A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial

This randomized, double-blind, active placebo-controlled pilot study (n=40) examined the effects of ketamine (49.7mg/70kg, n=17) or the active control midazolam (1.75mg/70kg, n=23) combined with motivational enhancement therapy to treat patients with alcohol use disorder. The preliminary data showed that a single ketamine infusion in combination with motivational enhancement therapy improves measures of drinking in patients with alcohol use disorder.

Abstract

“Objective: Pharmacotherapy and behavioral treatments for alcohol use disorder are limited in their effectiveness, and new treatments with innovative mechanisms would be valuable. In this pilot study, the authors tested whether a single subanesthetic infusion of ketamine administered to adults with alcohol dependence and engaged in motivational enhancement therapy affects drinking outcomes.

Methods: Participants were randomly assigned to a 52-minute intravenous administration of ketamine (0.71 mg/kg, N=17) or the active control midazolam (0.025 mg/kg, N=23), provided during the second week of a 5-week outpatient regimen of motivational enhancement therapy. Alcohol use following the infusion was assessed with timeline followback method, with abstinence confirmed by urine ethyl glucuronide testing. A longitudinal logistic mixed-effects model was used to model daily abstinence from alcohol over the 21 days after ketamine infusion.

Results: Participants (N=40) were mostly middle-aged (mean age=53 years [SD=9.8]), predominantly white (70.3%), and largely employed (71.8%) and consumed an average of five drinks per day prior to entering the study. Ketamine significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days compared with midazolam. Infusions were well tolerated, with no participants removed from the study as a result of adverse events.

Conclusions: A single ketamine infusion was found to improve measures of drinking in persons with alcohol dependence engaged in motivational enhancement therapy. These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use disorder. Further research is needed to replicate these promising results in a larger sample.”

Authors: Elias Dakwar, Frances Levin, Carl L. Hart, Cale Basaraba, Jean Choi, Martina Pavlicova & Edward V. Nunes

Summary

Pathological alcohol use leads to 3.8% of all deaths globally, and 1% of the gross national product in developed countries. Most affected individuals are not in treatment.

Maladaptive patterns of alcohol use may stem from pre-existing vulnerabilities and may be driven by neural adaptations resulting from problematic alcohol use itself. Ketamine, a high-affinity N-methyl-D-aspartate receptor antagonist, may be an effective treatment for problematic substance use.

Ketamine may have similar benefits to midazolam in persons with alcohol dependence. The study evaluated the effect of ketamine on heavy drinking days and time to relapse or study dropout.

METHODS

Adults with alcohol dependence were randomly assigned to receive an intravenous ketamine infusion in the second week of a 5-week outpatient trial. The infusion was given on a quit day during week 2, and participants were required to abstain from alcohol for at least 24 hours before the infusion.

Participants

Participants were assessed with the Mini-International Neuropsychiatric Interview for DSM-IV and underwent medical and psychiatric evaluation, including serum collection (electrolytes, CBC, and liver function tests) and other diagnostic tests. They were excluded if they had a history of severe withdrawal symptoms.

and Outpatient Visits

Participants in Project MATCH received motivational enhancement therapy, which was considered unlikely to obscure medication efficacy.

Six motivational enhancement therapy sessions were provided over 5 weeks to achieve the participants’ goals. A session was provided 24 hours after the ketamine infusion to capitalize on the hypothesized motivation-enhancing effects of ketamine.

Participants were counseled to reduce the number of drinks per day, and came to the clinic twice weekly for motivational enhancement therapy and to meet with a psychiatrist. They were also assessed for alcohol-related vulnerabilities, and a telephone follow-up was conducted 6 months after the trial.

Infusion Procedures

Participants were asked to abstain from alcohol and fast before the infusion, and were informed they might receive any of several medications.

Participants were administered a 2-minute saline bolus followed by a 50-minute slow-drip intravenous infusion of midazolam or ketamine hydrochloride between 10:00 a.m. and 12:00 p.m. on the second appointment day of week 2. Blood pressure, heart rate, and blood oxygen saturation were continuously monitored.

Statistical Analysis

The study participants’ baseline demographic characteristics are summarized in Table 1, and a longitudinal logistic mixed-effects model with a logit link and a random intercept was used to analyze the longitudinal primary outcome: abstinent days during the 21 days post-infusion.

