Without fanfare, great strides are being made in developing effective medications for the treatment of addiction to stimulants " the powerfully addictive drugs such as cocaine and methamphetamine that exact a high price in personal and public health.

The same science and medications development methodologies that have proved effective in bringing new opiate treatment products to market " such as the opiate agonist levomethadyl acetate hydrochloride (LAAM) and the partial agonist buprenorphine " are being applied to the research and development of treatment for the psychostimulants.

Within the next 10 years, we at the National Institute on Drug Abuse (NIDA) believe that a number of medications will be made available for the treatment of stimulant addiction. While there are several medications approved for use in treating opiate (heroin) addiction, including the well established maintenance medication, methadone, and the newer medications such as LAAM (similar to methadone, but with longer-lasting effects) and buprenorphine, there are no FDA-approved pharmacotherapies for the treatment of cocaine and related stimulant addiction. To fill this gap, NIDA, a component of the National Institutes of Health in the U.S. Department of Health and Human Services, has given top priority to developing medications for treating cocaine and methamphetamine addiction. The development of pharmacotherapies " or drug abuse treatment medications " is based on the increasingly accepted concept that drug addictions are a chronic, relapsing brain disease, with specific neurobiological, molecular, and behavioral components.

NIDA is using a two-track process to develop the medications. The first track is the "top-down" approach which takes advantage of developmental short-cuts of screening already-marketed drug products, which are readily available and for which data from use in humans is also available. Some of the pharmaceuticals in the top-down development process are antidepressants, such as Prozac, Zoloft, and Effexor, which typically are tested in humans alone or in combination with another treatment medication candidate.

The second approach is the "bottom-up" method. It is a basic science, discovery-driven process utilizing both biochemical and behavioral studies. For example, in developing treatments for cocaine addiction, the medication development strategies build on the knowledge of how cocaine works. Cocaine blocks reabsorption of a signaling neurotransmitter called dopamine by nerve cells, or neurons, in one of the brain's key pleasure centers. The resulting buildup of dopamine in the space between nerve cells (the synaptic gap) causes continuous stimulation of receiving neurons. Scientists believe this action plays a major role in the euphoria or "high" felt by cocaine abusers and they are using this knowledge to develop medications to treat cocaine addiction.

The following sections outline these "top-down" and "bottom-up" approaches to the development of medications for the treatment of cocaine addiction.

"Top-down" approaches
There are several medications already approved that NIDA researchers are testing as possible treatments for cocaine addiction. They are outlined as follows:
Selegiline: Originally developed for treatment of Parkinson's Disease, selegiline is believed to restore depleted dopamine supplies during abstinence from cocaine. Other mechanisms may be involved because selegiline blocks cocaine euphoria in cocaine-experienced human subjects. A four-site study was completed and now a 16-site, 300-patient study using adhesive patches applied to the patient's skin is underway.

If continued safety and efficacy are shown in future trials, selegiline could become the first pharmaceutical product approved for use in the treatment of cocaine addiction. Disulfiram (Antabuse): Marketed as aversive therapy for treating alcoholism, Disulfiram also shows promise in the treatment of cocaine addiction. Three efficacy trials conducted with different populations of cocaine-addicted individuals suggest that disulfiram in combination with each of three different therapeutic interventions (cognitive behavioral treatment, 12-step facilitation, or clinical management) might be effective in treating cocaine addiction (Carroll, 2000). NIDA is planning a safety study of the interactions between disulfiram and cocaine, prior to launching a large-scale trial of this medication.

Naltrexone with relapse prevention therapy: Naltrexone, an opioid antagonist, can be effective in the treatment of alcohol and opioid addiction if compliance issues are addressed. One recent study showed there was less cocaine use over time among subjects receiving naltrexone therapy in combination with a behavioral therapy called Relapse Prevention. The results are consistent with the theory that substance use in addicted patients can be reduced by a combination of coping skills training and pharmacological treatments.

Propranolol: Propranolol hydrochloride is a beta-blocker commonly used to treat hypertension, angina, and abnormal heart rhythms. It is helpful in controlling the fast heart rate and other symptoms caused by over-activity of the thyroid gland and in reducing the palpitations, sweating, and tremors caused by severe anxiety. It also is used to prevent migraine headaches.

A clinical trial found that propranolol may improve cocaine addiction treatment outcome (Kampman, 2001). Researchers used a Cocaine Selective Severity Assessment (CSSA) scale to rate severity of withdrawal symptoms, such as anxiety, cocaine craving, depressed mood, and sleep disturbances. Although propranolol-treated subjects had lower cocaine withdrawal symptom severity, they otherwise did not differ from placebo-treated subjects in any other outcome measure, such as dropout rates. However, in a secondary, exploratory analysis, subjects with more severe cocaine withdrawal symptoms responded better to propranolol, compared to placebo. It was determined that based on results, propranolol may be most useful for the treatment of cocaine-addicted patients with severe cocaine withdrawal symptoms.

