Blum’s Scientific Work in Addiction Medicine

As a young budding scientist Kenneth Blum, PhD working at Southwest Biomedical Foundation in San Antonio continued his post-doctoral studies on dopamine in 1968. At that time he and his mentor Irving Geller received a grant from the National Institute of Alcohol Abuse & Alcoholism (NIAAA) related to the role of neurotransmitters, stress and aberrant alcohol drinking in animal models. As a consequence of this funded grant Dr. Blum was the first to evoke the concept of darkness induced drinking based on the effect of pineal gland melatonin.

Following this tenure in 1972 Dr. Blum was appointed to the faculty of Department of Pharmacology, University of Texas Health Science Center, at San Antonio, Texas (UTHSCSA). Following a very active research career Dr. Blum retired as full-professor in 1995.

During his time at UTHSCSA, he made a number of very seminal discoveries having significant impact upon addiction medicine. Specifically, Dr. Blum along with his associates, students and post- doctoral fellows provided the scientific community with the concept of shared neurochemical mechanisms between alcohol and opiates by showing that the narcotic antagonist naloxone could not only block alcohol-induced sleep –time in mice but published a paper in Nature showing that Naloxone could block ethanol dependence as well. This finding led to the clinical development of Vivitrol (Naltrexone) used currently as an FDA approved pharmaceutical to treat both alcoholism as well as opiate addiction. Dr. Blum’s group turned their attention to evaluating the role of Isoquinolones in alcoholism and is credited with the first study to identify a metabolite in the brain of mice following ethanol ingestion-which helped support the common mechanism theory of alcohol and opiates and edited a book on this novel concept in 1978. In the late 70’s and early 80’s he dedicated his research to endorphinergic research and was the first group to show the unequivocal of role methionine –enkephalin (METENK) as the basis for alcohol intake whereby he published in the prestigious journal PNAS that alcohol intake in genetically bred mice was  a function of  brain content of METENK.  Specifically, low METENK induced high ethanol drinking and visa versa high METENK induced low ethanol intake. In 1982, Blum’s group published their seminal work in Science showing that ethanol drinking in Golden Syrian hamsters freely drinking for one year (equivalent to 20 years in humans) had very significant impairment in striatal leucine-enkephalin synthesis.  This finding has been confirmed in humans and shown by others to occur with chronic intake of opiates, diazepam and cocaine. It is noteworthy that simultaneously his group was the first to show that intra-cerebellum injections of  enkephlamide (a methyl analog of enkephalin) induced a significant reduction of ethanol intake in high ethanol seeking C57/blk mice. Following these important findings Blum’s group was the first to report on the concept of pharmacogenomic engineering when by utilizing a substance known to inhibit carboxyl- peptidase (basically enkephalinase) D-Phenylalanine for 18 days in c57/blk mice , they showed that this substance raised endorphin levels in both the pituitary and striatum and converted the genetically prone alcohol seeking mice to significantly reduce their alcohol intake to similar levels of non-preferring alcohol mice like the DBA. This published work in the journal Alcohol provided the basis for the role of enkephalinase inhibition as a therapeutic target for the treatment of alcoholism and was the basis for the first patent in the United Sates ever given for an amino –acid following many high court appeals.

In 1982, Dr. Blum began to develop KB220 experimenting with a male human alcoholic realizing that an anti- alcoholic agent must constitute a number of select precursor neurotransmitter based amino –acids ;  an enkephalinase inhibitor and inhibitors of both mitochondrial and synaptic enzyme catabolizes  of catecholamines such as serotonin and dopamine. Following many iterations the first ever neuronutrient was therefore formulated and resulted in successful attenuation of heavy drinking in a male alcoholic. Further reiterations also resulted in successful amelioration of serious drinking in a female alcoholic. Over the next eight years the first commercialization of this neuronutrient called SAAVE was utilized in over 1,000 treatment centers in the USA. Blum’s group continued to develop related formulations for cocaine dependence (Tropamine), opiate dependence (SAAVE PLUS) and even obesity (PhenCal). During this period many research papers related to clinical outcomes including double –blind –placebo investigations appeared in the scientific literature.  The response from the recovery community was very positive and as such amino-acid therapy for the treatment of drug addiction was born.

