THE SEARCH FOR DRUGS TO BREAK THE CYCLE OF DRUG ADDICTION

Like asthma and high blood pressure, drug addiction is a chronic disease and should be treated as such. That's the opinion held by a growing number of researchers. Detox is not enough, they say. Counseling may not suffice, either. Even after getting the drug out of their systems and receiving behavioral therapies, many recovering drug addicts may forever need a medication to help them fend off relapse.

The problem is, for addictions to most illicit drugs, such medications don't exist. And large pharmaceutical companies have shown little interest in developing medications that aren't likely to be profitable and may carry a stigma for the maker.

The National Institute on Drug Abuse has several research programs under way to test medications developed for other conditions -- including Parkinson's disease and depression -- on drug addiction. Other researchers, with grants from the institute, from the Office of National Drug Control Policy (better known as the drug czar's office), or from small biotechnology companies, are taking a different tack: They are trying to develop pharmaceuticals designed specifically to treat addictions.

Although effective medicines exist for heroin addiction, "we don't have anything for PCP or methamphetamine or cocaine," says Frank J. Vocci, director of the division of treatment research and development at the drug-abuse institute. Most of the current research is focused on cocaine because of the size of the societal problem and, some scientists say, the tractability of the cocaine molecule.

One strategy is to develop a medicine that acts as a substitute for an addictive drug, the way methadone works for heroin addicts. Methadone interacts with the receptors for heroin in the brain, satisfying cravings for the drug, but doing so more slowly than heroin itself, and producing less of a high and no crash as the medication wears off. A newer heroin substitute, LAMM (levo-alpha acetyl methadyl), is based on the same principles.

However, users of methadone and LAMM tend to become addicted to them, too. Another medication for heroin users, buprenorphine, is less likely to cause addiction. Mr. Vocci says it will probably be approved by the U.S. Food and Drug Administration this year.

Recently, researchers have developed potential substitutes for cocaine. F. Ivy Carroll, a medicinal chemist at North Carolina's Research Triangle Institute, an independent, nonprofit organization, has created compounds with a chemical structure similar to cocaine's. Michael J. Kuhar, a professor of neuropharmacology at Emory University, has tested those compounds in addicted rats and monkeys and found that the animals stop taking the drug. The new compounds work in much the same way cocaine does in the brain, he says, but "they are less toxic than cocaine, and they are longer-lasting." Mr. Kuhar thinks that humans who take them will experience less of a high than from cocaine.

"We think they have a lot of potential," says Barbara S. Fox, president of Addiction Therapies Inc., a start-up biotechnology company in the Boston area. "They should act to reduce the craving for the substances." She hopes to test the cocaine analogues on humans in 2002.

An alternative to finding substitutes for addictive drugs is to immunize against them, an approach that is drawing a lot of attention. The idea is that if immunized addicts were to give in to their craving, the antibodies in their bloodstream would latch onto the drug and prevent it from entering the brain.

Kim D. Janda, a professor of chemistry at the Scripps Research Institute, has developed both passive and active immunization approaches. In the active approach, addicts would receive a vaccine inducing their immune systems to create antibodies against cocaine. Immune systems don't naturally do that, because the cocaine molecule is too small. So Mr. Janda affixed a protein to a cocaine-like molecule. "It's like painting a bull's-eye on it," he explains. "The immune system says it's foreign and makes antibodies to it." Those antibodies then are ready to bind to cocaine itself.

Passive immunization involves giving a patient a large dose of antibodies against cocaine that have been generated by a mouse's immune system. The antibodies would be restructured so that the human body would not recognize them as foreign.

Mr. Janda has found that a combination of his two treatments prevents relapse in addicted rats. He is working with a small biotech company, Drug-Abuse Sciences Inc., in Menlo Park, Calif., to bring his medications to the clinic.

One vaccine has already made it to clinical trials. Thomas R. Kosten, a professor of psychiatry at Yale University, has found an active immunization strategy to be safe in tests on 34 cocaine addicts. Now he plans to test it in larger trials, to determine the vaccine's appropriate dose and efficacy.

Another immunization project is dedicated to treating addiction to phencyclidine, otherwise known as PCP or angel dust, a drug that dulls pain and can cause schizophrenic behavior. "It's a lot more dangerous than cocaine. It's extremely toxic," says S. Michael Owens, a professor of pharmacology and toxicology at the University of Arkansas for Medical Sciences.

Like Mr. Janda, Mr. Owens has created purified antibodies from mice that, when given to PCP-addicted rats, make them uninterested in the drug. He is working on the same strategy for methamphetamine addiction.

Some scientists have found fault with both the drug-substitute and the drug-vaccination strategies. In either case, they point out, a high dose of the illicit drug could overwhelm the treatment, by trumping the substitute in the competition for brain receptors, or by exceeding the capacity of the antibodies in the bloodstream.

Mr. Kuhar, of Emory, acknowledges the problem among unmotivated patients. "It's just like a guy who's got high cholesterol and is on a cholesterol-lowering drug. If he eats enough cake and pizza, he will obviate the effect of the drug."

New results from Mr. Owens, meanwhile, suggest that the criticism may be less pertinent to the immunization strategy. In the March issue of The Journal of Pharmacology and Experimental Therapeutics, he reported that among rats given a single dose of his medication and then continuously given PCP, concentrations of the illicit drug in the brain were far lower than in other organs. Despite being greatly outnumbered by the PCP molecules, the antibodies seemed to protect the brain. He isn't sure how they kept the concentration so low.

Yet another approach avoids that concern altogether. Donald W. Landry, an associate professor of medicine at Columbia University, has created an antibody that is also an enzyme. That is, it breaks down a molecule of cocaine, ejects the now-harmless fragments and starts over with another molecule. "When you break an easy bond on cocaine, you get products that are neither toxic nor reinforcing," he says.

Like the other new medications, his molecule makes rats uninterested in cocaine. It has attracted interest from a biotechnology company, MedImmune Inc., in Gaithersburg, Md. Dr. Landry is fine-tuning the enzyme to try to get it to break cocaine down more quickly.

Despite positive experimental results, however, most experts aren't expecting any panacea against cocaine addiction. "There's probably been at least 50 different drugs that have been tested," says Charles P. O'Brien, a professor of psychiatry at the University of Pennsylvania. "So far, nothing has been consistently successful." He suspects that cocaine's complex interactions with the brain will require a combination of medications.

Mr. Vocci, of the National Institute on Drug Abuse, agrees. Even though many medications seem promising, he says, "I don't think that we've got anything that looks like it's robust beyond belief." Still, he holds out hope for the future. The key, he says, is a better understanding of how addiction works in the brain. "Then I think we'll move further along."