Rebalancing the Meso-Limbic Reward Center:
A Bridge to the Enhancement of Synaptic Splendor and Legal Rehabilitation
Kenneth Blum, Ph.D., Judith Miller, Ph.D., and Steve Sewell, CACIII

Abstract

In this article we explore a number of important issues related to achieving a better quality of life after drug (s) and alcohol abuse. It is our opinion, that recovery from chemical dependency requires more than the "just say no" philosophy. The psychological training. the formal or experiential, that counselors and recovering mentors receive to prepare them for work in treatment and rehabilitation centers. focuses on helping the patient develop refusal skills. utilize grief and loss, improve skills and build a stronger self-image. It is quite apparent that the support ofa solid social network. such as that provided by self help programs such as Alcoholics Anonymous (AA) and the Secular Organization for Sobriety (SOS), also makes the recovery process easier and reduces the chance of relapse. But we caution, even if we succeed in improving the psychological and social components. if the patient's brain chemistry is out of balance due to genetic antecedents and/or environmental factors, such as chronic substance abuse! dependence. as well as prolonged stress. recovery is difficult and relapse is a greater threat We suggest. therefore, a closer look at the "biogenetic" component of the bio-psycho­ social condition we know as chemical dependency. Through our approach of enhancing "reward" and wellbeing via neuro-nutrient healing. as a method by which additional supplies of amino-acid building blocks and herbal enzymatic regulation of neurotransmitters are provided. enables the brain to manufacture substances that are deficient. This novel approac~ may be the key to more successful treatment and recovery programs. The era of the brain and the insights derived from the genome project, provides the basic tools to achieve the Homo sapien dream ­ THE SEARCH FOR SPLENDOR.

Introduction

During the last four decades, something profoundly exciting has been happening in the field of addiction medicine. It is increasingly clear that addiction research in a physiological condition involving neurochemical imbalances or deficiencies.

Scientists are beginning to understand the addiction process, opening up avenues of medical intervention, and treatment professionals are beginning to apply this knowledge in developing more effective treatment protocols.

With every new advance the chances of recovery improve, the recovery process becomes less stressful, and the chances of maintaining sobriety after treatment improve.

Addiction is still a "family of disorders with out a cure", but researchers are discovering the Physiological and genetic variants and irregularities that produce it. Our ability to cope with this complex behavioral condition is enhanced, better pharmacological and nutritional adjuncts to therapy are being developed, and our hope for the future is stronger.

Brain Chemistry: Our Neurotransmitters and the Limbic "Reward Site"

Since the sixties, scientific investigation focused on the neurobiological mechanisms underlying the addictive process. However, from our stand point the most germane work in the field of "ADDICTION MEDICINE" has to do with an even more profound concept. The so called "Pleasure Principle". In this concept the animal is driven by three important visceral elements:

HUNGER, THIRST, AND SEX

These are all natural drives and under "normal" physiological conditions are sought after in a moderate way having little impact on social functioning. However, if deprived by either the environment or by an inability to perceive the powerful benefits of reward or "Pleasure" physiology via genetic antecedents, the animal is uncontrollably driven to seek out any substance or behavior which will induce a pleasurable state or well-being. In fact, as we approach the twilight years, knowing that our brain chemistry is compromised by certain molocular deficits (losing brain cells specific to well­ being like endorphin and dopamine neurons and receptors as well as blood flow and brain oxygenation) our goal is to achieve neurochemical re-balancing so that once again the "spark of life" os rediscovered even in elders. It is our hope that through biogenetic research, specifically geared toward understanding our limbic system, we may be able to find a solution to this quest for "SPLENDOR".
MAYBE WE ALREADY FOUND IT!

Neurotransmitters

The brain is a community of cells that communicate with each other by means of special chemical messengers called neurotransmitters.

These neurotransmitters are either excitatory or inhibitory. Each cell receives its instructions through nerve processes called dendrites and it passes on instructions to the next cell through its axon. The gap between the axon of one cell and the dendrite of the next is called synapse.

