Kenneth Blum, Ph.D., David Siwicki, MD, Mary Hauser, Msc. and Jennifer Neary, Ph.D.

Following 27 years of extensive worldwide research, a panel of ten reward gene risk variants, along with a proprietary scoring index called the Genetic Addiction Risk Score (GARS™), has been developed. In unpublished work, when GARS was compared to the Addiction Severity Index (ASI) used in many clinical settings, GARS significantly predicted the severity of both alcohol and drug dependency. In the midst of an epidemic where we see over 100 Americans (of all ages and backgrounds) dying daily from opioid overdose, we believe that early testing (maybe in future at birth) for addiction and other Reward Deficiency Syndrome (RDS) subtypes is a clinical tool with great potential benefit to providers and patients. Recent evidence in Science Journal clearly shows shared common genetic mechanisms between autism, schizophrenia and even bipolar disorder previously suggested by our group in 1995 as all subtypes of RDS. In the past, families may never have worried that their loved ones could harbor increased risk for opiate addiction, but the dangers of opioid use have become clear in recent years. Further, links between other RDS behaviors and elevated addiction risk are increasingly evident. In the 1990’s, author Bill Moyers (Parade Magazine) insightfully reported that as he traveled around the United States he observed that many children with ADHD and Autism Spectrum Disorders also had related conditions like substance abuse. He called for better ways to identify these children and treat them with approaches other than addictive pharmaceuticals. The GARS addresses this need.

The Brain Reward Cascade and Implications of Chronic Low Dopamine

The interaction of genetics and neurotransmitters controlling the release of dopamine is termed the brain reward cascade (BRC). Variations in the BRC, possibly genetic or epigenetic, may predispose individuals to addictive behaviors and altered pain tolerance. The GARS panel is based on established polymorphisms (gene variations) that are known to perturb the BRC; to our knowledge, GARS is the only panel of its kind to have been correlated with the ASI-MV alcohol and drug risk severity score. Further studies are in development to confirm, and also enlarge, the GARS test by adding additional polymorphisms associated with hypodopaminergia (low dopamine function). GARS results have the potential to improve clinical interactions and decision-making. To further support addiction recovery, Blum’s laboratory has developed pro-dopamine regulatory neuro-nutrients (tested, to date, in more than 35 clinical trials [figure 1]) which enable personalized treatment for all behavioral addictions following GARS testing.

The interaction of at least four neurochemical pathways: serotonergic, GABAergic, endorphinergic, and dopaminergic, together constitute the “brain reward cascade” (see Figure 2). BRC is a natural sequence of events that produce feelings of well-being. These events include the synthesis, storage, metabolism, release, and activity of neurochemicals. These processes are regulated at the genetic level, where genes are transcribed to messenger RNA, and RNA is translated to protein. Genetic testing can be utilized to better predict individual neurochemistry, and then respond with more personalized treatment options [5].

Figure 2. Brain Reward Cascade [6,7]. In this cascade, the stimulation of the serotonergic system within the hypothalamus, through innervation, stimulates delta/mu receptors via the release of enkephalin. Further activation of the enkephalinergic system leads to inhibition of GABA transmission in the striatum via enkephalin stimulation of mu receptors upon GABA neurons. This inhibition allows the fine-tuning of GABA activity. Additionally, this provides the normal release of dopamine at the projected area of the Nucleus Accumbens (NAc).

The dopaminergic pathway is most directly involved with addiction. Dopamine is a neurotransmitter with multiple essential functions in-cluding behavioral effects such as “pleasure” and “stress reduction.” In the absence of typical dopamine function (hypodopaminergia), an individual will suffer from cravings and may have difficulty coping with stress. Therefore, the hypodopaminergic brain predisposes people to seek out substances and/or behaviors that can be used to over-come the craving state by activating mesolimbic brain dopaminergic centers. This represents the “Addictive Brain” first proposed by our group in 1990. Self-medication with psychoactive substances (such as alcohol, psychostimulants, and opiates) and/or risky behaviors (for example gambling, overeating, and thrill-seeking) induce the release of dopamine in the synapse at the NAc, temporarily overcoming this hypodopaminergic state, and resulting in temporary relief from the discomfort, and a false sense of well-being.

With regard to RDS behaviors, it is noteworthy that both substance and non-substance addictive behaviors (like music, food, sex, internet, gaming), cause a preferential release of dopamine in the NAc, suggesting that people self-medicate in many forms to obtain their required dopamine fix. The acute release of dopamine leads to feelings of well-being in the very short term, especially in individuals who through either gene polymorphisms (variants), or gene/environment interactions (epigenetic-methylation, reduced expression) and or inhibition of deacetylation (increased expression) on histones in the chromatin material involving many genes affecting mRNA expression, have compromised dopaminergic function. This concept is clarified by the simple formula, whereby Phenotype = Genetics + Environment [P = G + E]. It is understood that this is a very complex interaction involving many polymorphic genes and their subsequent interaction with the environment (genes X environment).