Amantadine: In addition to his work with propranolol, Dr. Kyle Kampman of the University of Pennsylvania School of Medicine is studying the potential of another approved medication, amantadine (Symmetrel), a drug used to treat Park-insonism and influenza. Yes, the flu. Amantadine is approved for use as a preventive and therapeutic agent against Type A influenza. Results of a preliminary trial of amantadine, which may alleviate cocaine's disruption of the brain's dopamine system, were promising (Kampman, 2000). Patients with severe cocaine withdrawal symptoms at the start of treatment used less cocaine during the trial than those who received a placebo.

Dr. Kampman and colleagues are now conducting a large study of the effectiveness of amantadine and propranolol individually, and in combination. The study targets those cocaine-addicted patients with severe withdrawal symptoms, as measured by the CSSA. It is believed that amantadine works by reducing dysphoria, the pervasive melancholy and restlessness that is associated with cocaine withdrawal. Researchers theorize: If amantadine can reduce dysphoria and propranolol can reduce the anxiety and the arousal associated with craving, together they may provide a winning treatment combination.

CREST Studies: Reserpine, Cabergoline, Tiagabine, and Sertraline
NIDA asked outside consultants to review data from its Clinical Research Efficacy Screening Trials (CREST) studies. Of the 23 candidate medications screened and reviewed, the experts recommended four that were worthy of continued development efforts as potential cocaine pharmacotherapies. These four are reserpine (an antihypertensive medication); cabergoline (a dopamine agonist); tiagabine (an anticonvulsant used to control some types of epileptic seizures); and sertraline (the antidepressant Zoloft, a serotonin reuptake inhibitor). A number of studies are currently underway with these medications.

"Bottom-up" approaches
Because neuroscientists now know the sites of action in the brain for all commonly abused drugs and have defined much of the underlying neurochemistry at these sites, it is now possible to search for compounds that are active at these sites. Not only can high-speed computers sift through the chemical make-up of these compounds, new compounds also can be synthesized to match a desired profile.

NIDA's Cocaine Treatment Discovery Program is developing a relapse model strategy, seeking to understand how withdrawal symptoms, mental stresses, and psychological phenomena work to compel patients in drug treatment to relapse and resume drug use, repeatedly. Medications are being tested for their ability to block cocaine "cues," (a cue-induced relapse occurs when an overwhelming urge to use cocaine is sparked by a prompt, in the patient's memory, of another person, or place, or experience related to previous drug use and its subsequent euphoria). Other drugs are tested for their ability to block or lessen stress-induced cocaine intake and cocaine "priming" (when, after abstinence, even a small dose of cocaine prompts an overwhelming urge to take larger doses). The program has been testing medications that may modulate cocaine's actions, thereby reducing its priming and other relapse-generating effects.

GBR 12909
Animal studies suggest that cocaine's blockade of the dopamine transporter plays a key role in producing cocaine's addiction and reinforcing effects. Studies show GBR 12909 (Vanoxerine) has a strong affinity for the dopamine transporter, greater than that of cocaine. Cocaine produces a huge spike of dopamine, causing a burst of euphoria, while GBR 12909, on the other hand, produces a relatively modest and long-lasting increase in dopamine, an indication that it could be used as a medication to dampen cocaine's euphoric effects (Rothman, 1989). An early trial of GBR 12909 showed promising results in modulating the dopamine transporter in ways that could undermine the effects of cocaine. A follow-up study is underway.

NS2359
Under an agreement with NIDA, a small Danish company, NeuroSearch, AD, conducted a human safety trial to determine whether NS2359 has the potential to treat cocaine addiction by increasing dopamine levels. Both GBR 12909 and NS2359 may restore the brain's neurotransmitter homeostasis (the tendency to maintain a relatively stable internal environment) and, as a result, these potential medications may help cocaine addicts overcome negative mood symptoms and loss of energy. Studies using both of these drugs are underway.

Anti-cocaine vaccine
NIDA is supporting the development of an anti-cocaine vaccine whose rights are now held by Xenova Group plc, a United Kingdom company. Pre-clinical tests show that the vaccine can block a significant percentage of cocaine from reaching the brain by preventing the cocaine from passing through the body's protective blood-brain barrier. An outpatient study of this vaccine is scheduled to begin in spring 2003.

