BACKGROUND AND AIMS: Ketamine assisted psychotherapy is a promising new treatment for alcohol use disorder (AUD). The psychoactive effects of repeated intravenous (IV) ketamine infusions in people with AUD and their mechanistic role in treating AUD are largely unknown. This study aimed to (1) quantify the subjective, psychoactive effects of IV ketamine in people with AUD, (2) investigate how these effects change over three dosing sessions and (3) test whether these effects mediate ketamine's therapeutic benefits in reducing alcohol consumption.

DESIGN: Secondary analysis of the randomised, parallel-arm, double-blind, placebo-controlled, phase 2 'KARE' clinical trial.

SETTING: Two clinical research facilities in England.

PARTICIPANTS: 96 adults (35 women) aged 18-64 years with moderate-to-severe AUD.

INTERVENTION: Three weekly infusions of either ketamine (IV 0.8 mg/kg over 40 minutes) or placebo (saline solution).

MEASUREMENTS: Psychoactive drug effects experienced were self-reported pre-, during- and post-infusion, every 20 minutes (eight times/infusion) on Likert scales (1-10), for: Effects of Drug, Liking of Drug, Altered Reality, Out of Body Experiences, Visual Distortion, Sound Distortion and Altered Time Perception. For each scale, we calculated area-under-the-curve (AUC) scores for each infusion and the AUC average across three infusions. The clinical outcome was percentage of days abstinent from alcohol in the 6 months after infusions.

FINDINGS: Ketamine produced strong psychoactive effects on every scale, relative to placebo (all P values < 0.001). Ketamine's psychoactive effects were moderated by infusion number (infusion 2 vs. infusion 1) for: Liking of Drug (P = 0.001), Altered Reality (P = 0.030) and Out of Body Experiences (P = 0.033), with small-to-moderate effect sizes. The remaining four psychoactive effects were not statistically significantly changed by repeated dosing. No psychoactive effect statistically significantly mediated the relationship between drug treatment and percentage days abstinent (all P values = 0.075-0.935).

CONCLUSIONS: People with alcohol use disorder experience alterations in consciousness from 0.8 mg/kg intravenous ketamine administration. Ketamine's effects appear to be broadly consistent across three repeated infusions. Ketamine-related reductions in alcohol consumption do not appear to be mediated by the acute psychoactive effects of ketamine.