COCAINE THERAPY

COCAINE THERAPY: The ‘Reward Cascade’ Link

by Kenneth Blum, Ph.D.

Michael C. Trachtenberg, Ph.D. Gerald P. Kozlowski, Ph.D.

Cocaine abuse is increasing rapidly and is seen by many as a threat to the integrity of American society. Inmost urban centers, use of “crack” is out of control, and the cocaine supply is increasing in spite of all efforts at interdiction. Cocaine addiction presents new and challenging problems to treatment personnel and places an enormous strain on treatment facilities. In addition, there is an inordinately high relapse rate following treatment. These problems underline the urgency of finding more effective means of treatment, recovery, and relapse prevention.

Research and clinical findings make it clear that cocaine addiction is one form of a compulsive disease syndrome that characterizes all chemical dependence and eating disorders. According to an early neurological model of addiction, cocaine seeking behavior results from a deficit or imbalance of neurochemicals (neurotransmitters and neuromodulators), particularly dopamine. This neurotransmitter serves as a target messenger in the limbic system of the brain, causing feelings of reward.

Under the traditional, though limited, assumption that dopamine depletion is the key to cocaine addiction, pharmacotherapies were developed using three alternate modes of dopamine substitution or restoration:

1) Substances that mimic the natural action of dopamine at its receptor sites in the reward area, such as bromocriptine mesylate or piribidi.

2) Substances that release dopamine, such as amantadine hydrochloride.

3) Substances that are used to synthesize dopamine, e.g., precursors, such as levodopa and L-tyrosine.

Under the assumption that depression is a contributory problem in cocaine addiction, monoamine oxidase inhibitors (e.g., pheneizine) or tricyclic anti-depressants (e.g., imipramine or desipramine) also were used. These drugs not only interfere with the breakdown of dopamine but reduce the breakdown of norepinephrine, a transmitter involved in depression.

FIGURE 1: A hemisection of the brain shows anatomical sites crucial to the “Reward Cascade"model. The wiring diagram of these reward cascade sites, including neurotransmitters operating at each site.

An analysis of clinical data indicates the following:

Bromocriptine reduces craving for cocaine in certain patients within minutes after administration. However, this drug has well-known side effects, including headaches, sedation, tremor, vertigo, and dry mouth. Furthermore, bromocriptine may itself create drug dependency since it has been demonstrated to be self-administered by laboratory animals.
Amantadine hydrochloride is thought to be more effective than bromocriptine and has fewer side effects. However, patients receiving this drug do experience, from time to time, such parkinsonian symptoms as muscular rigidity or impaired reflexes. The most important problem, however, is that if the patient exhibits severe dopamine depletion, the dopamine releaser does not work because there is no dopamine to release.
Levodopa by itself is less satisfactory in reducing cocaine craving than bromocriptine or amantadine. Furthermore, levodopa can produce hallucinosis as one of its side effects.

Turning to the antidepressants:

Phenelzine appears to be effective with cocaine patients in reducing sleep disturbances and depression, enhancing concentration, and augmenting energy, but requires several weeks before results are obtained. If the patient relapses during this time, the interaction between cocaine and pheneizine can cause a fatal hypertensive crisis due to adrenalin surge.
Desipramine and similar antidepressants seem to hold the greatest promise in treating depression, even though they are slow acting. They seem to ameliorate dysphoria and anhedonia during the post-cocaine crash. Other clinical results, however, raise some questions about the efficacy oftricyclic antidepressants in reducing both cocaine craving and usage.
Considering the dopamine deficit and antidepressant models together, it is clear that, although these therapies mark an advance in the treatment of cocaine abuse, we must look further if we want to develop a truly effective solution to the cocaine dilemma. We believe the answer will be found in a deeper understanding of the complex neurochemistry of the reward system.

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Based on research carried out over the last decade, we propose a “reword cascade” which depicts interactions of the several chemicals involved in the activation of dopamme in the mesolimbic area of the brain.

The reward cascade begins in the hypothalamus, which is the principal site for emotional and ingestive behavior. Under normal stimulations:

When in balance, this cascade provides homeostatic regulation of activity and inactivity. However, if a neurotransmitter or neuromodulator becomes dysfunctional, or its receptor site is nonresponsive, the homeostatic balance is upset, causing a change in feelings or behavior.

Imbalances in the reward system can arise through:

1) genetically inherited neurotransmitter defects.

2) stress resulting in neurochemical dysfunction.

3) hormonal and immune system alterations.

4) drug abuse alterations.

5) nutritional imbalances.

Genetic defects occur in brain content and receptor activity of all elements of the reward cascade in every animal model of craving. For example, serotonin is lower in alcohol-preferring rat strains than in nonpreferring rat strains, and the serotonergic receptor activity is enhanced. In alcohol- and cocaine-preferring mouse strains, methionine enkephalin is lower in the hypothalamus, and serotonergic receptor activity is higher. In addition, defects in the other neurotransmitters involved in the reward cascade have been observed in numerous animal experiments of drug-seeking behavior.

