Ketamine and psychological therapy helped severe alcoholics abstain for longer in trial

The Ketamine for reduction of Alcohol Relapse (KARE) trial was led by the University of Exeter and funded by the Medical Research Council. 

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 University of Exeter to use in their clinics and partnerships. 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. 

Published in The American Journal of Psychiatry, 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 per cent 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.

Professor 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’s 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 on the experiences of 12 KARE trial participants were previously published in a separate paper, published 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.” 

Patrick Chinnery as MRC Clinical Director said: “Additional research is still needed, but it is promising that MRC funding for this study has facilitated these early results, which could lead to new ways to treat addiction. Funding this type of clinical neuroscience research, in humans, is important as it will help us improve our understanding of addiction and find more effective therapies that could prevent relapse.”

The study was led by the University of Exeter in collaboration with Imperial College London and University College London.  It was conducted in the NIHR Exeter Clinical Research Facility ad the NIHR UCLH Clinical Research Facility.

The paper ‘Ketamine adjunctive to relapse prevention based psychological therapy as a treatment for alcohol use disorder’ is published today in the American Journal of Psychiatry.  

The paper on participants’ experiences, entitled ‘This is something that changed my life”: a qualitative study of patients’ experiences in a clinical trial of ketamine treatment for alcohol use disorders’ was published in Frontiers in Psychiatry on August 16.  

Case studies:  

1. Ketamine trial helped Grant realise binge drinking stemmed from childhood  

Grant grew up in a busy household full of love, but where attention was in short supply. Only when he took part in the Ketamine for Reduction of Alcohol Relapse (KARE trial) did he realise that vying for his parents’ time was linked to his adulthood drinking, helping him finally kick the habit.  

“I was a binge drinker,” said the events manager, 54. “If I was drinking, it would be at least a couple of bottles of wine every night, on a night in, and probably a bottle of vodka if I was at a party. Then I’d clean up my act for a few weeks and not touch a drop, like Dry January of Stoptober or whatever. But when that period ended, I’d start off with just the odd couple of glasses of wine, and then get sucked back in hard. It’s pretty common, but it was a really unhealthy yoyo.  

“I was functioning well in my job and my health was ok. I’d try and compensate by keeping really fit. I’d drink two bottles of wine then run 16 miles the next day. But it’s the double-whammy of alcohol and the sugar that wakes you up at night. I just didn’t want it in my life anymore. I wanted to be free of it, so I grabbed the opportunity to take part in the trial with both hands. I really liked the idea of taking part in research that could give people on their last legs a real chance.”

On his second infusion of ketamine, Grant has a “kind of out-of-body experience”. He explained: “I was floating above myself and I was just… white. I was this entity, up on the ceiling. I felt serene and humble, and I finally understood my place in the universe. Now, whenever I face problems in life, I know I can get through it. I find myself thinking ‘at least I’m not a white blob’.” 

Later, the psychotherapy helped him realise that his drinking was linked to his childhood, living with parents who were loving, but incredibly busy, working and providing a home to more than 200 foster children across their married life. “My parents gave plenty of love, but they just didn’t have time to give me much attention. Through the ketamine and therapy, I realised that’s what I had been craving in my drinking. It was really a case of acting out to get attention. Realising that has helped me kick the habit for nearly three years now.  

“I still love a party, but now I don’t even think about booze. I’ve grown to love the fact that I can drive where I want, wake up feeling great and not have to worry about what I did or said the night before. I’m finally free from alcohol.” 

2: Ketamine trial helped Alex kick 20 years of daily drinking  

Alex had been trying to kick his daily drinking habit for years, and finally found success when he took part in the Ketamine for Reduction of Alcohol Relapse (KARE trial).  

The father of two young girls was successful in many aspects of his life. The 42-year-old had a career as a freelance sports photographer under his belt before changing tack to graduate in Psychology at the age of 42.  

His life in South London was busy, and Alex would take up every opportunity to drink socially. Then every night, without fail, he would head home and drink four or five beers in the evening. His lifestyle had facilitated a habit, which had become a problem.  

“When I was freelancing. I could do as I pleased. Drinking on shoots was commonplace and it was always followed by a few more beers back at home. For years, I didn’t see it as a problem, but when I decided I wanted to stop, I found I couldn’t.  

“I’d say I was on the moderate end of having a drinking problem, which I suspect is quite relatable to a lot of people. I wasn’t missing any work deadlines and I was coping in my everyday life, but I wanted to stop drinking every day and I just couldn’t do it. 

“I kept making excuses to allow myself to drink, to nip to the supermarket late at night because we were out of milk or eggs, and pick up a few more beers, and drink them on the couch.  I’d been trying to stop for a year, but I’d never managed it.”  

When Alex heard about the University of Exeter-led KARE trial, which investigated whether low-dose ketamine and psychotherapy could help alcoholics in remission to stay off booze, he thought “I have nothing to lose”. “I thought it could help me break my habit, and I was interested in contributing to research in this area. 

“I went into it with some apprehension. I gave up alcohol two weeks before the trial to fulfil the criteria for abstinence, and it was the longest time in two decades I’d gone without booze. I’d never tried ketamine before, and it was pretty odd not knowing what arm of the trial I was going to get.   

“Within minutes of that first treatment, it was clear that I was in the ketamine arm. It was one of the more intense experiences of my life. Everything was completely internalised – no body, no outside world. I felt sucked into an internal void.”  

Some initial anxiety gave way to a strong sense of internal monologue, and a feeling of dissociation. “At times it felt like I no longer existed, like I was in some kind of afterlife, but I was accepting of that. I’d say acceptance was a big theme of my experience throughout. It was interesting, but it left me quite confused and it took me a while to make any sense of it.” 

Alex was sceptical about the psychotherapy that followed each of three ketamine sessions, but diligently threw himself into the tasks set, such as keeping a diary and listing high-risk situations in which he would be prone to drink.  

“It’s impossible for me to know which aspect is responsible for the benefits I experienced, whether it’s the ketamine, the therapy or the combination. I haven’t had a drink since that first treatment nearly three years ago, and before that I drank virtually every day for 20 years before that. 

“It’s not like the trial flicked a switch. For the first year I struggled. It was a daily battle, and I was irritable and short-tempered. My wife and family really supported me. But now I can go into a pub where my friends are drinking, and it doesn’t even cross my mind to order alcohol. The trial changed my life  - there was absolutely no chance I’d have got to this point on my own.”