Dr. Blum’s research continued and along with Gerald Kozlowski of Southwestern Medical School in Dallas began to laydown various ways the neurotransmitters interact in the brain. This basic research resulted in the development of the understanding of the well-known reward circuitry of the brain whereby they coined and published in 1989  the term “ Brain Reward Cascade “ (BRC) as well as a detailed map. Over 25 years later this basic conceptual framework has stood the test of time and is considered a blue –print of neurotransmitter interaction and subsequent workings of the reward system and reward dependent behaviors.  The basic tenant of this work revealed that the feeling of well-being can be achieved only when the molecule dopamine is released in the nucleus accumbens at “homeostatic” levels. Any deviation causes “dopamine resistance” and as such could result in abarrant cravings. Specifically, too much dopamine can lead to schizophrenia and too little dopamine could lead to depression.   

    

Following this seminal research Blum’s group turned their attention to unraveling the long known history that alcoholism was an inheritable disorder but was lacking any specific studies related to associating any gene (s) with this familiar global problem. Along with Ernest P. Noble, the former director of the NIAAA and Psychiatry Professor at UCLA, and Dr. Blum and their associates began to analyze brain tissue from both alcoholics and non-alcoholics utilizing “Restriction Fragment Length Polymorphism (RFLP) techniques to discover the first ever genetic association of alcoholism in the world. Utilizing BRC they published their seminal findings in JAMA in 1990, showing the now famous association of the dopamine-D2 –receptor gene (DRD2) A1 allele (variant) and sever alcoholism.  Initially, this astounding discovery met with controversy worldwide but is now considered a major breakthrough in addiction medicine and has been researched in almost 4,000 scientific studies cited in PUBMED. In fact, the JAMA study sparked the entire field known as “Psychiatric Genetics” and Dr. Blum is considered by some as the father of this most important discipline. Subsequent to their finding  Noble, Blum and associates were the first to report in  JAMA Psychiatry (formerly Archives of General Psychiatry) that carriers of the DRD2 A1 allele were born with a 30-40% lower number of D2 receptors and as such are at high risk for all addictive behaviors both substance and non-substance related.  Currently the DRD2 gene is considered to be one of the most important genes that has impact on all reward behaviors and as such has been considered a “reward gene” as first espoused by their JAMA paper. Immediately following the announcement of the finding of the DRD2 association with severe alcoholism a Gallup poll revealed that the majority of Americans now believed that alcoholism was genetically based and was not simply an infraction of a moral characteristic.   

In 1995, understanding the nature of common shared neurogenetic and neurobiological mechanisms across the major abusable licit and illicit drugs and the importance of a hypodopaminergic trait/state Dr. Blum first conceived and coined the term “Reward Deficiency Syndrome”(RDS)  to describe addictive, impulsive disorders including alcoholism, attention deficit disorder drug abuse and food bingeing having a common genetic basis acting as an umbrella term. The first concept was described in a general article in the American Scientist and today over 500 articles are listed in PUBMED. RDS is currently found and defined in MSN word and will be included in SAGE Encyclopedia on Abnormal Psychology and Mental Illness.  The basic concept has been adopted in the ASAM new definition of Addiction in 2011. This concept expanded on the Dackis & Gold “dopamine depletion hypothesis” for cocaine abuse. The emergence of this concept worldwide has now reached scientific interest and provided the basis of the first journal on RDS. Dr. Blum along with Rajendra Badgaiyan, MD are Editors- In-Chief and have successfully developed and published (United Scientific Group)  their inaugural issue with over 70 editorial board members. One important outcome derived from this work resulted in a paper by Blum’s group published in the Royal Society of Medicine revealing that carriers of the DRD2 A1 allele variant have a 74.4% predictive risk for RDS.

