Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder

This double-blind placebo-controlled trial (n=96) assessed the effectiveness of 1) three weekly ketamine infusions (56mg/70kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education, in people with alcohol use disorder (AUD). Participants in the ketamine groups abstained from alcohol for a significantly longer number of days at 6-month follow-up, while the greatest abstinence was in the ketamine plus therapy group. Relapse times did not differ across the four groups.

Abstract

“Objective: Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. The authors investigated the safety and efficacy of ketamine compared with placebo in increasing abstinence in patients with alcohol use disorder. An additional aim was to pilot ketamine combined with mindfulness-based relapse prevention therapy compared with ketamine and alcohol education as a therapy control.

Methods: In a double-blind placebo-controlled phase 2 clinical trial, 96 patients with severe alcohol use disorder were randomly assigned to one of four conditions: 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at 6-month follow-up.

Results: Ninety-six participants (35 women; mean age, 44.07 years [SD=10.59]) were included in the intention-to-treat analysis. The treatment was well-tolerated, and no serious adverse events were associated with the study drug. Although confidence intervals were wide, consistent with a proof-of-concept study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up (mean difference=10.1%, 95% CI=1.1, 19.0), with the greatest reduction in the ketamine plus therapy group compared with the saline plus education group (15.9%, 95% CI=3.8, 28.1). There was no significant difference in relapse rate between the ketamine and placebo groups.

Conclusions: This study demonstrated that treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up. The findings suggest a possible beneficial effect of adding psychological therapy alongside ketamine treatment.

Authors: Meryem Grabski, Amy McAndrew, Will Lawn, Beth Marsh, Laura Raymen, Tobias Stevens, Lorna Hardy, Fiona Warren, Michael Bloomfield, Anya Borissova, Emily Maschauer, Rupert Broomby, Robert Price, Rachel Coathup, David Gilhooly, Edward Palmer, Richard Gordon-Williams, Robert Hill, Jen Harris, Merve Mollaahmetoglu, Valerie Curran, Brigitta Brandner, Anne Lingford-Hughes & Celia J.A. Morgan

Notes

Psychedelics are poised to be both viable and effective treatment options for many people living with mental disorders whom conventional treatments have failed. One of these disorders is substance use disorder (SUD), commonly known as addiction. At present, there is no cure for SUDs disorders but a range of therapies and tools exist depending on individual needs. With current treatment needs unmet, psychedelics have the potential to help people with these disorders. A well-known example of this is the psilocybin for smoking cessation trial which was carried out by researchers at Johns Hopkins. The results of this trial, and other research, has led many in the field to believe other psychedelic compounds have the potential to treat SUDs. One of these compounds is ketamine.

Since the early 2000’s some research has taken place into using psychedelics to treat different SUDs. Professor Celia Morgan and colleagues reviewed the state of this research in 2017. While the results of trials at this point were positive, the stated randomized-controlled trials (RCTs) are needed. In terms of ketamine research, some RCTs have taken place exploring its effectiveness in treating SUDS including cocaine dependence and alcohol use disorder (AUD), with both trials finding positive results.

The present study is the first in the world to explore the effects of serial ketamine infusions in combination with psychotherapy to treat AUD over a 6 month follow up period. Sponsored by Awakn Life Sciences and led by Celia Morgan at the University of Exeter, the Phase II study involved 96 participants with severe AUD as defined by the DSM-V. Participants were required to achieve initial abstinence from alcohol for at least 24hrs prior to undergoing the randomization process which allowed the researchers to examine the effects of ketamine on prolonging abstinence. Participants were randomly assigned to four groups:

1. Three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy
2. Three saline infusions (placebo) plus psychological therapy
3. Three ketamine infusions plus alcohol education (placebo control for therapy)
4. Three saline infusions plus alcohol education

Following baseline measurements and randomization at visit one, participants received either psychological therapy or alcohol education on visits 2 to 8 after which marked the end of treatment sessions. These therapy/alcohol education sessions always preceded infusions. Known as KARE, the therapy sessions lasted on average 1.5 hours and were based on manualized mindfulness-based relapse prevention to help participants live a meaningful life without alcohol. Participants were taught a number of relapse prevention techniques, kept a journal and completed various other exercises. The alcohol education group did not involve any formal psychological components and instead focused on things like the driving forces of addiction, the biological effects of alcohol and ways to improve healthy living. Infusions were administered on visits 2, 4 and 6 and were always separated by a minimum of one week.

The sober findings:

• In the ketamine plus KARE (therapy) group, the rate of alcohol abstinence in 6 months increased from 2% before the trial to 86% after the trial.
• The risk of relapse at 6 months was 2.7 times less in the ketamine plus KARE group than in the placebo plus alcohol education group but overall, relapse did not significantly differ between groups.
• Several measures of liver function indicated liver function improved across groups during the trial. However, the fitted curve for the ketamine groups indicated a more linear improvement compared to the placebo groups which showed a more U-shaped response.
• Although baseline depression scores were low on average, improvements on the Beck Depression Inventory but not the Hamilton Depression Rating Scale were found at 3 months.
• Anhedonia (the inability to feel pleasure) was reduced at 3 months.

The findings of the present study indicate that ketamine-assisted therapy can be used to help those living with AUD by promoting alcohol abstinence. The results point toward the added value of psychotherapy when used in tandem with ketamine. The therapy component is often excluded in trials with ketamine and other mental disorders like depression and therefore, the addition of therapy in future ketamine research and clinical practice may prolong the clinical benefits. Moreover, treatment was generally well tolerated with no serious adverse events reported.

The authors do acknowledge a number of limitations in their study. Primarily, the generalizability of results is limited due to the strict enrollment criteria. Blindings was also difficult, especially if participants had any past experiences with ketamine and/or psychotherapy. The researchers reported that nearly all participants in the ketamine group were able to identify that they had received the active drug which may have affected results. Furthermore, some study participants had prior experiences with ketamine which also raises issues surrounding blinding.

Despite these limitations, the trial is the first to show that three subanaesthetic doses of ketamine support abstinence from alcohol and that this abstinence may be further enhanced when ketamine treatment is combined with therapy.

Summary of Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder