This Is Something That Changed My Life: A Qualitative Study of Patients' Experiences in a Clinical Trial of Ketamine Treatment for Alcohol Use Disorders

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist originally developed as an anaesthetic, has attracted renewed interest for treating psychiatric disorders at sub-anaesthetic doses. Previous quantitative work has demonstrated rapid antidepressant and other therapeutic effects and some studies have suggested ketamine can influence substance use outcomes. However, comparatively little qualitative work has examined patients' phenomenological experiences of therapeutic ketamine and how those acute psychoactive effects might relate to clinical change. Existing scales used in ketamine trials emphasise dissociation and may not capture the full range of subjective effects, including mystical, spiritual or awe-related experiences, that could plausibly contribute to therapeutic mechanisms. J. and colleagues set out to explore, through semi-structured qualitative interviews, the retrospective subjective experiences of participants who received at least one ketamine infusion as part of a Phase II randomised controlled trial (the KARE trial) for alcohol use disorder. The study aimed to characterise motivations for participation, the role of set and setting, the nature of acute and subacute ketamine experiences (including perceptual, dissociative and mystical phenomena), and participants' perceptions of lasting or transformational effects on their relationship with alcohol and broader life perspective. The authors frame this work as complementary to quantitative trial outcomes and as a means to inform future measurement and clinical practice in ketamine-assisted treatment.

This qualitative follow-up involved semi-structured interviews with 12 participants (nine males, three females) who had taken part in the KARE Phase II double-blind randomised controlled multisite trial. The KARE trial delivered up to three weekly ketamine infusions (0.8 mg/kg) or saline placebo alongside seven sessions of either psychological therapy or alcohol education; the talking sessions were scheduled immediately before and approximately 24 hours after each infusion. Participants for the qualitative study were a subset of those randomised to ketamine; of 48 ketamine-assigned participants, 25 were contactable and 12 agreed to be interviewed. Interviews were conducted online over Zoom by two researchers, audio-recorded, transcribed verbatim and de-identified. Ethical approval was obtained from the University of Exeter Institutional Ethics Committee. The interview schedule covered acute and subacute ketamine experiences, experiences of psychotherapy/education, rumination (reported elsewhere), current drinking and motivations for trial participation. Before interviews, participants were asked to guess their allocation; all 12 correctly guessed they had received ketamine. The authors used Reflexive Thematic Analysis (Braun & Clarke) with a realist/essentialist stance to identify patterns of meaning across transcripts. Two researchers independently coded transcripts line-by-line, discussed discrepancies and reached consensus with input from a third researcher when needed; theme development was iterative and involved the full team. The analysis drew partly on existing ketamine literature to structure attention to pre-trial, acute, subacute and longer-term effects.

