The key to reversing the cognitive dysfunction caused by substance abuse has eluded researchers for decades. Recreational drugs mimic the brain’s natural chemical messengers, scrambling how information is sent, received, and processed. When a drug enters a user’s system, dopamine, a neurotransmitter in the brain that regulates learning, motivation, pleasure, and emotion, is overproduced, and it bombards the brain’s reward system. The resulting euphoria teaches the addict to continue to reach for the drug that produces these incredibly pleasurable feelings. To stay clean or sober, they have to unlearn what the brain has taught them to do so well.

This is where cognitive behavioral therapy (CBT), a psychotherapeutic approach to changing behavior and emotions, comes in. CBT alone is helpful for preventing some addicts from returning to drugs or alcohol. But what if it were combined with a memory-enhancing drug to speed up the process of extinguishing unhealthy behaviors?

“The drugs are aimed at improving memory for what happens in therapy. It’s an entirely new approach.”Michael W. Otto

“What’s unique about what we have been doing over the last few years is combining CBT with drugs that are not aimed at the primary condition of addiction,” says Professor of Psychology Michael W. Otto, director of the Translational Research Program at the Center for Anxiety & Related Disorders. “Instead, the drugs are aimed at improving memory for what happens in therapy. It’s an entirely new approach.”

D-cycloserine, an antibiotic used to treat tuberculosis, has shown remarkable promise in combination with exposure (also called “extinction”) therapy to deter drug-seeking behavior in rats that were trained to self-administer cocaine. Exposure therapy is a procedure involving repeated confrontation in a controlled environment with the stimuli or cues that trigger addicts to relapse.

Otto, along with colleagues Kathleen M. Kantak, director of the Laboratory of Behavioral Neuroscience, and Research Assistant Professor Bríd Á. Nic Dhonnchadha—part of a team working with rats and squirrel monkeys—published their findings in Neuropsychopharmacology in 2010.

“My research with rats mimics human drug abuse,” says Kantak. “People who use drugs recreationally self-administer drugs. They take drugs in certain environments, and there are other stimuli involved. We wanted to get at the cues that play a role in relapse.”

With a seed grant from the BU Center for Neuroscience, Kantak and Stefan G. Hofmann, director of BU’s Psychotherapy & Emotion Research Laboratory, launched a study that was the basis for the first-ever human trial using D-cycloserine with 50 problem beer drinkers. The subjects were challenged by stimuli, including handling glasses of their favorite brew and inhaling the aroma of hops but not drinking.

As an example of how cues or stimuli work, ­Hofmann cites a dog-phobic individual—a person who was bitten and is now fearful of dogs. By introducing the individual to a friendly animal in a controlled environment, the person learns a new association: not all dogs bite. In theory, drinkers could learn that they can be exposed to alcohol and not drink, and the alcohol cues would be extinguished.

The researchers postulated that D-cycloserine would enhance extinction learning in the beer drinkers the way it had in individuals struggling with anxiety disorders (Hofmann and Otto have published articles on the successful use of D-cycloserine in the treatment of anxiety disorders). But a surprising thing happened. D-cycloserine actually increased the alcohol craving.

“We’re trying to figure out how D-cycloserine enhances the urge to drink,” says Hofmann, who is unfazed by the results. “Research is like peeling an onion, one layer at a time.”

Indeed, research into substance abuse poses unique issues, as Domenic Ciraulo, chair of psychiatry in the School of Medicine and psychiatrist-in-chief at Boston Medical Center, can attest. The author of four books and more than 100 papers, he would be the first to acknowledge that alcohol dependence is complex.

“When someone stops drinking, the brain is left unbalanced, and the brain wants to restore its equilibrium,” says Ciraulo, about why problem drinkers are often unable to stay away from alcohol.

His research with behavioral therapy and two FDA-approved, anti-seizure drugs—zonisamide and levetiracetam—has produced encouraging results. Unlike D-cycloserine, these two drugs target brain signals to reduce cravings. Another area of Ciraulo’s research centers on transcranial magnetic stimulation (TMS), approved by the FDA to treat depression. It involves a helmet that monitors brain activity and stimulates the prefrontal lobe responsible for impulse control.

Ciraulo, Kantak, Otto, and Hofmann have submitted a multimillion-dollar proposal to the National Institute on Drug Abuse for a research project that would encompass four animal and three human studies aimed at enhancement learning with D-cycloserine and CBT for cocaine addiction. If the proposal is approved, Ciraulo plans to research the effects of treating cocaine addicts using TMS and D-cycloserine.

“I believe that these studies are important,” says Kantak. “We know that cues are a main contributor as to why drug abusers relapse. A key tactic is to reduce the salience of those cues. The best way to do that is extinction training. But we have to know how to make it stick.”