How Psychogenetics &
Nutrigenomics Began
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The Kenneth Blum, PhD Life Story: A man seeking truth while reaching for the Stars.
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day on was never the same. Between the years 1975-1977 I was one of the 63 academicians chosen by NIDA/NIAAA to become a Career Teacher in Substance Abuse where I interned with David Smith at the Haight Ashbury Medical Free Clinic in San Francisco and with Benjamin Kissin and Henry Begleiter at Downstate Medical School Kings County, New York. At this time, I still maintained an active research laboratory and in conjunction with my colleague, Maurice Hirst from the University of London-Ontario in Canada and a graduate student, Murray Hamilton, who came to Texas to work with me, we found the first metabolite of TIQ, paving the way to measure TIQ in the brain. Remembering back, I was so excited that jumping widely into the air I accidently pulled the laboratory fire safety water casing completely soaking myself as if I was drowning in delight. Based on all this research we suggested and, like others, provided evidence for linking TIQ to both alcohol and opiates. The intensity of research began to decline but the concept still remains cogent and recently scientists have synthesized compounds linking TIQ with enkephalins, which may have a role in Parkinson disease treatment21 and potentially substance abuse.
By 1978, I had a strong interest in the emerging field of pharmacogenetics. I entered the University of ColoradoInstitute of Behavioral Genetics to train with Gerald McLearn, the father of modern animal genetics of alcoholism and such notables as Allen Collins, Gene Erwin, Andrew Smolen, and Richard Dietrich. Following an eight -week intensive fellowship, on the last night of the training I sat down and began to formulate a genetically based Trieste of craving behavior and by day-rise slumped over a chair clutching a notepad I had developed the concept known as the "Genotype Theory of Drug Seeking." 22
Back at the University of Texas Health Science Center we performed a number of experiments in genetically bred mice having different preferences for alcohol (some loved alcohol and some hated alcohol). My thought was that animals born with low levels of the substance endorphin should have a higher preference for alcohol than animals born with high levels of endorphins or closely related peptides.23 This was the first experiment to verify the fact that brain opioid peptides such as Beta -endorphin and metenkephalin influenced alcohol intake. Our published findings in mice have been verified over the years24 and most recently in humans.25
In 1979, two initiatives filled my life and culminated in excitement not only for me but for the field in general. Hesitantly, I took a call from Dr. Murphy at NIDA who requested that I write a textbook on Drugs of Abuse. When he informed me that the deadline for submission was in 12 weeks being both shocked and dismayed I exclaimed, "You have to be crazy to do that." Murphy responded loudly, "that is why we are asking you". Accepting the challenge, and surprisingly meeting the deadline, my second highly acclaimed book [a book of the month club selection], "Handbook of Abusable Drugs,' was written and published later by Gardner Press.26 The second event turned out to be a pinnacle in my scientific career. Following the early House Gordon Research on opiates, I felt it was time to have the first ever Gordon Research Conference on Alcohol. Together with Ernest Noble, we founded and developed the conference, which was accepted by the Gordon Research Board of Directors (John Hopkins). Having a Gordon Conference strengthens the field as providing acceptance of the research discipline in the global scientific community. My deal with the board was to have the conference in Santa Barbara and not in Maine with all the nasty flies. Fortunately, the conference was quite successful; limiting it to 100 scientists working in the alcohol field at the time including Arvid Carlsson, later to receive a Noble Prize in medicine. His last published paper involved the Dopamine D2 receptors. In 1982 following my appointment of Full Professor, I chaired the second Gordon Research Conference on Alcohol.
In 1980, another milestone in my career occurred when I was approached by Elsevier, the largest scientific publisher in the world, to develop a rapid communication in the field of substance abuse. I chose Ernie Noble as my co-editor-in-chief and the Journal of Substance and Alcohol Actions & Misuse was born. We enticed a very large board of editors and attracted a number of outstanding papers. It was honored during the five years we were editors by being indexed in National Library of Congress (PUBMED etc).
I was still focused on proving the relevance of the proposed "Genotype Theory." Importantly, we found that when Golden Syrian Hamsters (love alcohol) chronically drink alcohol for a one-year period, which equates to 20 years of alcohol drinking in humans, the brain shuts off the synthesis of endorphins bringing about a deficiency and an impairment of the brain reward cascade.27 This was confirmed for morphine as well at the Max Planck Institute in Germany .28 The results of the two articles furthered the notion of commonality between alcohol and opiates. Following the excitement of the Science paper, I was invited to Italy to present a seminar for the Italian Ministry of Health and 100 journalists in a castle in Milan. While the response by most was positive, the next morning walking across the street from the Excelsior Hotel in Rome, I found myself viewing a front page article showing my picture with the words in Italian " Strange American -Stranger Ideas!".
In the" Genotype Theory" we suggest that stress induces alcohol drinking via alterations in opioid physiology. Candice Pert's group showed that swim induced stress in rats reduces the binding characteristics of the opiate receptor suggesting a deficiency29. An experiment performed at the University of Ohio suggested that when rats are stressed (allowed to swim in ice-cold water) they drank higher amounts of alcohol, and this correlated with a reduced amount of endorphins in the brain. This initial finding has been confirmed most recently in genetically selected mice having different levels of endogenous opioids showing mice with low brain opoids after swim stress drink higher amounts of alcohol compared to high opioid system mice.30
In 1981, we began to explore ways to alter alcohol intake by manipulating the endorphin system. Understanding the basic structure of enkephalins, for example, led to the finding that an D- amino-acid such as D-phenylalanine, could block the subsequent breakdown of the amino-peptide sequence (enkephalin is five amino acids strung together one of which is phenylalanine), by fooling the cell's response to an enzyme called Carboxypeptidase A (enkephalinase). The D-form has a higher binding constant and as such acts like a sponge holding the enzyme at bay instead of allowing it to destroy the natural enkephalin.31, 32 At that time we found that if we injected D-phenylalanine, we could virtually wipe out craving for alcohol in rats that loved it. It was one of the first pharmacogenetic engineering experiments performed in the field, converting an animal genetically prone to love alcohol to one that hates alcohol.33 I presented the idea to the University committee on patents, and after waiting 6 months being turned down for submission of the patent, I received the legal assignment for this discovery. This resulted in a 1987 Supreme Court appeals decision to award me the first patent on an amino-acid for the treatment of drug and alcohol abuse.
Leaving my secure tenure position, I struggled with a public based penny stock company located in Denver, for about 6 months. Fortunately I was able to return to my secure tenure position after my 6-month trial failed, sending people to jail for stock fraud, vowing never to commercialize again. This thought only lasted for two years. In 1984, I was approached by a small number of people in Houston to develop a small biotech company based on the anti-drug abuse discovery. The company was called Matrix and by 1988 we had contracts to utilize our amino-acid precursor-enkephalinase inhibition therapeutic nutraceutical with over 1000 treatment clinics in the United States and Mexico.
During that period, a number of researchers found that drug craving was linked to abnormalities found in the neurotransmitter system of the brain. The substances that were primarily involved included serotonin, the endorphins, the inhibitory substance GABA, and dopamine. My goal at that time was to develop a nutritional supplement that would restore the balance in the brain of humans who were addicted to alcohol or who had a vulnerability to craving behavior. We believed that the key to overcoming craving could be found in the brain and probably had to do with an endorphin deficiency.
In the early 80's I received a frantic call from someone I didn't know at the time would become my lifelong friend, and collaborator on a number of books and popular magazine armchair articles. Answering the phone James Payne told me about his desperation to save his marriage as well as Marjorie his wife from the devastation of alcoholism. "Dr. Blum I read about your work and I am wondering if you could help her -I would be indebted to you for the rest of my life" With some trepidation, I stated that I was working on an amino-acid formula with one other male person and I could try. After visiting with Marjorie and providing a formula, I received a second call from Payne -"Dr. Blum It's gone -it's gone after five days" I then asked "What's gone? " Jim full of emotion and weeping -" Marjorie woke up in bed and said -"My cravings are gone!" Although it is not always as simple as that, this was truly unprecedented and encouraging news.