In the mid 2000’s, Dr. Blum joined the scientific advisory board of Dominion Diagnostics, LLC. Together Blum and Dominion in conjunction with members (Andrew Smolen and Brett Haberstick) of the Institute of Behavioral Genetics at Colorado University  Boulder developed the first ever Genetic Addiction Risk Score (GARS).  In unpublished work they show significant predictability of a ten gene reward gene panel to associate with ASI-Media Version alcohol and drug severity scores (patents pending).  This genetic test will be highly beneficial to predict stratification of genetic liability in both addiction and most importantly pain clinics. The launch of this test is planed following validation and CLIA certification early fall 2015 which will culminate the 25th anniversary of the first DRD2 gene association.      

Dr. Blum was honored with an adjunct professorship in the Department of Pharmacology, Wake Forest University Medical School and was appointed a volunteer Professor in the Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine as well as the Department of Psychiatry University of Vermont. He also serves as scientific director of Path Foundation NY.  Along with Dr. Mark Gold and others they have published a series of important papers on drug and food addiction sharing common mechanisms and reviews dealing with vaccines, gene therapy and most importantly dopaminergic agonistic therapy for all RDS behaviors. Since the 80’s until the present time Blum’s group has published close to 30 peer reviewed articles showing clinical benefits of KB220 variants. The major highlight of this work has been focused on the utilization of neuroimaging tools. Blum’s group in conjunction with John Giordano and others published a series of articles showing significant regulation in the pre-frontal cortices especially at the cingulate gyrus (a region for drug relapse) in abstinent psychostimulant abusers, alcoholics and opiate addicts utilizing qEEG analysis following both intravenous and /or oral administration of KB220. The most seminal finding to date concerning KB220Z (one glucoside variant) has been accomplished with Drs. Febo, Liu, Gold, Thanos, Badgaiyan, Oscar-Berman,  Simpatico and others showing that KB220Z in a placebo controlled cross over study significantly restored resting state functional connectivity in abstinent heroin addicts across a putative network including  the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In other unpublished rat work they show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior thalamic nuclei, hippocampus, pre-limbic and infra-limbic loci.

In conjunction with a number of respected ASAM physicians and Dominion Diagnostic Blum’s group utilizing the Comprehensive Analysis of Reported Drugs (CARD)™  published the first article showing both compliance to FDA approved Medication Assisted Treatment(MAT) and abstinence from drugs of abuse in drug urine screening of thousands of addicted patients in 6 states on the east coast of America published in the prestigious journal PLOSONE. In addition similar analysis of Suboxone has been submitted to the Journal of Drug & Alcohol Dependence.  Work related to the long-term effects of Buprenorphine/naloxone has been published in PLOSONE by Blum’s group in conjunction with MIT and  McGill University  showing that long-term ( 1,66 years) on this combination results in significant reduction of affect compared to the general population and  members of the AA community. Blum’s group has also now published in peer reviewed journals the complete elimination of terrifying PTSD induce nightmares following administration of KB220z.  

This summary of research and the development of the first ever aqua -nano delivery of KB220Z (Synaptamine) [patent issued and pending] provides solid scientific support for the utilization of this improved and potent neuronutrient based on almost 40 years of research. Synaptamine™ is now available for the pain and addiction professionals interested in assisting patient recovery through true dopaminergic agonist therapy.

In a number of published articles Dr. Blum has now coined the term “ Reward Deficiency Syndrome Solution System” ™ consisting of genetic testing utilizing GARS™,  medical monitoring utilizing CARD™ and dopamine agonist therapy using Synaptamine.™ In the future through these enormous efforts it is possible to provide the first nutrigenomic solution for those individuals suffering from RDS with the promise of true delivery of personalized addition medicine.