Special molecules in the dendrite are called receptors. They are shaped to receive only one type of neurotransmitter, which fits into it like a key in a lock. The result is that if an excitatory neurotransmitter reaches the specific receptor, the cell tends to fire. If an inhibitory neurotransmitter reaches the receptor, the cell does not fire.

If neurotransmitters of either type are in short supply, or if they are blocked from reaching their proper receptors, (as a result of either genetics and/or over drug use) cell function tends to be abnormal. The lack of neurotransmitter function, then results in the aberrant control of behavior.

The neurotransmitters are manufactured from amino acids in the cell, and the supply is controlled by substances called enzymes that have the capacity to destroy neurotransmitters, such as "enkehalinases" (controls enkephalin supply) and catecholamine-o-methyl-transferase (controls serotonin and dopamine supply in the synapse). In the normal brain, enzymes keep the supply if neurotransmitters in balance with the demand for normal cell stimulation. If these regulatory enzymes are over supplied, neurotransmitter deficiencies may result.

Reward Areas

The process of addiction seems to develop in specialized sectors of the brain called "reward areas". Here, incredibly, scientist found that there are receptors that are shaped to receive molecules that could by opiate or opiate-like substances. This discovery shook the research establisment. There seemed no logical explanation other than the unbelievable one: that the brain utilizes opiates! Confusion was compounded when molecules were found in mammalian brains that are close cousins of morphine. In fact, they were immediately named opioids, or opiate-like substances.

These substances, called endorphins, demonstrated the ability to act on opiate receptors in the reward areas of the brain to suppress pain or reinforce pleasure. If they were present in adequate concentrations, the experimental animals had a high tolerance for pain and were able to perceive pleasure states.

There was growing evidence that alcohol metabolism in the body produces other substances that also behave in an opiate-like manner: Tetrahydroisoquinolines, or TIQ's. These substances, too, were shown to act on opiate receptors in the reward areas to reduce pain or enhance pleasure.

These findings were controversial, but appeared to create a bridge between drugs and alcohol and opened the possibility that all addictions had a common underlying mechanism.

As investigations into these mechanisms progresses, it became clear that problems of addiction center around imbalances of neurotransmitters.

The behavior of an organism, especially as it relates to the three simple drives, thirst, hunger, sex, (when all are intact it equates to splendor or pleasure) becomes distorted is complex and destructive ways in the following ubstances: if the stimulatory messengers are in short supply; or there is an inadequate number of receptors; or blocked at the receptor site; if inhibitory messengers are oversupplied; if regulatory enzymes destroy neurotransmitters before they can cross the synapse to reach the receptors.

Over the last 40 years scientifists discovered many neurotransmitters in the brain. In fact there may be hundreds. Fortuitously, scientists now agree that five neurotransmitters pathways are involved as agents in changing cell function in the reward area and subsequent behavior. They are serotonergic (serotonin), opioidergic (enkephalins, dynorphins and endorphins), catecholaminergic (dopamine and norepinephrine), GABAergic (GABA) and cholinergic (acetycholine).

The basic work in this area was somewhat disappointing, however, in that use of individual agents to modify the action of individual neurotransmitters produced inconsistent outcome results in terms of treatment.

A word of caution was stated in 1977 by KB in ALCOHOL AND OPIATES. a book on neurochemical and behavioral mechanisms. Speaking of work on the biochemical link between opiates and ethanol, it read:

"caution must be used in interpreting these results because of the complex interrelationships among various neural elements and their respective neurotransmitters. Thus, while a particular agent is considered to affect only one system, and while biochemically that may indeed be true, the loss or increase of the specific system may inhibit or excite several others. Nevertheless, studies of this nature are extremely important in unraveling the complex interrelationships that exist in the nervous system."

As work has continued, this conclusion seems to be increasingly justified.

The Brain Reward Cascade

Scientific evidence accumulated over the past three decades, backed by a growing body of clinical data, indicates that addiction to alcohol, drugs, and other abusable substances is a human condition resulting from an imbalance or deficiency of neurotransmitters acting in a cascade mode.

For a highly simplified scenario, let us review the interaction of serotonin, enkephalins, GABA, dopamine norepinephrine. It is certain that others are involved, but at the present time, we are not certain which ones, or in what specific role.

