Mechanisms of anti-depressant and anti- alcohol effects of ketamine in patients with alcohol use disorder
Merve Mollaahmetoglu, Joy Krecké, Charlie Oldfield, Raphaelle Grimaud, Ella Anthes, Chris Dodds, Bethan Marsh, Meryem Grabski, David Nutt, Celia J. A. Morgan
Research Square September 30, 2026 preprint DOI: 10.21203/rs.3.rs-11194569/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of a randomized triple-blinded controlled clinical trial |
|---|---|
| Population | People with alcohol use disorder participating in the KARE trial |
| Interventions | Ketamine psychological support |
| Duration | 3-month and 6-month follow-up |
| Topics | Addiction Esketamine Ketamine |
| Key findings | Ketamine treatment reduced anhedonia and repetitive negative thoughts at 3 months but not 6 months. Family history of alcohol use disorder moderated these effects, with greater reductions in anhedonia and repetitive negative thoughts among those with such a history. In that group, ketamine reduced craving, which mediated its effect on percentage of abstinent days; this mediation was absent in those without a family history. |
Abstract
Abstract Ketamine is known to have anti-depressant effects and is suggested to reduce substance use. However, little is known about the mechanism of these effects. Given evidence from studies in depression of a greater therapeutic effect in those with a family history of AUD, this latter factor was also investigated as a moderating factor. We used data from the KARE trial, a randomised triple-blinded controlled clinical trial, examining the efficacy of three infusions of ketamine each followed by psychological support as a treatment in people with AUD. State anxiety, anhedonia, repetitive negative thoughts (RNT) emerged as factors from a factor analysis of all the trial questionnaires. We replicated original trial analyses to show a significant reduction in percentage days abstinent and extended to demonstrate this survived including data on alcohol use from a time point before participants had become abstinent from alcohol. Ketamine treatment was found to significantly reduce anhedonia and RNT at 3-months follow-up though not at 6-months. Family history of AUD was found to moderate the relationship between drug group and anhedonia and RNT at 3-months, with individuals with a family history of AUD reporting a greater effect of ketamine on anhedonia and RNT. Among people with a family history of AUD, ketamine reduced craving and this reduction then mediated its effects on percentage of abstinent days. This effect was not evident among those without AUD family history. . Neither anhedonia nor RNT scores at 3-months were found to mediate the effects of ketamine on abstinence at 6-months follow-up. Family history of AUD emerged as an important patient characteristic to consider in the clinical use of ketamine in psychiatry.
Comparable studies
Other randomized controlled trials on ketamine for addiction, most cited first.