Although new knowledge about the brain’s reward circuitry has provided insight into the biology of addiction, this has not yet resulted in new treatments. In animal models of addiction, it has been possible to therapeutically modify reward circuits using techniques that alter gene expression or switch individual neurons or groups of them “on” and “off.” But such experiments, which involve genetic engineering and surgical interventions in the brain, are not directly translatable in human subjects.

Looking for novel approaches, researchers at Columbia University and the New York State Psychiatric Institute have taken another path. In separate randomized clinical trials reported in the American Journal of Psychiatry, they have combined an existing form of therapy that has so far proven only modestly beneficial in addiction with an experimental therapy that has been neither validated nor approved for use in addiction.

The existing therapy involves behavioral modification. The experimental therapy is a drug—a single, low-dose infusion of the anesthetic ketamine. It has repeatedly shown its power to act rapidly (within hours) as an antidepressant in individuals who haven’t responded to other forms of depression therapy. A chemical derivative of ketamine called esketamine received FDA approval last year for use in treatment-resistant major depression.

In the two trials they designed, the Columbia team, led by Elias Dakwar, M.D., and Edward Nunes, M.D., and including BBRF 2000 Independent Investigator Frances R. Levin, M.D., employed ketamine—at a sub-anesthetic dose, given a single time—in patients with cocaine and alcohol addictions who were also receiving behavioral therapies.

In the cocaine trial, ketamine was combined with mindfulness-based behavioral training; in the alcohol trial, it was paired with motivational enhancement therapy.

In both trials, while all participants received behavioral therapy, only some received ketamine; participants who served as controls instead received what researchers call an “active” placebo: the drug midazolam (Versed), a tranquillizing agent that can be used as a sedative, anesthetic, or sleep aid.

In both trials, patients who received ketamine and behavioral therapy fared markedly better with their substance-use problem than did those who received the placebo plus therapy.

Specifically, in the cocaine trial: 55 cocaine-dependent individuals received an intravenous ketamine infusion or placebo during a 5-day hospital stay, during which they also began a 5-week course of mindfulness-based relapse prevention therapy. Overall, 48% of those in the ketamine group maintained abstinence over the final 2 weeks of the trial, compared with only 11% in the group that received placebo. Also, the ketamine group was 53% less likely to relapse and had cravings scores that were 58% lower than those who received placebo.

In the alcohol trial: 40 alcohol-dependent individuals (averaging 5 drinks per day) received either ketamine or placebo during the 2nd week of a 5-week outpatient regimen of motivational enhancement therapy. Ketamine as compared with placebo “significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days,” the researchers reported.

The results tended to support, although could not in themselves prove, the hypothesis that drove both clinical tests. Ketamine is thought to affect the glutamate neurotransmitter system, possibly by modulating cellular docking ports for glutamate called NMDA receptors. It is also thought to have “downstream” effects on synapse formation in the prefrontal cortex. Noting that these mechanisms may also be relevant to treatment of cocaine-use disorder, the team proposed to see if ketamine might help overcome resistances known to impede the progress of people who are treated with behavioral therapies: craving, low motivation to quit or abstain, and difficulty controlling behavioral reactions.

In the cocaine trial, “mindfulness training” sought to teach participants “an attitude of deliberate, present-centered awareness, coupled with a suspension of behavioral reactivity, cognitive associations, judgments, and distortions.” Noting the positive results relative to controls in the cocaine trial, the team proposed that ketamine may indeed affect brain biology in ways that make the behavioral therapy component more effective than when given alone.

The researchers reached a similar conclusion in the trial with alcohol-dependent participants. It appeared that, compared with placebo or no complementary therapy, “ketamine provided protection against a lapse [in abstinence] evolving into continued use—relapse—or into a dropout from treatment.”

Given the general lack of progress in addiction treatments, the team in each trial expressed the hope that their results would be replicated in much larger trials—perhaps, in the process, validating a broad new potential use for ketamine and ketamine-like molecules in combination treatment for addiction and substance abuse.

Sanjay Mathew, M.D., a 2009 BBRF Independent Investigator and 2006 and 2001 Young Investigator, was also on the research team in the cocaine trial.