There is a cascade interaction in the reward area (Figure 1,3):

• Serotonin releases enkephlin in hypothalmus.
• Enkephalin inhibits the release of GABA in the substantia nigra.
• The inhibition of GABA permits the release of just the right amount of dopamine in both the nucleus accumbens (final reward site) and the hippocampus.
• Norepinephine acts in the hippocampus to reinforce and enhance feelings of well-being.

In the cascade, the interaction of serotonin and enkephalin and the control of GABA cause a net release of dopamine and norepinephine which act as reward messengers of the brain.

When the system becomes imbalanced. There is a loss of neurochemical homeostasis, and the individual feels restless and fatigued, vulnerable to substances that cause the release of dopamine at the brain reward site, that will relieve his or her discomfort or "dis-ease". This is an unconscience biochemical self-healing approach which initially results in an attainment of pleasure states or euphoria and following chronic abuse induces dysphoria.

To reiterate, these neurochemical deficiencies which affect the reward cascade can result either from genetic anomalies, from stress, or from excessive use or abuse of addictive substances.

Early BioGenetic Clues: Understanding "Reward Behavior"

Oddly enough, it was the special breed of laboratory mice that opened new avenues of research. These eventually led to our present understanding of the actual physiological basis of the addictive process.

Jorge Mardones, director of the Institute for Alcoholism Research at the University of Chile, and the late Roger Williams, former director of the Clayton Foundation at the University of Texas at Austin, probably were the first to notice that some strains of rats or mice show a preference for alcohol over water.

This finding was confirmed by Leonora Mirone, head of the food and nutrition department at the University of Georgia, who found that black mouse strain C57 shows a pronounced preference for alcohol. In other words, they are alcoholic mice.

Gerald Mclearn, in the department of Psychology at the University of California at Berkeley, investigated this preference and found that the memebers of the C57 strain of mice are genetically predisposed to prefer alcohol over water, and that they breed true. It was recognized that these mice, properly used in experiments, could become a powerful tool for research into the causes of alcoholism. The past thirty years, have yielded 1000's of papers which refer to the use of these and other animal models of not only alcoholism but numerous addictive pyschoactive drugs such as opiates and stimulants. It is well established that for example the Lewis rat strain, has a genetic hypodopaminrgic deficit in the "brain reward site" that predisposes these rats to self-administer a number of drugs including alcohol, morphine, cocaine, THC (marijuana), nicotine and glucose. Probably, if tested they would also show a high proclivity toward gambling behavior and sex addiction. In other words, these animals are polysubstance abusers, not too dissimiliar from their human counterpart.

"Reward Deficiency Syndrome": Etiology

In a highly condensed form, this article presents the summary of our present scientific view and an approach to enhancing the recovery process. We know from the scientific literature that any type of behavior (phenotype) is determined by the interaction of our genes (G) and environment (E) or simply: P=G+E.

In this regard, based on animal and human studies, we know that genetic predisposition and stress causes addiction. Moreover, forced intake or excessive intake of the potentially addictive substance over time can also be a cause of addiction independent of the genetics.

Along these lines the work of Kenneth Blum, Ph.D. along with Ernest P. Noble, former director of the National Institute of Alcohol Abuse and Alcoholism (NIAAA) now at UCLA, with their colleagues have been credited with finding the first gene associated with severe alcoholism in humans. The work published in the prestigious JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (JAMA) referred to a gene, better known as the dopamine D2 receptor gene (DRD2). This was first found in 1990, and became a topic of great controversy. However, a credit to their perseverance, their work has been now confirmed by numerous scientists throughout the world and suggests that this gene may be a "reward gene" and carriers of one form of this gene (DRD2a1 not the a2 form) may have genetic antecedent to a predisposition to poly-substance seeking behavior. The current work also suggests that many other gene variants are involved in the genetics of a syndrome coined by Kenneth Blum- "Reward Deficiency Syndrome (RDS)" which links our genes to multiple addictions including but not limited to alcohol, heroin, cocaine, marijuana, nicotine, glucose, gambling, sex, violence, and even to attention deficit hyperactivity disorder (Figure2). Thus, the book subtitle-ADDICTION IS FOR THE B.R.D.S.(Blum's Reward Deficiency Syndrome): The Pleasure Genes.

