Measuring the psychoactive effects of ketamine in alcohol use disorder: When assessment shapes experience

A commentary on the KARE trial argues that the study's conclusion—that ketamine's dissociative and perceptual effects do not mediate abstinence outcomes in alcohol use disorder—may be premature due to measurement issues. The authors note that subjective effects were assessed repeatedly during infusions, which could alter the experience, and that non-validated Likert scales were used instead of validated instruments like the Mystical Experience Questionnaire or Emotional Breakthrough Inventory. They highlight that mystical-type experiences, not dissociation, have been linked to therapeutic benefits in other studies of ketamine and psilocybin for addiction and depression. The commentary calls for future trials to minimize in-session interruptions, use validated psychedelic-specific scales after the acute phase, and distinguish dissociation from mystical or transformative experiences before concluding that the altered state is mechanistically irrelevant.

Study at a glance

Abstract

Bloy et al. [1] provide an important and methodologically rigorous secondary analysis of the Ketamine for the reduction of Alcoholic Relapse (KARE) trial, examining whether acute psychoactive effects mediate the therapeutic impact of ketamine in alcohol use disorder (AUD). Their finding that dissociative and perceptual effects did not mediate abstinence outcomes is clinically relevant, and contributes meaningfully to ongoing debates about whether the therapeutic action of ketamine depends in part on its subjective effects [2, 3]. However, we believe that how psychoactive effects are measured, and when they are measured, deserves closer scrutiny. In this study, two important issues arise regarding the measurement of psychoactive effects. First, subjective effects were assessed eight times per infusion, even though the repeated in-session probing of internal states may meaningfully alter the very experience being studied. Second, the study used non-validated Likert scales (e.g. altered reality, out-of-body experiences, visual distortion); though commonly used in psychopharmacology, they are not validated instruments for capturing psychedelic-type experiences. As clinicians and researchers working with ketamine within a psychedelic-informed therapeutic model since 2018 [4], we have observed that attentional focus, set and immersion critically shape the subjective experience [5-7]. Repeatedly interrupting participants during the acute state to complete rating scales may shift attention from immersive, meaning-making processes toward self-monitoring and cognitive appraisal [8]. In psychedelic research, subtle contextual factors can significantly influence phenomenology and downstream therapeutic integration [2, 9]. It is therefore plausible that intensive, repeated measurement during peak effects could attenuate the depth, coherence or perceived meaningfulness of the experience. The choice of scales also matters. Psychedelic research using validated instruments derived from the psilocybin literature—such as the Mystical Experience Questionnaire (MEQ) and the Emotional Breakthrough Inventory (EBI) has shown associations between experiential qualities and therapeutic outcomes [6, 7]. In our own work in treatment-resistant depression, higher MEQ and EBI scores following ketamine were significantly associated with antidepressant response [7]. These findings align with prior psilocybin trials, where mystical-type experiences robustly predict clinical improvement in both AUD [10-12] and depression [13]. Similarly, Dakwar and colleagues demonstrated in cocaine use disorder that ketamine produced greater mystical-type experiences (Hood Mysticism Scale, HMS) relative to active controls, and that HMS but not dissociation measured by the Clinician Administered Dissociative States Scale mediated improvements in motivation to quit and reductions in cocaine use [14]. These findings were replicated in subsequent work, again showing that mystical-type effects, rather than dissociative intensity per se, mediated clinical benefit [15]. Bloy et al. acknowledge that their scales did not assess mystical or spiritually salient dimensions. This distinction is crucial. Dissociation, perceptual distortion and ‘strength of drug effect’ are not equivalent to experiences characterized by unity, transcendence, insight or emotional breakthrough. Concluding that subjective effects do not mediate therapeutic response may therefore depend heavily on which aspects of subjectivity are measured—and how the experience is sampled. We fully agree that the therapeutic action of ketamine may involve neuroplastic and circuit-level mechanisms independent of conscious experience. Yet current evidence from psychedelic and ketamine-assisted models suggests that phenomenology is not monolithic [2]. Scales and assessment timing can meaningfully shape both what is measured and what unfolds. Future trials should consider: (i) minimizing in-session interruptions; (ii) using validated psychedelic-specific instruments administered after acute resolution; and (iii) distinguishing dissociation from mystical-type and emotionally transformative experiences. Clarifying these methodological dimensions will be essential before concluding that the ketamine-induced altered state of consciousness is mechanistically irrelevant in AUD. Christina McAnulty: Conceptualization; writing—review and editing. Nicolas Garel: Conceptualization; writing—original draft; supervision. None. None.