an essential part of the evaluation”
There is a continued need for gene-directed research for identification of the risk potential, prevention, and treatment of RDS. Our hypothesis, based on existing scientific evidence as
reviewed, suggests that parents, pediatricians, psychiatrists, and primary care physicians think about the potential importance of appropriate genotyping of at least dopaminergic genes as part of the overall assessment for identifying children at risk for RDS and related risk behaviors like ADHD and SUD. We are cognizant that in pediatrics, it may be dangerous to worry families unnecessarily with data showing risk alleles in their offspring; most of which are probably also carried by their parents and siblings. We want to emphasize that our intent is not to genotype children at a young age for purposes of labeling them thereby influencing their future successes and failures. Our objective instead is to suggest careful and appropriate use of the information obtained from postnatal genotyping for preventive, treatment, and improvement options, which could ultimately lead to appropriate safe treatment early on to reduce behavioral risk, including poor scholastic performance and SUD.
Prophylaxis of SUD
It is noteworthy that tobacco may be a gateway to other drugs of abuse, including marijuana use, especially in cocaine abuse [Kandel & Kandel, 2015]. It has been argued that among current college smokers, 40% started smoking by learning to inhale marijuana and then started using tobacco, or they started using tobacco at the same time [Strong et al., 2016]. The conundrum here is, without a precise diagnosis of early-onset SUD, it is difficult to ascribe the concept of the gateway theory generalized to any specific drug because the misuse of any particular psychoactive drug, such as marijuana or tobacco, may occur with or without the RDS- phenotype. However, gene testing, as proposed, will provide additional and pertinent information regarding the connection between RDS-symptomatology and SUD, including marijuana or tobacco use and other behavioral risks. More importantly, existing
polymorphisms could then be targeted to provide a personalized RDS solution to the individual child, especially in carriers of the DRD2 A1 allele (among other gene polymorphisms).
According to Volkow and Wise Abstract [2017,] in support of our RDS concept:
“Behaviors such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behavior. Both this motivational drive and the behaviors that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', (‘RDS’) which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.”
Future Perspectives
Any behavioral outcome in Homo sapiens is the result of nature (genes) combined with nurture (environment). They contribute approximately 50% genes and 50% epigenetics (environmental influence on gene expression), especially in alcohol use disorder [Verhulst et al., 2015]. Molecular genetics or DNA testing is therefore fundamental to linking aberrant behaviors to any individual.
Blum's et al., [2012a] proposed that any disturbances along the reward cascade that might be due to either gene variations (polymorphisms) and environmental influences (epigenetics) can result in various SUD (RDS). Despite a continued globe-wide search to find specific candidate genes or clusters characterized from high-density SNP arrays, many attempts have failed to replicate and have been inconclusive. However, recently, Palmer et al., [2015] demonstrated that between 25–36% of the genetic variance might be attributable to common single nucleotide polymorphisms in the generalized vulnerability to substance dependence. Also, common single nucleotide polymorphisms share the additive effect across principal indicators of various co-morbidities. Also, as a result of such research studies, even more, recent evidence has shown that specific gene variants may account for risk-prediction.
As described at the beginning of this chapter, Blum's et al., [1995b] Bayesian study concluded that the DRD2 A1 allele appeared to be an indication that if a child is born with this polymorphism, they will have a much higher risk for engaging in excessive potentially unhealthy reward-seeking behaviors. The study demonstrated a Positive Predictive Value (PPV) of 74%, for future RDS behaviors. Since the 1990 finding of the association of the DRD2 gene Taq A1 allele with severe alcoholism, laboratories across the world including NIDA and NIAAA have done work that confirmed and extended on the importance of various candidate genes, specifically, genes for secondary messengers in the reward system [Reilly et al., 2017].
An example is Moeller et al., [2013], whose neurogenetic results identified the DAT1R 9R allele as a risk allele for relapse, especially during detoxification and early abstinence. They also suggested that drug cues contribute to relapse. As mentioned earlier, the DAT1R 9R allele influences the fast-acting transport of dopamine, sequestered from the synapse, leading to a hypo-dopaminergic trait.
The use of genetic testing to uncover reward circuitry gene polymorphisms is essential, as a method of obtaining better treatment results, mainly, those linked to dopaminergic pathways, including opioid receptors. Knowing the relationship between buprenorphine the reward circuitry is a model that can enhance a patient’s clinical experience and prevent relapse during opioid substitution therapy.
While there are other proposed genetic panels, linked to OUD, none have provided evidence of reward gene polymorphisms associated with known increased genetic risk for addiction and other RDS behaviors. Unpublished analytic evidence demonstrated that the GARS panel predicted ASI drug and alcohol severity and a newly validated RDS Index (RDSI) was developed in Hungary.
Finally, we propose that PBM a genetically based approach to achieving required dopamine homeostasis via customized dopamine regulation should be considered. In addition to early identification of genetic risk for RDS and early intervention, this new dopaminergic regulatory approach seems more prudent than continuing to “lock people into addiction to potent opioid-like molecules” rather than finding ways to ameliorate a potential hypodopaminergia (a root cause of all addictive behaviors). Dopaminergic regulation combats not only the opioid crisis but all RDS non-substance addictive-type behaviors as well. The implementation of this approach
now is indeed a laudable positively forward-thinking goal, especially while being cognizant of the complexity of the brain.
We must keep in mind that while childhood internet gaming or even smartphone addiction may seem innocuous, it warrants serious consideration within the family. If the gravity of this behavior is unrecognized as an RDS behavior it could indeed contribute to future fatality of our loved one, due to, for example, an unwanted fentanyl overdose as they move from internet gaming to opioid abuse. Epigenetic studies have found that nurture or deprivation, as practiced by maternal rodents, can have an effect on the dopamine homeostasis for up to two generations [Szutorisz and Hurd, 2016]. The best medicine then is to embrace the concept of “Love Your Pups.” Stop the guessing and join the 21st century of the genome, unraveling genetic risk, to prevent anhedonia and redeem joy once again with a concomitant enhanced quality of life.
