Esketamine combined with a mindfulness-based intervention for individuals with alcohol problems

Alcohol misuse is described as a leading global health problem with high relapse rates despite available pharmacological and behavioural treatments; only 18% of alcohol-dependent drinkers receive treatment in the UK and those who do are reported to be 70%-80% likely to relapse within the first year. Ketamine, and specifically esketamine (the S-enantiomer), has emerged in addiction research as a promising adjunctive treatment: prior studies have reported reductions in alcohol craving and consumption and improved abstinence when ketamine is combined with psychotherapy, but the mechanisms behind these benefits remain unclear. Gent and colleagues set out to test one proposed mechanism — that esketamine enhances engagement in psychotherapy — by combining a single dose of sublingual esketamine with a brief mindfulness-based intervention (MBI) in hazardous drinkers. The primary aim was to determine whether esketamine increases psychological and/or physical engagement with daily mindfulness practice and whether any increase in engagement mediates improvements in alcohol-related outcomes such as craving and consumption. The authors hypothesised that esketamine would enhance engagement in MBI and that this enhancement would be associated with better drinking-related outcomes.

The study was pre-registered and used a double-blind, placebo-controlled mixed within- and between-subjects design. After screening, participants were randomised 1:1 to receive either two oral thin film strips of esketamine hydrochloride (AWAKN002; total dose 115.1 mg) or two oral thin film strips of vitamin C (placebo). The protocol involved a baseline screening visit (day 1), drug administration visit (day 8) and an online follow-up at day 14; participants remained in the research centre until clinically assessed as recovered after dosing. The recruitment target reported in the extracted text resulted in 28 enrolled participants after exclusions and drop-outs. Eligible participants were adults scoring 8–40 on the AUDIT (hazardous drinking to moderate–severe AUD), fluent in English and seeking to reduce alcohol consumption. Exclusion criteria included history of psychosis or schizophrenia, current treatment for a substance use disorder, uncontrolled hypertension (>140/90), BMI <16 or >35, medications contraindicated with ketamine, positive urine ketamine screen and signs of alcohol withdrawal on psychiatric assessment. The psychological intervention consisted of 14 daily MBI sessions (5–25 minutes each) delivered by email and introduced at baseline. Sessions included basic meditative practice for beginners and, on days 7 and 14, relapse-prevention material tailored to problem drinking (e.g. mindful breathing, body signals, acknowledging thoughts). At the drug visit participants were prepared via a researcher script, dosed, given an eye mask and optional relaxation music for 40 minutes, and monitored until discharge. Outcome measures comprised self-report indices of engagement (a four-item psychological engagement questionnaire on a five-point scale and a two-item physical engagement measure combining days practised and frequency), mindfulness (FFMQ-15 and MAAS), alcohol-related measures (ACQ-SF-R for craving and Timeline Follow-Back for consumption), subjective drug effects (CADSS for dissociation, BSS for bodily symptoms, MEQ-30 for mystical experiences), and mood/well-being (PHQ-8, GAD-7, WEMWBS). Analyses followed the pre-registered plan: demographic comparisons used t-tests and chi-squared tests (Mann–Whitney U for non-parametric data), primary analyses used multilevel modelling with time and group as fixed effects and participants as a random effect, and mediation was tested using the jAMM model with bias-corrected 95% confidence intervals and 5,000 bootstrap samples. Jamovi v2.3 was the analysis platform.