Thematic analysis yielded six overarching themes spanning motivations, context, the acute phenomenology of ketamine, and perceived longer-term transformations. Motivations for participation were multifaceted, including concern about problematic drinking, having reached a crisis point (“hitting rock bottom”), altruism, curiosity and reassurance derived from the trial's legitimacy in a university/hospital setting. Participants reported both internal motives (health, desire for abstinence) and external influences (trust in the research setting). Set and setting were described as influential: prior experience with altered states, participants' mindset and spiritual beliefs shaped acute experiences, and many participants felt comforted by the professionalism and controlled clinical environment. Staff interactions and preparatory scripts (including suggestions to set an intention) were reported to affect how sessions unfolded, and earlier infusion experiences affected expectations for subsequent sessions. Acute experiences were characterised by apparent contradictions and rapid fluctuation. Nearly all participants reported dissociation, detachment or floating sensations (loss of bodily self, paralysis-like immobility) alongside episodes of ego dissolution (a diminished sense of self and feelings of unity or connectedness). Visual and auditory perceptual distortions were ubiquitous and often changed dynamically within a session; some participants reported vivid hallucinations or visions. Many described profound meaningful, spiritual or mystical-type experiences (epiphanies, insights about life/values, encounters framed in religious terms) and frequent distortions or transcendence of time perception. Positive acute effects included relaxation, calmness, feelings of relief and descriptions of the experience as ‘‘life changing’’ for some; many participants reported brief mood improvements in the hours or days after infusion. Transient negative effects were common: fear or panic (notably fears of losing self or being stuck in the state), intense paranoid thoughts about the trial/staff, nausea, vomiting and subjective paralysis. These distressing episodes were reported as short-lived and resolved without persistent psychosis or lasting perceptual disturbance. Participants reported perceived transformational effects of the infusions and the broader trial. Although only three of the 12 interviewees were completely abstinent at the time of interview, all who completed treatment reported changes in their relationship with alcohol: longer periods of abstinence than previously, reduced craving or pleasure from alcohol, reduced use for coping and more socialised drinking motives for some. Several participants linked these changes to acute ketamine experiences (e.g. forgetting the taste of preferred drinks, diminished self-absorption), whereas others were uncertain whether changes owed to ketamine, the psychotherapy/education, or non-specific trial effects such as care from staff. Four participants had received psychotherapy; some described the talking sessions and ketamine as mutually supportive, with ketamine enhancing receptivity to psychoeducation. A minority described nonspecific benefits attributable to attention, therapeutic alliance, or a desire to ‘‘do well’’ for trial staff. Sample and timing details relevant to interpretation: participants' ages (n=10 reporting) ranged 22–59 (mean 46.5 years), time from last infusion to interview ranged 11 months to 3 years 4 months, four had received psychotherapy, craving scores (Alcohol Craving Questionnaire Short Form–Revised) averaged 2.91 (SD 0.82). All interviewees reported they had received ketamine (i.e. guessed allocation correctly).

J. and colleagues interpret the findings as highlighting a wider phenomenological range of ketamine's acute effects than is captured by its standard label ‘‘dissociative anaesthetic.’' The authors note that participants commonly experienced dissociation and transient distress but also reported paradoxical feelings of connectedness, ego dissolution, awe, altered time perception and meaningful or mystical-type insights. These phenomena parallel constructs reported in classic psychedelic research (for example, mystical experiences and the ‘‘small self’’) and the authors propose that such experiences — including ‘‘awe’’ — may be therapeutically relevant for alcohol use disorder by disrupting compulsive patterns of thought and self-focused coping. The authors emphasise the importance of set and setting: participants generally felt reassured by the professional clinical environment and by preparatory procedures and staff support, which appeared to mitigate challenging experiences. They discuss measurement implications, arguing that common instruments such as the Clinician Administered Dissociative State Scale (CADSS) may inadequately capture the breadth of ketamine-induced subjective effects; they recommend developing new measures to assess mystical, awe-related and other experiential domains alongside dissociation. The possibility that acute subjective effects mediate therapeutic outcomes is raised as an empirical question requiring analysis of the main trial data. Practical considerations suggested by the authors include preparing participants for possible transient paranoid or time-distortion experiences, considering screening for baseline paranoid tendencies, and potentially titrating doses across sessions to manage tachyphylaxis (rapid tolerance) and to aim for ‘‘peak’’ or ‘‘mystical’’ experiences when clinically appropriate. They also note that short-lived intense distress can be tolerated safely within a supportive trial setting and that recorded misuse following the trial was limited in this sample, though abuse potential remains a general concern. Limitations acknowledged by the authors include retrospective interviews conducted on average two years after treatment (recall bias), a small and self-selected sample drawn from the subset of trial participants who could be contacted (limiting generalisability), and the difficulty of disaggregating effects of ketamine from psychotherapy and nonspecific trial factors (therapeutic alliance, attention, expectancy). The authors conclude that qualitative insights such as these can inform outcome selection in future trials (beyond binary abstinence/relapse measures), guide measurement development for ketamine's acute effects, and help tailor preparatory and supportive elements of ketamine-assisted interventions. They emphasise that the extent to which acute psychoactive experiences contribute causally to clinical benefit in alcohol use disorder remains to be determined.