In humans, opioid peptide defects have been observed in adult children of alcoholics; enhanced serotonergic activity has been observed in alcoholics and in nondrinking adult children of alcoholics. The regulatory enzymes monoamine oxidase and adenylate cyclase, which are involved in the metabolism and functioning, respectively, of dopamine, norepinephrine, and serotonin, are known to be altered in genetic (Type Two) alcoholics.

Stress, food deprivation, and drug abuse similarly alter amounts, metabolism, and receptor responsivity of serotonin, opioid peptides, GABA, and dopamine in the reward cascade.

FIGURE 2: Synaptic vesicles (circles) typically store both primary transmitter (e.g., dopamine, norepinephrine, or Serotonin—dark dot) and a neuromodulator peptide (e.g., enkephalin—light bread slice). Primary transmitters are cleared from the synapse primarily by reuptake (arrows), though they can be destroyed by enzymes (moon shapes). In contrast, neuromodulator peptides typically are destroyed by enzymes (moon shapes filled with broken bread slice peptides). Generic receptor sites are shown as square holes in the postsynaptic cell. Synthesis-controlling feedback sites (autoreceptors) are shown on the presynantic cell as protruding triangles.Genetically dependent decrease in the number of neurotransmitter containing synaptic vesicles represents decreased availability of transmitter. Thus, fewer receptor sites are filled. The resulting decrease in neuronal activity is read by the brain as craving and distress

When cocaine is introduced into a normal reward system, the acute (shortterm) response is:

The net effect is to oversupply or flood the synapses with neurotransmitters, resulting in a euphoric state.

For a clearer understanding of cocaine’s effects, let us look first at FIGURE 2: Brain Transmitter Adequacy. Neurons are monitoring and controlling all of the body senses and organs including the brain. In response to sensory information and central nervous system processing, neuronal information is communicated by increases or decreases in the release of neurotransmitters. Under normal conditions, chemical messengers cross the synapse and enter receptor sites, where they fit like a key in a lock. In this case, there is a balance between the amount of transmitter released and the number of receptor sites filled, resulting in normal feelings of well-being. Brain Transmitter Deficiency. When insufficient amounts of neurotransmitters are produced and released, and many receptor sites are unfilled, feelings of craving and distress result. This is an abnormal condition that may result from a genetic anomaly, the effects of stress, drug abuse, or nutritional imbalances (e.g., food deprivation).

The entry of cocaine molecules into the system causes an abnormal increase of neurotransmitters at the synapse, leading to an overstimulation of the reward areas and a feeling of intense euphoria. This state may be accompanied by paranoia and hyperexcitability. With continued use, cocaine molecules further interfere with the release of neurotransmitters and block the receptor sites in the reward area. At the same time, the number of receptor sites increases, resulting in an even greater discrepancy between the amount of transmitter available and the number of receptor sites occupied. Since cocaine works by stimulating the release of neurotransmitters, and they are now in short supply, more cocaine is required to obtain a “high.” Craving remains at a high level, and the user experiences a generalized feeling of depression and unhappiness. Eventually, these symptoms become severe and terminate in the “crash,” which is characterized by intense craving, insomnia, restlessness, and anhedonia (profound depression, total absence of pleasure, and increased feelings of worthlessness).

Restoration of Neurotransmitter Deficits. Neurotransmitter deficits are restored by utilizing nutritional supplements. These promote the synthesis of neurotransmitters that are in short supply, facilitate the release of the stimulant neurotransmitter dopamine, prevent the breakdown of enkephalin, and allow natural processes to stimulate the reward sites, leading to feelings of well-being.

One promising approach to restoration of the neurotransmitter deficit involves precursor amino acids, and their production requires certain vitamins and minerals. While amino acid supplements have a long and useful history in treatment of substance abuse, the reward cascade suggests that a specific mixture of amino acids and vitamins would be even more beneficial.

One question in the use of amino acid precursors is the ability of these compounds to reach the brain from the blood. Large neutral amino acids (LNAAs), such as tryptophan, tyrosine, and phenylalanine, are transported across the blood-brain barrier (BBB) by a special carrier. The BBB normally serves to isolate, to a large degree, fluids of the brain from compounds dissolved in blood plasma. A number of circumstances can alter the action or effect of the LNAA carrier or of the BBB. Diet, stress, and drugs are three such factors.

Diet: LNAA transport to the brain is virtually in direct ratio to the concentration in the blood. Carbohydrate and protein rich diets have very different effects on blood LNAA concentrations. A carbohydrate meal increases insulin secretion. Insulin moves certain LNAAs to muscle and changes the amount of other LNAAs bound to blood proteins. Thus carbohydrates increase the amount oftryptophan, tyrosine, and phenylalanme that reach the brain. A protein rich meal has the opposite effect.

Stress breaks down the BBB. In rats, for example, stress caused by immobilization enhances BBB penetration of albumen, a substance that normally does not access the brain. Similarly, immobilization of rats resulted in decreased LNAA plasma concentrations, with brain LNAA.

