01. A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial

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Let’s look at an article on ketamine as an adjunct for cocaine cessation. When I first looked at this, I thought, ketamine, like, for everything? So, even if this worked, what problems emerge down the road by giving people with a cocaine problem another drug that they can sometimes access on the street? Nevertheless, let’s have a look at the results. The results are huge. One ketamine infusion improved relapse-free rates from 10% to 40%.

This article is from the American Journal of Psychiatry in June 2019. In this study, 55 people with cocaine dependence were given inpatient mindfulness-based relapse prevention therapy, and this is called MBRP. Half of them also received a single session of intravenous ketamine, while the other half got IV midazolam as an active control.

So, first, what is this MBRP? Mindfulness-based relapse prevention cultivates mindfulness, which they describe as an attitude of deliberate presence-centered awareness, coupled with a suspension of behavioral reactivity, cognitive associations, judgments, and distortions. So, this suspends the cognitive associations and distortions in association with cocaine. These mindfulness practices are thought to provide a benefit via neuromechanisms that are similar to those attributed to subanesthetic ketamine, including the regulation of mesolimbic functioning, the promotion of prefrontal neural plasticity, synaptogenesis, and sustained modulation of default mode network hyperconnectivity. All of these previous studies have associated with both ketamine and mindfulness practices. So, one would hope that those mindfulness practices would have a significant impact, but we also know from previous experience that treating people with cocaine dependence is very difficult. So, relapse rates are going to be very high, even with MBRP, as they were.

However, the infusion of ketamine made a significant difference in outcome. After the inpatient week, subjects were followed for 5 weeks with twice-weekly therapy sessions outpatient. As soon as they got out of the hospital’s research inpatient unit, 90% of them went right back to using unless they got ketamine, in which case only about half went straight back to use. By the end of the 6-week study, a few more ketamine subjects had relapsed. So, the final result again, 40% relapse free with ketamine adjunctive to MBRP vs 10% relapse free in the controls. These were urine-sample–confirmed abstinence rates with twice-weekly sampling through the study. They also looked for ketamine, benzodiazepines, alcohol, and everything else.

Even more impressive perhaps is the 6-month follow-up by phone without a urine test to confirm this, but self-reported abstinence rates were 44% in the ketamine group, nearly half, vs zero in the midazolam group. Regarding my concern about long-term risks, like a new substance use problem with ketamine, the authors have been studying ketamine and substance use for several years. They have a 2017 randomized trial without the mindfulness component. Moreover, they point out, “there has been no incidence of ketamine misuse in any of the research to date suggesting that this risk can be effectively managed even when this agent is given to substance users.”

In their limitations, they note that cocaine treatment does not usually start with a week-long inpatient stay, so their results are not the final word on the efficacy of ketamine as an adjunctive treatment for cocaine dependence. However, they also point out that cocaine-dependent individuals with depression or anxiety might respond even more robustly to ketamine, further justifying the risks of ketamine. What were the risks in this study? What problems did they encounter? There was mild sedation, less than 12 hours for a few subjects, more of them in the midazolam group. The acute dissociation with ketamine did not produce any lasting problems in both groups. All psychoactive effects resolved within 30 minutes of infusion.

In summary, these results, especially the self-reported abstinence at 6 months, are impressive. If ketamine infusion is somehow an option in your area, and you see patients with cocaine dependence, these data suggest you would see a strikingly better treatment result by incorporating into the treatment a single ketamine infusion.

Abstract

A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial

Elias Dakwar, Edward V Nunes, Carl L Hart, Richard W Foltin, Sanjay J Mathew, Kenneth M Carpenter, C J Jean Choi, Cale N Basaraba, Martina Pavlicova, Frances R Levin

Objective: Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention.

Methods: Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout).

Results: Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events.

Conclusions: A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.

Reference

Dakwar, E., Nunes, E. V., Hart, C. L., Foltin, R. W., Mathew, S. J., Carpenter, K. M., Choi, C. “., Basaraba, C. N., Pavlicova, M., & Levin, F. R. (2019). A single ketamine infusion combined with mindfulness-based behavioral modification to treat cocaine dependence: A randomized clinical trial. American Journal of Psychiatry, 176(11), 923-930.