Neural Basis Of Addiction

For the first time in over a decade, some neuroscientists are experiencing what amounts to a natural high. In 1996, for the first time, they have captured images of the brains of addicts in the throes of craving for a drug revealing the neural basis for addiction. In support of our earlier thinking, work in a number of laboratories here and abroad have come to the conclusion that, no matter what the addictive substance is-amphetamines, cocaine, heroin, alcohol, nicotine, or glucose-- all seem to activate a single circuit for pleasure deep in the most ancient part of the brain. This circuit, as mentioned earlier, involves the neurotransmitter dopamine, is the site of the high that addictive drugs bring.

In the event a person carries the A 1 allele of the dopamine D2 receptor gene, whereby there is a reduced expression ofD2 receptor density (identified in a number of experiments in humans using imaging techniques such as PET scans), craving for substances of abuse increase. Fine grained studies of brain cells reveal that repeatedly dosing the brain with addictive drugs is akin to a chemical assault that alters the very structure of the neurons in the circuitry for pleasure. These changes starve brain cells of dopamine, triggering a craving for more of the addictive drugs that will once again swamp the brain with it.

In fact a number of PET scan studies reveal that when people are in a profound state of craving for cocaine or alcohol, primed to seek it out and take it, the mesolimbic dopamine system shows heightened metabolic activity. When there is intense craving the dopamine system is also activated. As a reminder, the nucleus accumbens, the ultimate source of dopamine, is the same brain region where psychologists stuck electrodes decades earlier to make rats endlessly stimulate themselves for pleasure.

Other work by Eric Nestler, a neuroscientist at Yale, found that the neurons with D2 dopamine receptors had become 25 percent smaller and had lost much of their ability to receive dopamine from nearby neurons. According to Nestler:

"When you take a drug like cocaine, it floods the neurons with levels of dopamine never seen in nature ... the addictive drugs have an impact on the dopamine ciruitry like a sledgehammer, storming through this pathway with an intensity that never occurs ordinarily. Taking drugs over and over perturbs these systems, and then try to adapt by making the dopamine less effective. "

Further support for these cellular dopaminergic changes, which seem to be the neural engine driving the craving for more of any drug, comeS from the most recent work of Nora V olkow, Director of the Division of Nuclear Medicine at Brookeheaven National Laboratory. Utilizing, a special piece of DNA called a cDNA construct of the dopamine D2 receptor gene implanted into the nucleus accumbens of rats, Vollows group found that following a four-day treatment, the dopamine D2 receptors increased to 150 percent above the pretreatment level and alcohol drinking was reduced by 50 percent. After a period of eight days, the D2 receptor density returned to pretreatment level and so did alcohol drinking. Twenty-four days later, second injections of the same construct caused a similar increase in receptor density with a two-fold decrease in drinking.

Interestingly, very recently, Alan Leshner, Director of the National Institute on Drug Abuse emphatically stated:

"The research to date suggests a common biological essence to all addictions .... though I don't think we'll ever have a single magic bullet. We might instead one day have neurochemical cocktails that are specific to each addictive drug that would break the cycle of craving. "

If addiction means the brain has changed and, it is vulnerable at birth, then the task is to change the brain back to some so called societal accepted brain form which is free of addiction proneness. In order to achieve this goal we must utilize both biological and behavioral modalities.

Nutritional Adiuncts

While we have simple techniques to obtain non-invasive samples of human DNA via buccall swabs for genotyping, until this is done on a regular basis as part of the treatment protocol, it is not possible to determine the precise defect that is causing as addiction; however, nutritional adjuncts are coming into use that are proving via clinical data beneficial in both treatment and during recovery.

To offset neurotransmitter imbalances that interfere with the cascade and cause compulsive and addictive behavior we call "reward deficiency syndrome", experimentation was begun by Kenneth Blum with amino acid loading techniques and enzyme inhibition at the University of Texas system as early as 1978.