Certain drugs, such as cocaine and alcohol, have been shown in animals to significantly increase the penetration of LNAAs and the neurotransmitters themselves, indicating BBB breakdown. This is seen in both acute and chronic conditions. Adrenalin, which is released by cocaine and alcohol, has been shown in humans to decrease plasma concentrations of tryptophan and tyrosine with a comparable increase in the brain.

In seeking to develop a neurochemical adjunct to cocaine therapy, we decided to combine the known deficits in the amino acids involved in the reward cascade model with the known increase in the permeability of the BBB. We also included the known vitamin and mineral deficiencies found in the cocaine abuser. Since cocaine euphoria is likely due to effects on a multiple neurotransmitter system, we decided to use a “polypharmacy” approach.

Tropamine was formulated to help restore the natural balance of neurotransmitters in the brain of individuals with a predisposition to involvement with stimulant drugs. As shown in Table I, each amino acid in Tropamine is targeted at a specific neurotransmitter involved in the reward cascade. In addition, Tropamine also contains the vitamins and minerals known to be deficient in the cocaine abuser and central to synthesis of these neurotransmitters.

In a clinical trial involving 54 inpatients in a 30-day treatment program at the Chemical Dependency Unit of Charter Forest Hospital in Shreveport, Louisiana, Tropamine significantly reduced both departure against medical advice (AMA) and drug hunger when compared with patients who had no supplement added to their treatment regimen. The AMA rate for controls was 37.5 percent; for Tropamine patients it was 4.2 percent—almost a ninefold improvement. For this study, a Drug Hunger Index was devised utilizing various behavioral observations, requests, and/or need for benzodiazepines, and threatened or actual departures AMA. Patients were rated throughout the 30-day program. Those using Tropamine were found to have significantly reduced drug hunger when compared to control groups.

Additionally, a survey of patients in an outpatient treatment program at the 14th Street Clinic in Oakland, California, following a nine month period during which Tropamine was used, revealed that the impact on client retention during the withdrawal and early recovery phases was significant.

The Cambridge Institute in San Francisco independently evaluated the efficacy of Tropamine in an outpatient setting over a 10-week period. Thirty cocaine addicted individuals (as assessed by the standard 800 Cocaine Test) were selected for this study. The patients were divided equally into a Control Group, which received only vitamin B complex and ascorbic acid (vitamin C), and an Experimental Group, which additionally received Tropamine. Significant differences were observed in self reporting; the Tropamine group had greatly reduced Building Up to Relapse Scores (e.g., drugcraving, stress, depression, irritability, paranoia, anger, and anxiety) and enhanced Recovery Scores (e.g., energy, self-confidence, feelings of wellbeing). Additionally, dropout rates (relapse), as assessed by failure to attend Cocaine Anonymous meetings at least twice a week at the institute, revealed that the Control Group (without Tropamine) had a fourfold greater relapse rate in comparison to the Experimental Group (with Tropamine). Specifically, dropout rate in the Control Group was 87 percent (13 of 15), in contrast to the Experimental Group, which had only 20 percent (3 of 15).

We believe further improvement in cocaine therapy will come through a deeper understanding of the role of neurotransmitters as they interact in the reward cascade. We believe this mechanism is fundamental to a conjoint therapy that restores biochemical balance through pharmacological intervention (antidepressants, neurotransmitter receptor stimulators or releasers), precursor amino acid loading techniques, and closer coordination between neurochemical restoration and environmental and psychosocial therapies.

*Kenneth* Blum, Ph.D., is professor of pharmacology and chief of the Division of Addictive Diseases, Laboratory of Molecular Genetics, University of Texas Health Science Center at San Antonio. He is the author of the “Handbook of Abusable Drugs” and more than 225 scientific articles. Founder and former editor of the international research journal “Alcohol and Drug Research,” he also is cofounder and consulting scientific director of the National Foundation for Addictive Diseases. Dr. Blum also serves as chief scientific affairs consultant for Matrix Technologies, Inc.
Michael C. Trachtenberg, Ph.D., is vice president for research and development at Matrix Technologies, Inc., a pharmaceutical firm specializing in addictive disorders. Previously director of Neurosurgical Research at the University of Texas Medical Branch at Galveston, director of Neurological Research at Boston University School of Medicine, and was on the faculty of Harvard Medical School and Massachusetts Gen eral Hospital. He has made important contributions in the fields of brain chemistry, physiology, and anatomy. Dr. Trachtenberg has authored more than 75 papers in professional journals. He is on the advisory board of numerous foundations dealing with addictive diseases.
Gerald P. Kozlowski, Ph.D., is an associate professor in the Department of Physiology, the University of Texas Southwestern Medical Center, Dallas. He has authored or coauthored 75 articles or chapters, and is a grantee of the National Institute of Alcohol Abuse and Alcoholism. Dr. Kozlowski is currently investigating the effects of alcohol on neuropeptides of the hypothalamus. He is a member of several professional societies including the Research Society on Alcoholism and the Society for Neuroscience.