Dopamine D1 receptor agonists
The reinforcing effects (cocaine's "high" is a reward that "teaches" users to seek more cocaine for more rewarding sensations) of cocaine are attributed to the stimulation of various types of dopamine receptors. Chemical compounds called "D1 receptor agonists" have been shown to block cocaine priming, the ability of low doses of cocaine to stimulate repetitive drug-seeking runs or binges, perhaps by preventing cocaine from disrupting the brain's normal inhibitory control of behavior. Researchers are using sophisticated computer procedures to screen vast "libraries" of chemical compounds with potential for use as D1 receptor agonists. NIDA has screened three libraries from Lexicon Pharmaceuticals containing some 65,000 compounds.

CRF antagonists
CRF is a neuropeptide that is an essential component of the brain's response to stress. The effects of withdrawal from cocaine and other drugs of abuse may be exacerbated by exposure to stressors, which have long been associated with drug relapse in humans. Recent studies have shown that stressors, as well as priming and drug associated cues, are powerful stimuli that reinstate drug-seeking behaviors in rodents, even after they spend weeks free of drugs. CRF antagonists (blockers) have been shown to be effective in blocking stress-induced drug re-use in rats, suggesting that CRF may be involved in stress-induced relapse to drug-taking in humans. NIDA is pursuing the development of a CRF antagonist so that this strategy could be tested.

Dopamine D3 partial agonist
A compound known as a dopamine D-3 receptor partial agonist is deemed by experts to have high-priority potential for development as a pharmacotherapy for cocaine addiction. It is believed that the compound may prevent relapse by suppressing the cueing phenomena said to be partially responsible for the re-use of cocaine after abstinence.
Tests in rats have found that the compound suppresses cocaine self-administration. Researchers are particularly interested in how the compound can suppress the "conditioned cueing" phenomena, in which cocaine users react to conditioned prompts, which they relate to their previous pleasures and experiences with cocaine use.

Glutamate compounds
Glutamate is a neurotransmitter associated with learning and it may modulate dopamine activity associated with reward and pleasure. Recent studies show that "knockout mice" lacking the glutamate receptor MGlu5 do not learn to administer cocaine regardless of how much or how often cocaine may be available. Perhaps the glutamate is blocking the priming response found in humans. NIDA is presently in the process of obtaining glutamate system compounds for testing as potential cocaine pharmacotherapies.

Development of medications for methamphetamine addiction
There is great concern about the recent rapid growth in use of methamphetamine, known as "speed," "meth" or "crank" and, when used in its smoked form, as "ice," "crystal," or "glass." Methamphetamine abuse and addiction appears to cause long-term changes in the human brain that are associated with impaired memory and motor coordination. Research shows that those who use methamphetamine are at risk for long-term damage to their brain cells, similar to that caused by strokes or Alzheimer's disease.

As in the case of cocaine, there are no approved pharmacotherapies for methamphetamine addiction. Any medications that are shown to be effective for cocaine addiction might or might not prove to be effective for methamphetamine or other stimulant addictions. Specific medications might be helpful at different stages of therapy. Propranolol, which has been in tests to relieve cocaine withdrawal symptoms, might also be shown to alleviate methamphetamine withdrawal.

NIDA has instituted a Methampheta-mine Treatment Discovery Program, utilizing both its laboratory and clinically based approaches. Some of the pharmacological actions of methamphetamine overlap with those of cocaine. Unlike cocaine, methamphetamine actually enters nerve cells. After entering a nerve cell, methamphetamine interacts with the vesicles where dopamine is stored and causes the dopamine to be released into the cell's cytoplasm, resulting in increased inside-the-cell dopamine concentrations. In addition, methamphetamine is very toxic, with potential to damage brain cells. It is believed that the actions of methamphetamine inside nerve cells account for its long duration of action and neurotoxic effects, which differentiate methamphetamine from cocaine.

Two FDA-approved drugs, selegiline and bupropion (Wellbutrin or Zyban, an antidepressant also used in smoking cessation therapies), are being tested for their safety and efficacy as methamphetamine medications. In an approach similar to that used for developing a cocaine vaccine, researchers are pursuing immunological approaches to methamphetamine treatment. The strategy is to develop antibodies to methamphetamine that will bind to methamphetamine in the blood stream, as opposed to blocking nerve cell receptors, thus posing no risk of disrupting normal functions within the brain.

The next big thing
NIDA will continue its commitment to finding pharmacotherapies to treat stimulant addiction. As new treatments become available, NIDA will disseminate and incorporate these important research findings into clinical practices. In the meantime, Counselor magazine readers who would like more information may wish to check NIDA's web site at www.drugabuse.gov where they will find Research Reports and other information about cocaine, methamphetamine, and other drugs of abuse. All of the material on NIDA's web site may be downloaded and reproduced without permission.

No one has commented on this article.

Please keep your comments brief and on topic, and remember that this is not a discussion thread.
Name :
Comment(s) :

J! Reactions 1.09.00 • Professional Site License
Copyright © 2006 S. A. DeCaro

---