People with severe alcohol disorder were able to stay off alcohol for longer when they were treated with low doses of ketamine combined with psychological therapy in a clinical trial, reports the University of Exeter in the United Kingdom.
The Ketamine for reduction of Alcohol Relapse (KARE) trial was led by the University of Exeter in collaboration with Imperial College London and University College London. It was funded by the Medical Research Council and published in The American Journal of Psychiatry on 11 January 2022.
The phase II trial is the first of its kind to examine whether a low dose of ketamine could help prevent people from quickly returning to heavy drinking after stopping, when combined with therapy.
A biotech company AWAKN Life Sciences has licensed the therapy from the University of Exeter to use in its clinics and partnerships. The University of Exeter and Awakn have also signed an agreement with Devon Partnership NHS Trust to explore NHS readiness for ketamine-assisted psychotherapy.
The trial followed preliminary evidence that controlled ketamine therapy can reduce the numbers of alcoholics who relapse. Currently, few effective treatments exist for severe alcoholism, which has a devastating impact on lives. The KARE trial was the first trial to compare ketamine with and without therapy in any mental health context.
The study included 96 people with alcohol problems who were abstinent at the time of the trial. The team found that people who had ketamine combined with therapy stayed completely sober for 162 of 180 days in the six month follow-up period, representing 87% abstinence.
This was significantly higher than any of the other groups, indicating that the therapy may also have promise for preventing relapse. This group was more than 2.5 times more likely to stay completely abstinent at the end of the trial than those on placebo.
The team also found some evidence that ketamine and therapy may prevent any drinking over six months, though the results were more mixed. Patients having ketamine also had lower depression after three months, and better liver function than those on placebo, regardless of whether it was combined with therapy or not.
Lead author Professor Celia Morgan of the University of Exeter said: “Alcoholism can destroy lives, and we urgently need new ways to help people cut down. We found that controlled, low doses of ketamine combined with psychological therapy can help people stay off alcohol for longer than placebo.
“This is extremely encouraging, as we normally see three out of every four people returning to heavy drinking within six months of quitting alcohol, so this result represents a great improvement.”
Before the trial, participants were drinking every day, consuming the equivalent of 50 pints of strong beer on average per week (125 units). Participants given ketamine and therapy drank over the recommended guidelines on just five days in total over the six month trial period on average. This represents cutting the risk of death from alcohol-related problems from one in eight, to one in 80.
Morgan said: “The number of alcohol-related deaths has doubled since the pandemic begun, meaning new treatments are needed more urgently than ever. Previously, there were some concerns about using ketamine in alcoholics due to liver problems, but this study has shown that ketamine is safe and well-tolerated in clinical conditions. In fact, we found liver function improved in the ketamine group due to them drinking much less alcohol.
“This was a phase II clinical trial, meaning it is conducted in people primarily to test how the safety and feasibility of the treatment. We now have an early signal this treatment is effective. We now need a bigger trial to see if we can confirm these effects.
“We’re certainly not advocating taking ketamine outside of a clinical context. Street drugs come with obvious risks, and it’s the combination of a low dose of ketamine and the right psychological therapy that is key, as is the expertise and support of clinical staff. This combination showed benefits still seen six months later, in a group of people for whom many existing treatments just don’t work.”
Professor Anne Lingford-Hughes, of Imperial College London, is a co-author on the study. She said: “The KARE trial is a significant step towards investigating a new approach to meet the immense unmet treatment need associated with alcoholism. The trial shows that ketamine therapy may be one way we’re able to reverse alcohol-related harms experienced by so many.”
Research into experiences of KARE participants
Research on the experiences of 12 KARE trial participants was published last August in a separate paper, in Frontiers in Psychiatry, in which researchers conducted detailed interviews.
Lead author Merve Mollaahmetoglu of the University of Exeter said: “The experiences people describe after taking ketamine infusions suggest the drug gives a new perspective that may be helpful in psychological therapy.
“Ketamine induces a sense of being outside of your body that some say can stimulate an ‘observer state’ similar to that described in mindfulness, which may help patients take a step back, and consider thoughts and emotions. Participants told us this experience helped change their relationship with alcohol.”
For one of the participants in the trial interviewed, thinking less about their own problems and feeling more connected with the world around seemed to affect their relationship with alcohol:
“The sense of oneness that I felt and the sense of moving away from focusing on the worries and the small stuff is helpful in terms of improving my relationship with alcohol. Because I think I used alcohol as a self-medication and as a blocking and avoiding mechanism. And I think feeling that those issues are less prevalent or at least less important means I feel less motivated to drink.”
Many of the participants saw the combination of ketamine and therapy as a beneficial combination. One interviewee said: “Not only did I get a life changing and mind-altering experience, but then the therapist did plug some new thoughts to me that made me think differently.
“I feel that it is really important that when you are split open, you know, in such an intense and life changing way that you are given new thoughts and you know that someone gives you something to refill that, so you do change stuff.”
Anthony Tennyson is Chief Executive of AWAKN, a biotechnology company developing and delivering psychedelic therapeutics (medicines and therapies) to treat addiction, which has acquired the rights to the research.
He said “We are so pleased to see such encouraging results in an area of treatment that has been stagnant for so long, leaving so many people with little or sub-par options available to them. With Ketamine being a licensed medicine, it means we can deliver this treatment now in our clinics and through partnerships, which is a radical shift in the alcohol addiction treatment industry.”
Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder
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, O Merve Mollaahmetoglu, H Valerie Curran, Brigitta Brandner, Anne Lingford-Hughes and Celia JA Morgan.
First published online in The American Journal of Psychiatry on 11 January 2022.
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.
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.
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.
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.
Frontiers in Psychiatry article – “This Is Something That Changed My Life”: A Qualitative Study of Patients' Experiences in a Clinical Trial of Ketamine Treatment for Alcohol Use Disorders (Open access)
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