From 1984-1988, research on a number of nutritional supplements were developed to assist patients in their attempt to achieve high-quality recovery; not the typical "white knuckle " sobriety frequently observed following treatment. By the way, the term "white knuckle" sobriety refers to the fact that staying sober is an extreme challenge that requires a white knuckle grip on responsible behavior to prevent 'falling off the wagon.' Starting this work in 1981 with just one male and one female, I spent the next seven years carrying out clinical trials with a number of colleagues including Ken Roy, Susanne Tarleton, Michael Trachtenberg, John Ramsey, Thomas J. Payte, John Newmeyer, David Smith, Eric Braverman, and others throughout the United States, to determine the efficacy of nutritional supplements not only for alcoholism but also for cocaine craving and carbohydrate bingeing. I believe this was the first attempt to utilize amino-acid therapy in conjunction with a substance that had enkephalinase inhibitory properties. This was indeed the birth of "Neuro-Nutrient Therapy" in the reward dependence field. I was very proud of this accomplishment, knowing that my work was actually translated from the "bench to the bedside". Then in 1989, the FDA decided to remove L-tryptophan from their marketplace erroneously suggesting that it caused eosinophilia-myalgia syndrome (EMS). This significantly affected confidence in the use of amino-acids for treatment for craving during withdrawal. Later l-tryptophan was shown to be safe.34 Meanwhile, in spite of being the first to replace l-tryptophan with the trace metal Chromium Picolinate as a brain tryptophan enhancer, the belief in neuro-nutrient therapy diminished.35 However, the work did not stop. Chromium picolinate was found to increase the sensitivity of the 5HT2a receptor requiring less serotonin for an effect. My associates and I published a number of studies on the clinical benefits of the Nutraceuticals for the adjunctive treatment of alcoholism (SAAVE),36 psychostimulant abuse (TROPAMINE),37 and carbohydrate bingeing behavior [PHENCAL].38
One afternoon in 1987, taking my friend and neuroanatomist, Gerald Kozlowski, to the airport, while sipping water and indulging in Hagen-Dazs ice cream, together we drew out on a napkin what was to become the "Brain Reward Cascade,'"39 which was based on our current knowledge of reward dependence.40 Publishing this in 1990, we believed it brought together the understanding of how a number of chemicals could interact in the brain and ultimately lead to dopamine release and the reward of the "feel good response".
Fortunately, meeting the young enthusiastic student of Carl Pfiefer, Eric R. Braverman, MD in 1987 in Princeton, led to not only a life-long friendship but also a plethora of important peer-reviewed published research papers on the electrophysiology of brain health and aging and the development of the PATH Foundation NY.
One summer afternoon in 1988, I found myself in the Medical Library of the University of Texas reading with interest a study by Joan Egeland using a relatively new genetic technique called RFLP (restriction length polymorphisms) and finding that the tyrosine hydroxylase gene was associated with depression in an Amish population. Not fully understanding the ramifications of this technique, I immediately felt a wave of excitement so strong that I began jumping, running toward the doors shouting "that's it!, that's it!"...with everyone looking at me as if I was crazy. Filled with excitement, I was racing to see Peter Sheridan, a molecular biologist who understood the world of genes. Calmly Sheridan explained the importance of RFLP, showing a recent article on the subject in Scientific American. Over the next three months, I became engrossed in journal articles, books, and ...
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Dr. Blum and Dr. Waite advocated a non-specific "healthy diet" and non-specific regular exercise to accompany a regimen of taking Synaptose
TM
, the nutrigenomic neuroadaptogen they developed based on Dr. Blum's many years of research to increase the endogenous production of Dopamine and reduce negative Reward Deficiency Syndrome behaviors. The scientific evidence they have thus far accumulated, they say, demonstrates that Synaptose
TM
changes the plasticity of the brain synapses while balancing the endogenous neurotransmitters, positively affecting the Brain Reward Cascade.