Recruitment yielded 38 respondents with 28 participants ultimately enrolled after exclusions and drop-outs; within the sample 15 met hazardous drinking criteria and 13 met criteria indicative of AUD. The groups were reported as demographically similar with no significant baseline differences. For the primary outcome, psychological engagement in MBI showed a significant main effect of group (F(1,26)=6.88, p=0.014), time (F(2,56)=5.47, p=0.007) and a time-by-group interaction (F(2,52)=6.45, p=0.003). Simple effects indicated a significant increase in psychological engagement from pre-drug to seven days post-drug in the esketamine condition (t(52) = -3.29, p = 0.002) but not in the placebo condition (t(52) = 1.71, p = 0.093). Physical engagement (frequency of practice) showed no significant main effects or interactions. Mindfulness scores on the FFMQ-15 did not show significant group or time effects or an interaction. The MAAS, however, showed a significant main effect of time (F(1,26)=6.21, p=0.019), indicating increased self-reported mindfulness across the study in both groups, with no group difference or interaction. Alcohol craving demonstrated a significant main effect of time (F(3,77.2)=15.23, p ⩽ 0.001) and a significant group-by-time interaction (F(3,77.2)=5.64, p=0.002). Simple effects revealed a significant decrease in craving immediately pre-to-post drug administration for the esketamine group (t(77.52)=2.76, p=0.007) but not for placebo (t(77.01)=-1.66, p=0.101). These reductions were described as transient and did not persist to seven days post-dose. Alcohol consumption measured by TLFB decreased across time for the whole sample (F(1,26)=9.48, p=0.005) but showed no group or interaction effects. Secondary outcomes for mood and well-being showed no significant time-by-group interactions. There was a main effect of time for depressive symptoms (F(1,26)=2.41, p=0.046) and for general well-being (F(2,52)=3.46, p=0.039), reflecting modest improvements over the study period in both groups. Subjective drug effects differed markedly by condition: esketamine produced significantly greater dissociative states (CADSS; time-by-group interaction F(1,26.22)=35.37, p ⩽ 0.001), bodily symptoms (BSS; F(1,26)=42.37, p ⩽ 0.001) and higher scores on the MEQ-30 for mystical-type experiences compared with placebo. Mediation analyses examining whether psychological engagement mediated the relationship between esketamine and alcohol craving returned non-significant results. A regression with craving as outcome and esketamine as predictor was non-significant overall (F(1,109)=1.44, p=0.233, R2=0.013). Although esketamine was significantly associated with psychological engagement (path a), psychological engagement did not significantly predict alcohol craving (path b), the direct path (c') was non-significant, and the indirect effect was not significant (β=0.03, p=0.565).

Gent and colleagues interpret their findings as initial evidence that a single dose of esketamine can enhance psychological engagement with a brief daily mindfulness practice and can produce short-lived reductions in alcohol craving. The increase in self-reported psychological engagement occurred without differential changes in self-rated mindfulness on the FFMQ-15, although both groups reported increased mindfulness on the MAAS and showed reduced alcohol consumption over the 2-week period. The authors position these results within existing theories about ketamine's therapeutic actions, noting hypothesised mechanisms such as antidepressant effects, disruption of reconsolidation of drug-related memories and enhanced neural plasticity. They suggest their data support the specific hypothesis that ketamine may improve treatment outcomes by boosting engagement in therapeutic practice, potentially by facilitating meditative-like subjective states that reduce avoidance and increase motivation to practise. Differences from prior ketamine studies are acknowledged: unlike some earlier trials that reported durable reductions in alcohol use, this study observed no group difference in alcohol consumption and only transient craving reductions. The investigators propose several possible explanations, including the non-treatment-seeking, predominantly hazardous-drinking sample (many being students), possible expectancy or nocebo effects in the placebo group, and lower baseline craving in this population relative to treatment-seeking samples. Key limitations are acknowledged by the authors. Blinding was difficult because esketamine produces distinctive subjective effects and 57% of participants had prior ketamine or recreational drug experience; the authors recommend an active placebo (e.g. midazolam) in future work to better preserve blinding. They note the MBI here was brief and may not match the potency of standard multi-week, in-person MBIs, and that engagement was measured by self-report rather than objective indices. The study also did not assess participants' motivation to reduce drinking, which could bias outcomes, and the sample — largely hazardous-drinking students — limits generalisability. The authors therefore recommend replication with longer and more intensive MBI protocols, objective engagement measures, assessment of motivation, and trials in treatment-seeking individuals.

Despite the pilot study's brevity and limitations, the authors conclude this is the first study to provide evidence that increased psychological engagement may be a factor in how ketamine-assisted interventions exert therapeutic effects in the context of mindfulness-based approaches for alcohol problems. They argue that elucidating these psychological underpinnings is important for the future development and optimisation of ketamine-assisted therapies for alcohol use disorder.