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National Institute on Drug Abuse -  NIDA NOTES
Director's Column
Volume 10, Number 5
September/October 1995

Progress and Potential Mark NIDA's Search for a Cocaine Treatment Medication

By Dr. Alan I. Leshner, NIDA Director

I believe this country's single most important need in the fight against drug abuse and addiction is a cocaine dependence treatment agent. Currently, we have no such medication. To address this critical lack in our means to treat drug abuse, NIDA has made the development of a medication to treat cocaine abuse and dependence the Institute's number one priority.

Our sense of urgency is prompted by the fact that cocaine abuse and dependence affect all segments of our society with devastating personal, social, and public health consequences. National surveys indicate that more than 23 million Americans have used cocaine at some time in their lives and an estimated 1.4 million Americans are current cocaine users. Cocaine use is associated with potentially life-threatening cardiovascular and pulmonary effects; possible damage to the health and development of infants born to women who abuse cocaine while they are pregnant; sex-for-crack exchanges that are spreading the AIDS virus among both drug-abusing and non-drug-abusing populations; and violence and neighborhood disintegration related to the cocaine marketplace.

In the last few years, NIDA's intramural and extramural researchers have greatly increased our knowledge about where and how cocaine works in the brain and what the acute and long-term effects of those actions are. At the same time, our Medications Development Division has standardized the process of identifying and assessing potential cocaine treatment compounds and established an outcomes-based structure to decide whether or not to proceed with the development of tested compounds. The progress we have made in building scientific knowledge about cocaine and about how to conduct and evaluate clinical trials of proposed treatment agents has now brought us to the point where the development of effective cocaine treatment medications has become not only conceivable, but achievable.

To make the best use of our resources, we are now working to integrate the relevant research from the Institute's intramural and extramural divisions into the efforts of our medications development program, under the direction of Dr. Charles Grudzinskas, to develop a cocaine treatment medication. We are also working cooperatively with private pharmaceutical firms to obtain promising proprietary compounds for testing and development as cocaine treatment medications, with the Department of Veterans Affairs to expand our clinical trials capabilities by creating clinical trials sites of excellence, and with the Food and Drug Administration to speed the medications approval process.

Our ultimate goal is to develop integrated treatment
approaches combining cocaine treatment medications
and behavioral interventions.

Because of our basic research findings about the neurobiology of cocaine addiction, our search for treatment medications has focused on the brain's dopamine system through which we believe cocaine produces its primary rewarding and reinforcing effects. However, we know that cocaine also interacts with two other neurotransmitters, serotonin and norepinephrine, which undoubtedly also play a role in modulating the drug's effects. In addition, recent work by NIDA's intramural and extramural researchers indicates that a number of opiate receptors may also be involved in mediating cocaine's effects.

Nearly 4 years ago, we achieved a significant milestone when intramural and extramural teams of NIDA researchers first cloned the gene for the dopamine transporter, thought to be the primary site of cocaine's action in the brain. Cocaine blocks the transporter from removing dopamine from the space between neurons, initiating a cascade of molecular events that produces euphoria. Other researchers have cloned five dopamine receptors and a number of serotonin receptors. These sites all represent potential molecular targets for medications to either block or attenuate cocaine's effects. In fact, NIDA researchers are currently working on promising experimental treatment compounds, based on new knowledge about the role specific dopamine receptors play in cocaine dependence. (See NIDA-Supported Scientists Identify Receptor Associated with Cocaine Abuse)

This year, we took another significant step. By manipulating the structure of the dopamine transporter, Dr. George Uhl, who serves as chief of NIDA's Molecular Neurobiology Branch and acting director of our Division of Intramural Research, has shown that we can develop a compound that will block cocaine's effects while preserving the normal functioning of the dopamine system. Although much developmental work and testing must be done before we can conduct clinical trials of such a compound, this is a tremendously encouraging advance.

While NIDA scientists continue to probe cocaine's underlying biological and behavioral mechanisms to gain a better understanding of such addiction-related phenomena as craving, relapse, and withdrawal, we are also supporting completely new approaches to the design of cocaine medications. For example, NIDA researchers are working on medications designed to neutralize the cocaine molecule directly, rather than act on the cocaine receptor in the dopamine system. (See New Strategy Would Neutralize Cocaine in the Bloodstream)

Meanwhile, NIDA's Medications Development Division has been applying the scientific advances we have made in basic research to clinical research. In the 5 short years since the Division was mandated by Congress to fill an unmet national need for addiction treatment medications, it has served as the centerpiece of a concerted Institute-wide medications development program that has:

  • launched an extensive cocaine medication discovery program in which molecular biologists and medicinal chemists are working together, using the findings from molecular research, to design and systematically test hundreds of compounds for their potential to block or attenuate cocaine's effects;

  • held a series of workshops that have helped treatment specialists become experts in conducting clinical trials of cocaine treatment medications. These workshops have also helped to standardize methods of conducting such trials and assessing their results (See NIDA Workshops Advance Clinical Trials of Cocaine Treatment Medications);

  • identified and thoroughly evaluated a range of medications already approved for treating other diseases that may offer fast-track potential as cocaine treatment agents;

  • conducted comprehensive reviews of the results of these early-stage clinical trials of proposed medications to determine whether or not they should continue to be tested;

  • established five Medications Development Research Centers across the Nation where 80 percent of the research is now directed toward finding a cocaine treatment medication; and

  • worked with the Department of Veterans Affairs to establish an extensive infrastructure of clinical trials sites of excellence that actively seeks promising clinically available compounds to treat cocaine dependence. These centers will be able to evaluate new cocaine medications that show enough promise to move into large-scale clinical efficacy trials.

At this point, we have tested many proposed treatment medications. A handful of these compounds has shown enough promise to warrant further evaluation to determine whether or not they should go forward in the development cycle. Our Medications Development Division is also planning to test compounds in small, single-site, double-blind, placebo-controlled clinical trials that will give us an indication of their potential treatment efficacy.

While building the scientific and clinical base for developing cocaine medications, we have also made considerable progress in developing nonpharmacological treatments for cocaine abuse and dependence. NIDA-supported treatment researchers have developed behavioral therapies that are showing great promise in helping diverse patient populations achieve initial abstinence from cocaine. (See Voucher System Is Effective Tool in Treating Cocaine Abuse) NIDA researchers have also developed therapeutic strategies that are helping patients who have stopped using cocaine deal with conditioned responses to stimuli that can trigger the little-understood phenomenon we call craving that often precipitates relapse to cocaine use and dependence.

Combining behavioral therapies with cocaine treatment medications would vastly increase our chances of treatment success. Therefore, our ultimate goal is to develop integrated treatment approaches combining cocaine treatment medications and behavioral interventions to address the biological, behavioral, and social aspects of cocaine addiction. By leveraging our available resources through the broad-based public-private coalition we have put together to develop a cocaine treatment medication, NIDA is working toward the day when effective behavioral therapies and pharmacotherapies will be available to help people recovering from cocaine dependence build productive lives.

From NIDA NOTES, September/October, 1995

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