Written by Tiago Vasconcelos.
A review of the recent paper – ‘Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder’ by Grabski et al., 2021
Alcohol abuse is one of the costliest conditions affecting modern health and a high proportion of people suffering from alcohol use disorder (AUD) are not responsive to the limited therapies currently available. There is a high correlation between depression and alcohol abuse, and the risk of developing AUD is increased in depressed people. Ketamine is a psychoactive drug which affects the brain in a number of ways. It has been used for a long time as an anaesthetic drug by medical professionals and more recently has become popular as a recreational drug. In addition to this, esketamine, a derivative of ketamine, has very recently been approved by the FDA for use in the USA as a fast-acting antidepressant, this is following research which started in the 70s exploring the anti-depressant effects of ketamine. Common antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) can take many weeks to have their effects, and are often ineffective, whereas ketamine can help to alleviate the symptoms of severe SSRI-resistant depression in a matter of hours in some patients. These recent developments in the study of ketamine for use in psychiatric conditions has prompted interest in its use in treating substance addiction with the earliest studies in the 90s showing its clinical utility in alcoholism.
Prof Celia Morgan and colleagues, from Exeter University in the UK, have recently published their findings in this field in a research paper entitled: ‘Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder.’ In this article, I will explain what the aims of this work were, the methods they used to investigate their scientific question, and the important findings of the work and their significance for society.
Given the strong link between depression and alcohol use, the authors hypothesised that ketamine may help to reduce alcohol use for two reasons – the first is by improving mood and reducing the patients’ need to drink heavily; the second is that the psychoactive properties of ketamine may make patients more responsive to traditional psychological therapy. A few previous studies involving a very small number of patients showed promising results from combining ketamine and cognitive behavioural therapy, with a reduction in the proportion of patients who had used alcohol several months following treatments with ketamine and therapy. In this study, the researchers aimed to demonstrate in a larger sample of patients that a ketamine infusion & psychotherapy significantly reduced alcohol use in people suffering from alcohol use disorder when compared with a placebo infusion & alcohol education.
In order to investigate the effect of ketamine and psychotherapy on alcohol use, the researchers recruited 96 people suffering from alcohol use disorder from the local community, and assigned each of them to one of four groups:
Group 1 received three weekly ketamine infusions. On the day of the infusion and the day after, these patients also received a mindfulness-based relapse prevention therapy session.
Group 2 received the same psychological therapy sessions as Group 1, but instead of ketamine infusions they received infusions of saline, to determine whether ketamine produced larger effects than placebo.
Group 3 also received the same ketamine infusions as Group 1, but instead of therapy, they received an alcohol education session for the same duration as the therapy. In contrast to the therapy sessions, these education sessions did not have formal psychological components relating to personal relapse prevention strategies, mindfulness, or the promotion of personal well-being.
Group 4 received the same control education sessions as Group 3, but received placebo saline infusions like Group 2.
Patients were asked to keep track of their alcohol use during the treatment period, and for a period of six months following the treatment’s conclusion. The patients also attended two follow-up appointments at three and six months after the conclusion of their treatment, where they were scored for depressive symptoms and symptoms of alcohol and nicotine craving. 45% of patients had a diagnosis of anxiety, and 40% had a diagnosis of depression at the start of the study.
The study showed that there was a significantly greater percentage of days abstinent from alcohol at six-month follow-up in the ketamine compared with the placebo group, with an average reduction of 10 additional days abstinent for the patients who were given ketamine infusions over the six months. This is a relatively small decrease, and no significant difference was found in the proportion of patients who relapsed (defined as having at least one episode of heavy drinking) during the six-month period following the treatments. When comparing Group 1 with Group 3, there was a small, but statistically insignificant decrease in the number of days on which the patients drank alcohol during the follow-up period. This suggested that the psychological therapy techniques used were marginally more effective than the education sessions in this study, though it is possible that over a large population of patients they may have a benefit – studies with a larger sample size will be necessary in the future in order to determine whether there is an additional benefit to this sort of psychological therapy combined with ketamine. Ketamine treatment caused a reduction in the severity of depression symptoms that the patients reported at three months following the treatment, but by six months there was no difference in depression between patients who had received ketamine vs placebo. A small proportion of patients experienced severe side effects of ketamine administration, and two had to withdraw from the study as a result. The greatest difference in response seen in this study was in the comparison between the ketamine & psychotherapy vs placebo and psychoeducation with non-overlapping confidence intervals. This gives early indications of the added therapeutic efficacy of ketamine & therapy in treating these patients as per the researchers a priori hypotheses.
Overall, this was a useful proof-of-concept study, providing another step towards understanding how ketamine with therapy may best be used in treating alcohol addiction. Decreases in the number of days on which patients drank were seen up to six months following treatment, a surprisingly long-lived effect of the ketamine infusions and superior efficacy was seen when compared to patients in the placebo arms of the study highlighting the clinical utility of this approach. While important, the results from this study must be treated with caution, this was an early-stage clinical trial, and as such contained a small number of participants. Larger studies will be needed in future to confirm whether ketamine and psychological therapy will be a valuable new tool in treating alcohol use disorder.