Since it became increasingly clear that problems of addiction center around imbalances of neurtransmitters, it was equally clear to utilize amino-acids as building blocks for these neurotransmitters.

It is well documented that the amino-acids, L-tryptophane or 5-hydroxytryptophane converts to serotonin; L-phenylalanine and L-tyrosine convert to dopamine and norepinephrine; and L-glutamine converts to GABA.

In addition, it had been observed that the amino acid D-phenylalanine is an inhibitor of the enzyme enkephalinse that destroys the endorphins or opioid peptides.

The trace metal Chromium, enhances the penetration of blood tryptophane through the blood brain barrier. Moreover, the Chinese herb known as Rhodiola rosea, inhibits two synaptic neurotransmitter metabolizing agents, mono amine oxidase (MAO) and catecholamine-o­ methyltransferase (COMT), thereby increasing the synaptic concentration of both serotonin and dopamine.

Over the last fifteen years a number of clinical trials have been accomplished with amino acids, chromium and herbals which show significant beneficial effects in victims of RDS. Out of this research a number of substance abuse specific formulae have been used in both inpatient and outpatient settings as adjuncts to therapy. Human support for the cascade theory of a drug seeking behavior in terms of treatment can be derived from a series of clinical trials with neuronutrients (precursor amino acid loading and enkephalinase inhibition), as described above, indicating reduced alcohol craving, reduced stress, facilitated recovery, reduce AMA rates, reduced relapse rates, weight loss, weight regain prevention, and percent fat reduction (see Table 1). Although polydrug abuse is an increasing problem, which is predicted by the RDS concept, for simplicity we will consider, briefly, the individual substances of abuse to which the reward cascade relates.

Downers

Substances known to induce a feeling of well-being and calming of the nervous system include alcohol and opiates. Utilizing a combination of amino acids the following studies have shown very promising results.

Alcoholics

A double-blind inpatient study of alcoholics carried out in a San Antonio chemical dependency treatment hospital showed that the patients taking the amino acid formula had the following outcomes:

• Had a 50% lower building-up-to drink (BUD) score than the control group;
• Required no benzodiazephine, compared to 94% for the control group;
• Exhibited no tremors at 72 hours, compared to 96 hours for the control group;
• Experienced no depression, in contrast to 24% of the control group who experienced depression.

A double-blind, placebo-controlled study of alcoholic inpatients was conducted at the Chemical Dependency Unit of the Glenwood Regional Medical Center in West Monroe, Louisiana. It indicated that the amino acid group had the following benefits, compared to the placebo:

• Significantly reduced stress;
• Significantly improved physiological condition;
• Significantly improved psychological, social, and spiritual status.

Compared with the amino acid group, six times as many patients of the control group, failed to complete the 28-day program.

The Cambridge Institute in San Francisco ran a one-year study comparing outpatient DUI­ alcoholics who were receiving amino acid therapy with those who received vitamin B complex.

The amino acid group had a significantly lower building- up to relapse (BUR) score. The scote included such variables as drug craving, stress, depression, irritability, paranoia, anger, and anxiety.

These patients also had a significantly greater recovery score (RS), which included such variables as energy, self-confidence, and feeling of well-being.

The relapse rate for the amino acid group was 15%, compared to 50% for the control group.

Opiates

In an unpublished open clinical trial at the Drug Dependence Associates in San Antonio, outpatient opiate abusers who had been previously detoxified by methadone were divided into two groups.

One group received the narcotic antagonist naltrexone plus amino acids; the control group received naltrexone alone. It was found that those subjects consistently using the amino acids remained abstinent for an average of 17 days, compared to 37 days for the control group.

Uppers

Substances that induce a heightened awareness, enhanced energy and intense sense of well-being are classified as uppers or pyschostimulants. Members of this group consist of amphetamines, phenylethanolamine, ephedrine, and cocaine.

Stimulant Abusers

At the Chemical Dependency Unit ofChater Forest Hospital, Shreveport, Louisiana, a 30 day open clinical trial was conducted on inpatient, serious stimulant abusers, including cocaine abusers.

