A single ketamine infusion combined with mindfulness-based behavioral modification to treat cocaine dependence: a randomized clinical trial

This double-blind, placebo-controlled study (n=55) investigated the use of ketamine (35mg/70kg) versus midazolam (an anesthetic), plus mindfulness-based therapy (5-week program) for cocaine dependence. The ketamine group scored significantly better and were 53% less likely to relapse.

Abstract

“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.”

Authors: 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

Summary

Although decades of medical research has been conducted to treat cocaine use disorder, there are currently no medications approved by the U.S. Food and Drug Administration. Ketamine, a dissociative anesthetic, may represent an exception, as it has been shown to have efficacious effects in cocaine-dependent research volunteers.

Ketamine may be a clinically feasible way to address cocaine use disorder by creating a reprieve from craving, low motivation, and high behavioral reactivity.

Mindfulness-based relapse prevention (MBRP) is a manualized treatment that incorporates practices to cultivate “mindfulness,” an attitude of deliberate, present-centered awareness, coupled with a suspension of behavioral reactivity and of cognitive associations, judgments, and distortions. Ketamine may work together with MBRP to promote sustained abstinence.

METHODS

Fifty-five individuals seeking treatment for cocaine dependence were enrolled in a 5-week trial that included ketamine or midazolam infusions and behavioral treatment. They returned twice weekly for 4 weeks for monitoring and measures, and physician visits.

Participants

Participants were medically healthy adults under age 70 who met DSM-IV criteria for cocaine dependence and had no psychiatric comorbidity. They were also required to have urine toxicology indicative of cocaine use on at least one occasion during screening.

Setting

All procedures and outpatient visits occurred at the New York State Psychiatric Institute, and all staff were blind to participants’ treatment assignment.

Infusion Procedures

On day 2 of the inpatient phase, participants were randomly assigned to either the ketamine condition or the midazolam control condition. They were not told which drug they would receive, and they did not eat anything after midnight the night before.

Ketamine hydrochloride (0.50 mg/kg) or midazolam 0.025 mg/kg) was prepared in saline and packaged by the NYSPI pharmacy for a slow-drip 40-minute intravenous infusion. Blood pressure, heart rate, and blood oxygen saturation were continuously monitored.

We provided relaxation and breathing exercises to prepare participants for the infusions, and guided them through the body scan if any discomfort or anxiety emerged during the infusions.

MBRP and Outpatient Visits

Participants engaged in MBRP delivered by trained master’s-level staff, shortened from 8 weeks to 5 weeks in collaboration with one of its lead authors. The sessions were recorded and overseen by a senior therapist or by the principal investigator.

Participants returned to clinic twice weekly for an MBRP session and a visit with a study physician. They were assessed for cocaine-related vulnerabilities, mindfulness, stress sensitivity, urine toxicology, and self-reported drug use.

Statistical Analysis

Baseline demographic characteristics, side effects, and adverse events were tabulated and summarized using means and standard error. Dissociative symptoms and peak blood pressure were analyzed using Wilcoxon rank-sum tests.

The primary outcome was 2 weeks of end-of-study abstinence, confirmed by urine toxicology. The research was stopped after an interim analysis demonstrated a significant difference in the treatment effect on the primary outcome.

We used longitudinal mixed-effect models to analyze data on cocaine use and craving scores during weeks 2 through 5. Route of use was included as a covariate in all analyses.

RESULTS

Fifty-five individuals underwent randomization. The median baseline cocaine use was $32.86 in the ketamine group and $36.43 in the midazolam group.

Infusions

Treatment with ketamine was significantly associated with higher ratings of acute dissociation on the CADSS compared with midazolam. There was no persistent dissociation in either group, and no instances of persistent psychiatric disturbances, clinical worsening, increased drug use, or emergence of new drug misuse were reported.

Abstinence

The proportion of participants with urine-test-confirmed abstinence over the last 2 weeks was 48.2% in the ketamine group, compared with 10.7% in the midazolam group.

Time to Relapse

The proportional hazards assumption was not violated because 53% less participants in the ketamine group went on to use cocaine or drop out compared to the midazolam group.

Cocaine Use

The two-way interaction between time and treatment on cocaine use was not significant, and the ketamine group maintained its early improvements over the course of the trial.

Craving and Other Measures

The two-way interaction between time and treatment was not significant, and the ketamine group had lower craving scores than the midazolam group. There was no significant change in craving scores over time for either group.

DISCUSSION

This is the first clinical trial to investigate the use of ketamine in cocaine-dependent individuals. The study found that ketamine was well tolerated and promoted abstinence, and that ketamine was associated with a lower likelihood of cocaine use, lower levels of cocaine craving, and longer time to relapse.

Ketamine infusions combined with existentially oriented psychotherapy can be used to treat addiction-related vulnerabilities. Ketamine’s mystical-type phenomena may work to provide an experiential stepping-stone toward deeper mindfulness training.

This trial was not designed to evaluate synergy between ketamine and MBRP, but demonstrated that ketamine enhances motivation to change drug use and supports engagement with behavioral treatment. MBRP also appeared to be helpful in carrying forward the effects of ketamine beyond what has been observed in previous research.

Ketamine may have several therapeutic mechanisms, including receptor-specific changes, neurotrophic, modulatory, and even psychological mechanisms. These mechanisms are relevant to substance use disorders as well, and suggest innovative strategies for enhancing or replacing ketamine.

A recent study suggested that opioid-related mechanisms may be involved in the antidepressant effects of ketamine. The study used a behavioral and mindfulness-based framework to guide participants to engage with the infusions in a therapeutic manner.

This trial has several limitations, including a small sample size, minor discrepancies between treatment arms, and a homogeneous sample with minimal psychiatric comorbidity. Future trials should examine the effect of ketamine on individuals with drug dependence and psychiatric comorbidity, as well as sex differences in the response to ketamine.

Although we did not test the integrity of the blind, the psychoactive effects of ketamine can be pronounced and easily identifiable in some cases. The minor deception we enforced to further protect the blind is a limitation as well.

Ketamine was effective at providing individuals already engaged in mindfulness-based behavioral modification with significant benefits, including greater odds of maintaining abstinence, substantial protection from relapse and craving, and lower likelihood of cocaine use.