Addiction Research Moves Beyond the Pleasure Pathway - 2007

New Treatment Approaches Target Multiple Brain Systems
by Brenda Patoine

February, 2007

BRIEFING PAPER


Recent insights about the complexity of drug abuse are driving a new quest for therapeutic options, moving away from the search for a “magic pill” that can singularly quash addiction and toward combination strategies that attack addictive behavior from multiple angles.

The realization comes from research showing that addiction hijacks more than the so-called “reward circuit,” the dopamine-driven pathway in the brain that has long been the primary focus of addiction science. It is now clear that multiple brain systems are critically involved in addictive behavior and relapse, including prefrontal regions that underlie executive function, inhibitory control, and motivational drive. These systems are increasingly the targets for fresh attempts to break the addictive spiral.

Currently, there is a paucity of effective treatments for addiction, and most previous efforts to develop new medications have failed. Part of the reason, according to Dr. Nora Volkow, director of the National Institute for Drug Abuse (NIDA) and a member of the Dana Alliance for Brain Initiatives, may be that expectations have been unrealistic.  

“Because most of those strategies have failed, we’re changing the paradigm,” says Volkow. “We are now targeting strategies that can improve the various processes disrupted by drug addiction.”

Of particular interest are executive-control brain systems, which are involved in decision-making, inhibiting impulsive behaviors, and judging the value of drug and non-drug “rewards.” They are intricately connected to classical reward circuitry centered in the nucleus accumbens, substantia nigra, and other parts of the brain’s basal ganglia. A series of recent findings from various laboratories has supported the idea that treating addiction successfully will need to engage these executive systems. Targeting the reward circuit alone may not get the job done.

Blocking the High

That’s not to say the reward circuit is unimportant. One of the few medications currently available to treat addiction acts on reward circuitry.  Naltrexone targets mu opiate receptors in the brain, the same receptors opioid drugs such as heroin occupy to induce the acute euphoric high and the subsequent brain changes that compel users to come back for more.

“Naltrexone completely blocks the actions of some drugs of abuse. The person won’t get high,” says Volkow. “It’s a perfect example of how you can develop medications that interfere with the rewarding effects of drugs.”

Naltrexone is approved for heroin addiction and alcoholism, but it’s not for everyone. It can trigger severe withdrawal symptoms in addicts if they are not detoxified, and this complicates compliance with the therapy.  

Immunotherapy for addiction represents another area of interest, and NIDA is supporting separate projects with two different pharmaceutical companies to develop vaccines against nicotine and cocaine. Both efforts are currently in Phase II clinical trials. The idea is to coax the immune system to produce antibodies that will capture the drug while still in the bloodstream and prevent the drug from entering the brain, thus blocking its rewarding effects. “There is some clinical data to suggest that a vaccine could be beneficial if you are able to elicit a large enough antibody response,” says Volkow.

Tackling Aberrant Learning

Several lines of evidence suggest that addiction entails “aberrant-learning” processes. The repeated rush of dopamine elicited by drugs of abuse causes enduring neurobiological changes that prompt the user to compulsively seek the drug even in the face of dire consequences. These same changes also underlie relapse. The result is a powerful memory of the intensely rewarding high that sets up an automatic “conditioned” response compelling the user to do it again and again. Even after long periods of abstinence, exposure to drug paraphernalia or environments associated with former drug use can trigger relapse. Interfering with these learned responses–to essentially “unlearn” the compulsive habit of drug-taking–is therefore a primary therapeutic strategy.

Animal studies have pointed to anti-epileptic drugs as one possible way to accomplish this, and Volkow is particularly excited about two of them: gamma vinyl GABA (GVG) and topiramate. GVG and topiramate work through different mechanisms to modulate levels of GABA and glutamate, two abundant neurotransmitters implicated in the aberrant-learning induced by chronic drug abuse and many of the impaired behaviors associated with addiction. 

Two pilot studies with GVG, one in cocaine abuse and one in methamphetamine abuse, have shown positive results, including efficacy in helping methamphetamine addicts remain drug-free for at least six weeks, even while living in their home environment with ready access to drugs. GVG is used widely in Europe and Latin America to treat epilepsy, but is not approved in the U.S. due to its tendency to produce visual or peripheral side effects.