It was found that those patients using the amino acids had a drug hunger score 50% lower than the control group and a dropout rate of only 4.6%, compared to the 37% for the control group.

The Cambridge Institute in San Francisco, conducted over a one year open clinical trial of outpatient cocaine abusers who were either receiving amino acids plus vitamin B complex or vitamin B complex alone.

It was found that the amino acid group had a significantly lower BUR score than the control group. The amino acid group had a greater recovery score and a relapse rate of less than 25%, compared to 90% for the control group.

Carbohydrate Bio2ers

An open trail of outpatient carbohydrate bingers enrolled in a weight-control program at Bariatic Medical Clinic, West Monroe, Louisiana, found significant differences in two groups of patients.

The patients who took the amino acid formula for 90 days lost an average of 27 pounds and had twice the abstionence score of the control patients. Their relapse rate was 18%. The patients not taking the amino acids lost an average of ten pounds and had a relapse rate of 82%.

In another study in an outpatient Behavioral Medicine Medical Group clinic in Sacramento, at 2 years, the experimental group that took the amino acid regimen compared with control showed a twofold decrease in food cravings for females and 63% decrease for males. Most importantly, the experimental group regained only 14.7% of the" weight they lost during fasting while the control group regained 41.7% of the lost weight.

Based on this and other data, the restoration of a normal balance in the reward cascade neurotransmitter system, should result in the reduction or elimination of the craving for abusable substances and should assist professional counseling and supportive therapy from programs such as AA and SOS.

One very important aspect is the recent study by Y.A. Boundy and Associates of the University of Pennsylvania, who found that in kidney cells, dopamine agonist occupation of dopamine D2 receptors induce a significant proliferation of dopamine D2receptors. This suggests that slow dopamine release should lead to dopamine D2 receptor proliferation. We further suggest that amino acid loading with enkephalinase, monoamine oxidase and COMT inhibition leads to a slow release of dopamine at reward sites. This ultimately leads to proliferation of dopamine D2 receptors thereby reducing aberrant craving behavior due to carrying the dopamine D2 receptor Al form of the gene. Unfortunately, carriers of the D2AI gene form will need to by on the amino acid formulation for life to maintain higher numbers of the D2 receptors.

The RD-System

Currently we have developed a nutritional system of a number of products with specific formulae dependent on the type of substance abused. The core product is called "REWARD". To date there ~e four "REWARD" products: reward I =downers; reward 2=uppers; reward 3=tobacco; and reward 4=weight.

The RD-system consists of oral tablets which utilize a special phase control time release for slow dopamine release and a specific anti-craving fast acting sublinguallipoceutical spray for immediate effects. We believe that these products in conjunction with group therapy, counseling and other modalities (chiropractic, auricular therapy, neurofeedback) should give all of us involved in the diagnosis prevention, treatment and recovery ofRDS victims, hope for the future.

Summary

Scientists have now concluded that compulsive craving for ALCOHOL AND/OR DRUGS in most instances has a genetic origin that is triggered by environment: stress or long, excessive use of abusable substances.

The mechanism appears to be irregularities in the brain's neurotransmitters, the messenger substances that regulate behavior. Addiction occurs when there is an imbalance that affects neurons in the brain's reward areas.

The authors present the Cascade Theory of neurotransmitters function, suggesting that these substances and their enzymes act in cascade fashion -a kind of chain reaction-to produce feelings of well-being.

If the cascade becomes imbalanced, having low dopamine D2 receptors due to the carrying of the DRD2AI allele (genetic antecedent to predict a RDS candidate), craving and addiction develop. Since neurotransmitters are made of amino acids, the nutritional factor takes on great significance.

"Amino acid loading" is mentioned as a method by which additional supplies of amino acid building blocks are provided, enabling the brain to manufacture substances (like dopamine) and receptors that are deficient.

We contend that through the revitalization of the reward site, those of us who are victims of our own genetic legacy may someday be free of addiction and pain and once again achieve pleasure states, allowing us to focus on individualized positive attributes. When that day occurs we could honestly say that our quest as a Homo-sapien has been truly achieved and thus the search for splendor has ended As bold as this seems, it is at least a dream worth dreaming.


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