The reduction in heavy drinking days was analyzed using longitudinal mixed-effects models with a random intercept and an AR process.

Time to first alcohol use and time to first heavy drinking day were analyzed by Kaplan-Meier survival curves and the log-rank test.

Participants

Ninety-five individuals were screened for participation, 50 were enrolled, and 40 were randomly assigned in an intent-to-treat analysis. Ketamine infusions were well tolerated, with the most common adverse effects being sedation and headache.

Across the 21 days after infusion, 47.1% of participants in the ketamine group used alcohol, 17.6% had a heavy drinking day, and 52.2% relapsed. Six participants dropped out of the midazolam group.

Primary Outcome: Alcohol Abstinence

A longitudinal logistic mixed-effects model was used to analyze the effects of ketamine and midazolam on alcohol abstinence. The model showed that the abstinence rate decreased with time and that the score on the Clinician-Administered Dissociative States Scale was not significant.

A sensitivity analysis was performed without the assumption that missing days were nonabstinent days, and results were similar to those reported above.

Telephone interviews were conducted 6 months after the trial. Seventy-five percent of participants in the ketamine group reported abstinence, compared with 27% in the midazolam group.

Secondary Outcomes

The interaction between treatment group and time was significant for midazolam, but not ketamine, in predicting heavy drinking days.

Time to Relapse, First Use, and First Heavy Drinking Day

Participants in the ketamine group had a longer time to relapse, compared with participants in the midazolam group.

DISCUSSION

A single ketamine infusion led to a lower likelihood of alcohol use over a 21-day period, as well as a lower likelihood of heavy alcohol use and longer time to relapse, compared with midazolam. This suggests that ketamine in combination with motivational enhancement therapy may be an effective pharmacotherapy for alcohol use disorder.

In this trial, motivational enhancement therapy was paired with ketamine to assess the impact of ketamine on motivation to quit and other dependence-related vulnerabilities.

In this trial, participants who received ketamine did not drop out, but six dropped out of the control group. Four of these participants resuming heavy alcohol use before dropping out.

The high rates of abstinence initiation irrespective of medication assignment and the low rates of drinking days and heavy drinking days suggest that ketamine may provide protection against a lapse evolving into continued use (relapse) or into dropout from treatment.

A problem in studying treatment with ketamine is blinding participants and investigators, given the distinctive psychoactive effects of these agents. We used an active control (midazolam) and a minor deception, but did not test the integrity of the blind by ascertaining what participants believed they received.

Participants in the control group sustained abstinence for the first 7-10 days after the infusion, suggesting that midazolam may have functioned as a good placebo or that there may be some transient benefit to a low-dose midazolam infusion.

Ketamine may have enduring effects on decision making and behavior, well after the drug and its metabolites are expected to have cleared. Neurotrophic, modulatory, and even psychological mechanisms have all been proposed to account for the sustained antidepressanteffectofasingledoseofketamine.

Individuals with a first-degree family history of alcoholism may have a heightened and more prolonged antidepressant response to ketamine, perhaps as a result of epigenetic changes, glutamate subreceptor variations, and environmental factors.

The neural vulnerabilities associated with problematic substance use are shared across different substance use disorders, including cocaine, alcohol, and opioids. The therapeutic effect of ketamine may be due to changes in functional connectivity as well as alterations in glutamatergic, opioid, and dopaminergic signaling.

Limitations

This study was small and homogeneous, with inadequate power to evaluate secondary outcomes. The duration of treatment was short (5 weeks), and some participants could not be reached for follow-up. The results show that ketamine promotes engagement with behavioral modification, although the approach for missing observations may not be entirely accurate, and the sample was selected for minimal psychiatric comorbidity, which limits generalizability.

Minor deception was employed to further protect the blind and minimize expectancy and placebo effects, and various safeguards were employed to minimize the risk of illicit use. There has been no incidence of ketamine misuse in any of the research to date.

CONCLUSIONS

Despite several limitations, the study findings suggest a potential role for ketamine in the treatment of alcohol use disorder. Further research is needed to determine whether ketamine works in conjunction with behavioral treatments.