Topiramate, a drug that is available in the U.S., has shown promise in early clinical trials for cocaine addiction and alcoholism, and NIDA is now collaborating with the drug’s maker, OrthoMcNeil Pharmaceuticals, to conduct a Phase II study in methamphetamine-addicted persons.  

Using an epilepsy drug to treat addiction makes sense if one considers that both conditions are marked by “hyperexcitability” in specific brain circuits, Volkow says. She points to imaging studies in addicts that show hyperactivity in certain areas of the brain when the addict is experiencing intense cravings. “In brain studies of patients with seizures,” Volkow says, “the areas from which the seizure emanates are hyperactive during the seizure and hypoactive when a seizure is not occurring. Thus while speculative, it may be that these drugs can work in addiction by decreasing the hyperexcitability in activated brain circuits,” she adds.

Targeting the Executive Suite

Judgment, decision-making, and impulse control are the province of the prefrontal cortex, what might be called the brain’s executive suite for its role in high-level cognitive processing. Dopamine, the key neurotransmitter involved in the reward circuit, also modulates executive function, raising the possibility that drugs that increase dopamine might improve executive control in drug addiction.

The questions before researchers, Volkow says, are “Can we use medications that improve dopaminergic activity to strengthen executive function? And would that improve the likelihood that people with addictions would follow remediation programs and therefore have better outcomes?”

The answers are not yet clear, but one drug that has attracted a great deal of interest for this use is modafinil, a medication used to treat the sleep disorder narcolepsy. While not a classical dopamine agonist like the Parkinson’s disease drug L-dopa (which has failed to show efficacy in addiction), modafinil enhances dopaminergic signaling by blocking a transporter that normally clears dopamine from synapses. Modafinil is a complex drug that has many apparent actions in the brain, and it is not yet entirely clear which action is relevant for its therapeutic effects, Volkow says. Regardless, early clinical data suggest a benefit in treating cocaine addiction, and additional clinical trials are underway in cocaine abuse as well as methamphetamine abuse.

Driving Motivation

A key aspect of addiction is loss of interest in normal everyday activities, which can lead to dysphoria or depression, social withdrawal, and increased drug use. Interventions that increase the value, or saliency, of stimuli other than the drug of choice may therefore be beneficial. Group therapy and behavioral interventions in which addicted individuals learn to recognize destructive lifestyle patterns and supplant them with constructive behaviors have had some success toward this end.

Cognitive behavioral therapy, a particular type of structured psychotherapeutic approach, is used extensively in addiction, and has been shown by multiple investigators to be effective. Another behavioral therapy, contingency management, appears to produce a strong response, Volkow says. The concept behind it is very simple: addicted individuals are given random prizes when they successfully stay off drugs, as evidenced by “clean” urine samples. 

“It is fascinating that something as simple as contingency management works,” she says. “The notion of a reward for staying drug-free becomes very relevant to the individual who is addicted, and significantly improves outcomes.”

Volkow is among those who are convinced that, in the final analysis, combination approaches to therapy hold the greatest hope for helping people break the drug habit and not go back.

“Rather than expect that modafinil, or any single drug, will get you clean urine, the approach we’re pursuing is to see if we can improve outcomes by coupling, for example, a cognitive behavioral treatment or a contingency management program with a medication that engages the executive function system or interferes with conditioned response,” Volkow says. Preliminary research on such combination strategies has been promising.

Translating the Science

The main problem in moving addiction treatment forward, Volkow notes, “is not the science; that’s developing with very fascinating findings. The problem is translating the basic science into medication, and that’s incredibly costly.”

She says pharmaceutical companies have not been very interested in developing medications for drug addiction because of stigmatization and concerns about not getting a good return on the investment required to bring a new medication to market. 

“Engaging the pharmaceutical industry to develop addiction medications is one of the major challenges that we have in the field,” Volkow says. “That is one of the reasons we are interested in developing treatments to disrupt the processes that mediate, for example, craving, conditioned responses, and loss of inhibitory control.” Drugs that act on these systems would likely have broad applications far beyond addiction that represent potentially lucrative incentives for drug companies.

“If you can interfere with craving, for example, you can do so whether the craving is for cocaine, chocolate, sex, or any behavioral compulsion triggered by conditioned responses,” she says. “The range of areas where these kinds of medications could be useful is enormous.”

Published February 2007