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September 01, 2000
NIDA Director Dr. Alan I. Leshner
NIDA Director, Alan I. Leshner

Remarkable research and technological advances in the past two decades have proved that brain disruption and damage play central roles in the consequences of drug abuse and addiction. Knowing the nature of a problem, of course, opens the way for systematic attempts to fix it. Thus, today, finding ways to restore normal brain function after it has been changed by drugs is a main goal of NIDA research. (See "NIDA Pursues Many Approaches to Reversing Methamphetamine's Neurotoxic Effects") This goal involves two challenges:

  • To reverse the brain changes that underlie addiction, and
  • To roll back the loss of cognitive and motor functions that occurs when drugs damage and kill brain cells.

To approach the first challenge, NIDA gives top priority to mapping the sequence of neurobiological changes that takes place during the transition from voluntary to compulsive drug taking. Researchers have already identified some of the changes involved in two of the key phenomena associated with addiction: drug tolerance and drug craving. With respect to drug tolerance-the abuser's need for increasing amounts of drug to achieve the desired effect-we now know that drugs significantly increase the availability of dopamine, a neurotransmitter that activates the brain's pleasure circuits. When cells are exposed to repeated surges of dopamine due to chronic drug abuse, they may eventually become less responsive to dopamine signals. In recent months, researchers presented evidence pointing to a specific change in the dopamine receptor molecule that may be instrumental in this loss of responsiveness.

Finding ways to restore normal brain function after it has been changed by drugs is a main goal of NIDA research.

As for drug craving-the intense hunger that drives addicts to seek drugs despite the strong likelihood of adverse consequences-researchers have shown that it is related to widespread alterations in brain activity, but especially to changes in the nucleus accumbens area of the forebrain. An important type of craving experienced by addicts, called cue-induced craving, occurs in the presence of people, places, or things that they have previously associated with their drug taking. Brain imaging studies have shown that cue-induced craving is accompanied by heightened activity in the forebrain, the anterior cingulate, and the prefrontal cortex-key brain areas for mood and memory. A next step in understanding craving will be to learn what brain processes tie drug abusers' memories so strongly to the desire to take drugs.

Interventions will be used first to stop ongoing brain damage and repair damaged brain cells, and then to retrain the brain.

Researchers have also made a solid start toward meeting the second challenge posed by drugs' effects on the brain: the restoration of cognitive and motor capabilities lost because of drug abuse. Studies have identified specific brain changes that are likely causes of the persistent losses that are caused by many drugs of abuse. For example, they have shown that:

  • Inhalants can produce a variety of deleterious effects-including reduced vision and hearing, impaired movement, and lowered cognitive ability, sometimes to the point of dementia-by stripping the protective myelin sheath from brain fibers;
  • Cocaine causes repeated microscopic strokes in the brain, leading to dead spots in the brain's nerve circuitry;
  • Methylenedioxymethamphetamine (MDMA) damages serotonin-producing neurons, which play a direct role in regulating aggression, mood, sexual activity, sleep, and sensitivity to pain;
  • As reported on page 1, methamphetamine amplifies apoptosis-the normal process by which the brain culls defective cells-to the point where it also eliminates healthy cells.

In extreme cases, drugs can cause such severe destruction that users become severely disabled. For example, some methamphetamine abusers have developed a syndrome marked by uncontrollable tremors similar to those seen in Parkinson's disease. The method of heroin self-administration by inhalation known as "chasing the dragon" has rendered some young people nearly comatose with large brain lesions.

To counteract the drug-related brain disruptions that produce addiction and cognitive and motor problems, researchers are seeking to mobilize two important brain capacities. First, under the right circumstances, the brain can self-repair some types of damage. Second, the brain is plastic-that is, when cell losses disrupt the neural circuits that the brain has been using for a specific function, it can learn to use other circuits to perform that function. Plasticity is extremely powerful, as shown by numerous patients' recoveries from extensive cerebral injuries.

Treatments that alleviate some drug-related brain damage are already here. In fact, in recent months, researchers have demonstrated that methadone therapy ameliorates a particular biochemical abnormality in the brains of opiate abusers. The longer patients stayed in therapy, the more this aspect of their brain biochemistry approached normal. NIDA is currently supporting several similar projects that use new brain imaging techniques to evaluate the full impact of current medication and behavioral treatments on brain neurology and biochemistry. Ultimately, such imaging is likely to become an important tool for assessing patients' treatment needs, their progress in treatment, and the effectiveness of treatment approaches.

Ultimately, researchers envision a two-stage process for helping restore drug abusers' impaired abilities. Interventions will be used first to stop ongoing brain damage and repair damaged brain cells, and then to retrain the brain. The rationale for this approach is that repairing the brain first will restore lost mental resources and capacities that patients then can apply in further treatment. Both behavioral and medication treatments may prove to be effective for both stages of treatment. The first stage may benefit from medications already in use to treat neurological conditions that produce brain abnormalities similar to those associated with abuse of some drugs. For example, deprenyl (used in Parkinson's disease) and acetylcysteine (being tested in Lou Gehrig's disease) have the potential to help people with drug-related neurological damage.

The new knowledge produced by drug abuse research not only brings present goals closer, it also makes possible new and farther-reaching goals. Today we are applying our understanding of brain processes to the development of treatments that directly target the brain mechanisms of addiction and to the alleviation or reversal of drug-related brain disruption. What we learn in that effort will undoubtedly lead to even more powerful insights and strategies for reducing drug abuse and addiction and their health and social consequences.