Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial

Forty participants were randomised and post-infusion drinking data were available for all; however, missing questionnaire data reduced the sample for some analyses (three participants missing HMS and two missing CADSS), leaving 35 individuals in the primary mediation analyses. Baseline average alcohol use across the sample was 6.6 drinks per day. No adverse events related to the infusions were reported. Compared with midazolam, ketamine produced significantly greater mystical-type and dissociative effects when measured immediately after infusion. The ketamine group scored on average 38.15 points higher on the HMS (ß=38.1490, p<0.05) and 12.955 points higher on the CADSS (ß=12.955, p<0.05). Ketamine also reduced the odds of engaging in at-risk drinking during the 21-day follow-up by approximately five times (p<0.05). On survival analysis, participants who received ketamine had a significantly longer time to relapse compared with midazolam (log-rank χ2=4.133, p=0.042). HMS and CADSS scores were moderately correlated (R=0.489, p<0.01). However, HMS scores correlated negatively with the number of heavy drinking days post-infusion (R=-0.466, p<0.05), while the correlation between CADSS and heavy drinking days did not reach significance (R=-0.315, p=0.054). In mediation analyses, the HMS score emerged as a significant mediator of the relationship between treatment assignment and at-risk drinking (Exp(B)=1.045, p<0.05); CADSS did not mediate this relationship (p=0.742). Consistent with mediation, the direct effect of treatment on at-risk drinking lost significance once HMS was included in the multivariate model (treatment p=0.719). Analyses of HMS subscales within the ketamine arm (n=17) identified specific associations with outcomes: ineffability scores correlated with percentage of heavy drinking days post-infusion (rs=0.624, p=0.01), while positive affect scores correlated with percentage of days abstinent (rs=0.613, p<0.05) and with average number of daily drinks post-infusion (rs=0.554, p<0.05).

Rothberg and colleagues interpret the findings as support for a role of mystical-type psychoactive effects in mediating ketamine’s beneficial impact on drinking in alcohol-dependent individuals engaged in MET. The data indicate that mystical-type experiences measured immediately after infusion, but not dissociative phenomena, accounted for reductions in at-risk drinking and longer time to relapse, suggesting that a specific subset of subjective effects may contribute to enduring behavioural change. These results extend prior laboratory findings in cocaine-dependent volunteers and parallel observations linking psilocybin-occasioned mystical experiences to therapeutic benefit in other populations. The authors propose several psychological pathways through which mystical-type experiences might aid recovery: enhanced motivation to change, a refreshed sense of self and values, greater connectedness to others and the world, and existential reappraisal that supports altered decision-making. They note that pairing ketamine with MET, a therapy designed to elicit “change talk” and goal-directed reflection, may provide a framework for translating infusion-occasioned experiences into concrete behavioural change. The ineffability dimension of mystical experience was highlighted as potentially especially relevant, given its correlation with heavy drinking metrics in the sub-analysis. Several limitations are acknowledged. Causality cannot be definitively established: shared neurobiological effects of ketamine might produce both mystical-type experiences and therapeutic benefit, making the mystical experience a marker rather than a causal mechanism. Mood enhancement from ketamine could also account for both increased mystical-type scores and improved drinking outcomes; although the trial screened out participants with DSM-IV depressive disorder to reduce confounding by antidepressant effects, subclinical mood changes may still have influenced results. Generalisability is limited by a small sample size and the selection of a non-depressed subset of the AUD population; many people with AUD have comorbid psychiatric disorders that were excluded here. Finally, the trial combined ketamine with MET, so interactions between the drug’s subjective effects and the psychotherapeutic platform might have been important and warrant further study. The investigators suggest future research should dissect existential and psychospiritual mechanisms, examine multiple facets of mystical experience in relation to outcomes, and explore how subjective effects of ketamine and other psychedelics interact with psychotherapy to influence clinical endpoints across substance use and mental health disorders.

This secondary analysis strengthens the evidence that mystical-type phenomena occasioned by ketamine are associated with subsequent reductions in problematic drinking when ketamine is delivered within a motivational enhancement therapy programme. The authors conclude that mystical-type experiences merit further investigation as potential psychological mechanisms of change in addiction treatment, and that future studies should more precisely characterise these subjective effects and their interaction with psychotherapeutic interventions across diverse clinical populations.