Chronic abuse of substances or continued risky behaviors often lead to further neurotransmitter imbalance and depletion, which further increase cravings and discomfort. Heightened pathological and substance-seeking behavior may then become necessary to provide the same pleasurable response and/or temporarily decrease uncontrollable cravings. The behavior, or drug of choice by the individual, is a function of both genes and environmental factors like stress, availability, and peer pressure.

GARS™ Testing for Clinicians and Patients

Previously, we presented data on the potential of GARS to predict vulnerability or risk for both drug and alcohol severity as measured by the Addiction –Severity Index (ASI). However, a frequently raised question relates to how GARS testing can be beneficial in known addicts already in treatment programs. We believe that there are many important reasons for GARS testing in people expressing addictive behaviors of all types.

The Genetic Addiction Risk Score (GARS), which predicts vulnerability to pain, addiction, and various other compulsive behaviors, provides benefits for individuals suffering from Substance Use Disorder (SUD). Knowledge of a person’s precise polymorphic associations can help in the attenuation of guilt and denial, and the corroboration of family genograms. For the clinician, GARS can help to inform risk-severity-based decisions including appropriate therapies (pain medications and risk for addiction), choice of the appropriate level of care placement (inpatient, outpatient, intensive outpatient, residential), length of stay in treatment, and relapse and recovery liability and vulnerability. GARS can also predict some pharmacogenetic clinical outcomes (e.g., the A1 allele of the DRD2 gene reduces the binding to opioid receptors in the brain, thus, reducing naltrexone’s clinical effectiveness), and support medical necessity for insurance scrutiny. Innovative strategies to combat epidemic opioid addiction, iatrogenic prescription drug abuse, and death, based on the role of dopaminergic tone in pain pathways, have been previously proposed. Sensitivity to pain may reside in the mesolimbic projection system, where genetic polymorphisms associate with a predisposition to pain vulnerability or tolerance [4]. These polymorphisms provide specific targets to assist in the treatment of pain and identify risk for subsequent addiction. Testing for inherited variations among candidate genes like DRD1, 2, 3, 4, MOA-A, COMT, DAT1, 5HTTLPR/SLC6A4, OPRM1 and GABRB3 could lead to more personalized prescribing and improved clinical outcomes. Genetically identified risk to RDS behaviors, especially within compromised populations, may also be a frontline tool to assist municipalities in providing better resource allocation.

It is important to be cautious of genetic testing that uncovers reward circuitry gene polymorphisms, particularly those linked to dopaminergic pathways as well as opioid receptor(s) as a method of obtaining better treatment results. Comprehending the relationship between the reward circuitry’s participation in buprenorphine outcomes and its corresponding genotypes deliver an innovative model to enhance a patient’s clinical experience and improvements throughout opioid replacement therapy. Both NIDA and NIAAA are desperately investigating an array of innovative ideas to help restore brain function, especially hypodominergia, and we believe that our approach should be carefully considered and tested. In due respect, we are encouraging scientists and clinicians to at least embrace these simple concepts in the near future, thus providing a new message of hope to the many victims of overdose and death. The future is now and we call it Precision Addiction Management (patent protected). A disruptive novel technology whereby we couple:

  1. Reward Deficiency Questionnaire;
  2. Urine drug screening with Comprehensive Analysis of Reported Drugs (CARD™);
  3. Genetic Testing with Genetic Addiction Risk Score (GARS™);
  4. Precision Neuro-nutrient therapy to induce dopamine homeostasis utilizing restoreGen™ technology.

Kenneth Blum, B.Sc. (Pharmacy), M.Sc., Ph.D. & DHL; received his Ph.D. in Neuropharmacology from New York Medical College and graduated from Columbia University and New Jersey College of Medicine. He also received a doctor of humane letters from Saint Martin’s University Lacey, WA. He has published more than 550 abstracts; peer-reviewed articles and 14-books.

Dr. Siwicki is board certified in emergency medicine and is also certified in addiction medicine. Dr. Siwicki was the co-founder of Dominion Diagnostics LLC; North Kingston, RI which is now the largest privately held toxicology laboratory in the U.S. Dr. Siwicki is also the co – founder of Geneus Health, LLC. He serves as President of Geneus Health and Igene LLC and is a member of Board of Directors on Dominion Diagnostics.

Mary Hauser has a Master’s Degree in Psychology and has worked in the addictions and behavioral health field for the past 42 years. She was the oversight Vice President of the Departments of Psychiatry and Behavioral Health at Mount Sinai Medical Center in Milwaukee and a founding member of the Board of the Wisconsin Alcohol and Drug Certification Board. Ms. Hauser was appointed Executive Administrator for Research, Psychiatry and Behavioral Medicine at The Miriam Hospital in RI. She joined Dominion Diagnostics as Vice President of Addiction Services. She continues in this position currently.

Jennifer Neary MS, PhD serves as Chief Scientific Officer for Avagen Health in San Antonio, Texas. Her research background includes microbial genetics, mammalian genetics/epigenetics, and bioinformatics, with specific emphasis on psychiatric and metabolic disorders.