Take home message
It is imperative to recognize that addictive disease, including pathologically rewarding behaviors, are increasing for most countries. As scientific and clinically experienced authors, we are compelled to fix our gaze on the most recent and probably the most lethal manifestation of our evolving drug epidemic; specifically, the mortality associated with opioid use disorder. In this sense, we are indirectly bolstering our belief in “reward deficiency” as the most viable determinant of the etiology and pathophysiology of not only addictive disease but also of the statistically significant concordant psychopathology, e.g., depression, anxiety disorders, PTSD, and ADHD. Accordingly, recent breakthroughs in neuroscience, brain imaging, and neuropharmacology have not only shed much-needed light on the skyrocketing worldwide psychopathology-- it is also a beacon of hope for those suffering from this debilitating condition. [Scholl et al., 2018; Gressler et al., 2018].
From Karl Menninger, MD. The Vital Balance 1961..
It is our duty as physicians to estimate probabilities and to discipline expectations. But leading away from probabilities there are paths of possibility, toward which it is also our duty to hold aloft a light. And the name of that light is Hope [Menninger et al., 1963].
(Menninger K, Mayman M et al. 1963)
Since we are discussing opioids primarily used as analgesics clinically, pain treatment is a significant public health crisis that costs US society approximately $560 to $635 billion annually, equal to about $2,000.00 for every person living in the U.S. The poor pseudo-solution had been to prescribe opioid medications to reduce pain. However, we are in the midst of an opioid overdose epidemic in which overdose mortality has never been higher [Pergolizzi et al., 2018, Rudd et al. 2016, Florence et al., 2016]. While there are several proven strategies available to manage chronic pain without opioids, there remain millions of non-addicted, but opioid-dependent patients with chronic or intractable pain syndromes [Amie et al., 2018]. Chronic pain, like so many other chronic conditions is phenotypical and widely diverse. The novel, analytically derived, evidence based PBM presented herein, provides a diagnostic tool for understanding the neurogenetic and neurobiological correlates of the many iterations of reward deficiency. This integrated technology can tip the balance in favor of patient-centered care, in which clinical practice guidelines of assessment and treatment modalities, including prescribing practices, based on data never before available on this scale. Indeed, this is an essential step in addressing the current opioid overdose epidemic and the devastating toll on individuals, families, and communities across the US and the world. [Blum et al., 2015a, Blum et al., 2018a ].
Summary
While RDS refers to both drug- and non-drug addictive behaviors, one major concern globally but, especially in the United States of America, is the current opioid crisis. While there are
several proven strategies available to manage chronic pain effectively without opioids like Transcranial magnetic stimulation [TMS] and H-Wave therapy), the principal agencies agree that we are being challenged to provide alternative non- addicting and non-pharmacological alternatives to treat pain and attenuate addiction. The medical establishment is now encouraging alternatives with no risk of side-effects. Moderate-quality evidence supports the use of Non-Steroidal Anti-inflammatory Drugs (NSAIDs) in chronic pain patients. A recent JAMA report provides strong evidence that non-opioid treatment, like NSAIDs, fares better than chronic opioids. Notably, the brain reward center plays a vital role in the modulation of nociception and that in dopaminergic circuitry adaptations may effect several sensory and affective components of chronic pain syndromes. Pain patients that present with analgesic tolerance should not be stigmatized as being addicts, unless they show evidence of inappropriate behaviors, including illicit opioid seeking and illicit analgesic doctor shopping. Knowing a patient’s GARS result could help provide an in-depth map of a patient’s brain and assist in prophylaxis, especially by early genetic identification of high addiction risk.
In this article, we are providing analytic, genetic and neurochemical evidence that could help addiction medicine and pain specialists in providing better care by eliminating guessing, especially as it relates to one’s risk of becoming substance dependent and providing a paradigm shift by embracing PBM and the induction of “dopamine homeostasis.” We argue herein that if key-opinion leaders continue to promote opioids to treat opioid use disorder without actually developing epigenetic manipulation of brain neurochemistry to induce homeostasis across brain circuitry, we are setting up patients and care providers for dismal failure. The missing link, however, is not just related to opioid use disorder, but the underpinnings of all addictions, including non-substance behavioral addictions. Understanding the RDS concept in this context certainly provides compelling arguments for the entire scientific community to explore non-addicting ways to target specific genetic antecedents with the primary goal to achieve “dopamine homeostasis.” With this stated, it is clear that because of transfer from one addiction to another, people may move from one addiction to another, including opioid-seeking behavior. This type of transference may result in premature deaths, and it is essential to provide real treatment options, not just symptom treatment. We, as clinicians and scientists, must look ahead and develop sound evidence-based modalities that will provide Homo Sapiens with a life free of the chains of addiction, and we must begin to identify addictive-like risk early on. Up until now, that would not have been possible.
However, as covered in this article, the authors provide a framework to accomplish this laudable goal by asking the addiction medicine community to embrace their novel model “Precision Behavioral Management” (PBM) or “Precision Addiction Management” (PAM). Following continued pre-clinical and human research, this approach couples genetic testing with Pro-Dopamine Regulation as a frontline gene-guided therapy to provide early identification of RDS behaviors. We believe that to ignore the role of brain circuitry, especially as it is related to net dopamine release at the reward center of the brain will constitute scientific negligence. Finally, RDS by any other name is still RDS!
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