A qualitative and quantitative account of patient’s experiences of ketamine and its antidepressant properties

Ketamine has emerged as a prominent investigational treatment for rapid-acting antidepressant effects. Earlier clinical work showed rapid symptom reduction in treatment‑resistant depression and, because ketamine produces acute alterations in consciousness, researchers have queried whether the psychedelic properties of ketamine contribute to its antidepressant action. Compared with classic serotonergic psychedelics such as psilocybin, ketamine differs in pharmacology and phenomenology, and prior studies relating ketamine's acute subjective effects to clinical benefit have been inconsistent, in part because typical scales (for example, CADSS or BPRS) emphasise dissociation or psychotomimesis rather than the richer, mystical-like features measured by instruments such as the Altered States of Consciousness (ASC) questionnaire. Sumner and colleagues designed a mixed-methods study to explore the acute psychedelic experience of sub‑anesthetic ketamine and its association with antidepressant response, and to characterise any sustained changes in perspective or mood that persist beyond the immediate therapeutic window. The study combined quantitative measurement using the 11‑dimension ASC (11D‑ASC) and clinician-rated depression scores with two rounds of qualitative interviews conducted shortly after infusion and 3–8 weeks later, using a randomised, double‑blind, active placebo–controlled crossover framework against remifentanil.

The study was a randomised, double‑blind, active placebo‑controlled crossover trial conducted in an MRI setting. Participants met DSM‑V criteria for major depressive disorder; 32 volunteers enrolled and 30 completed both study days (two participants completed only the ketamine day). On one session participants received racemic ketamine administered as a 0.25 mg/kg intravenous bolus followed by 0.25 mg/kg/h infusion for 45 minutes (participants with BMI >30 were dosed by ideal body weight). On the other session participants received the active placebo remifentanil via a target‑controlled infusion to a plasma concentration of 1.7 ng/mL over 9 minutes. Drug order was randomised and counterbalanced; all infusions were given while participants were undergoing MRI scanning. The primary clinical outcome was change in the Montgomery‑Åsberg Depression Rating Scale (MADRS) at 1 day post‑infusion versus baseline; responders were predefined as those with ≥50% reduction in MADRS. Acute psychedelic phenomenology was measured with the 11D‑ASC: the validated 42‑item subset was administered about 3.5 hours after drug administration, producing subscale scores (spirituality, unity, insight, disembodiment, impaired cognition, anxiety, complex imagery, simple imagery, audiovisual hallucinations, changed meaning and blissfulness). Associations between 11D‑ASC dimensions and antidepressant response (% change MADRS at 24 h) were tested using Spearman's rho with false discovery rate correction. Qualitative data collection comprised two semi‑structured interviews following COREQ guidance. An acute interview was conducted face‑to‑face within an hour of infusion (average 15–20 minutes) to probe immediate perceptual and emotional effects; a second debrief telephone interview occurred 3–8 weeks post‑infusion after unblinding to explore longer‑term changes, expectations and views about future treatment. Reflexive thematic analysis was applied iteratively to transcribed interviews using NVivo 12 Pro. Multiple authors independently coded transcripts without knowledge of responder status; codes were refined by consensus and the final analysis reviewed to ensure consistency. The study used an active opioid placebo to improve blinding against ketamine's prominent psychoactive effects; the MRI environment and its likely influence on subjective experience were acknowledged as a methodological factor.

Clinical outcome: Linear mixed models showed ketamine produced a rapid antidepressant effect relative to remifentanil, with significant reduction in MADRS by 3 hours that remained significant at 1 day and 7 days post‑dose but was not significant by 14 days. There were no significant carryover effects from the crossover design. The authors report that 70% of participants experienced at least a 50% reduction in MADRS at 24 hours. Remifentanil produced a smaller, short‑lived reduction in MADRS at 3 hours and 1 day (paired t‑tests uncorrected), but this was not sustained to 7 days. 11D‑ASC associations: The 11D‑ASC showed that the sub‑anesthetic ketamine produced a marked psychedelic response (mean global score M=28.53%, SD=16.94) versus remifentanil (M=5.52%, SD=7.59). Significant correlations were observed between percentage change in MADRS at 24 h and three 11D‑ASC dimensions during ketamine: experience of unity (Spearman r s = −0.440, p=0.039 FDR), spirituality (r s = −0.429, p=0.039 FDR) and insight (r s = −0.398, p=0.044 FDR). Other ASC subscales (blissful state, disembodiment, impaired cognition, anxiety, imagery, audiovisual phenomena, changed meaning) were not significantly related to antidepressant response after correction. Acute qualitative interview (31 participants): Reflexive thematic analysis identified five major themes. All participants reported perceptual change; common subthemes included body‑distortion (18/31), distortions of space and time, dreamlike experiences (15/31), feelings of detachment and pseudo‑hallucinations. Visual pseudo‑hallucinations were reported by 26/31 and auditory distortions (often linked to MRI scanner noise) by 14/31. Emotional and mood changes were frequent, with positive and negative affect reported; 12/31 described negative experiences such as anxiety. Loss of control was reported by 21/31, and physiological symptoms (nausea, dizziness, numbness/tingling) by 24/31. Final qualitative interview (29 participants): Six main themes emerged, foremost among them changes in perspective (reported by 28/29), including reappraisal of life, people and problems (life changes 19/29; problem‑reframing 17/29) and reconceptualisation of depression (12/29). Change in mood was reported by 23/29 (the five reporting no mood change were all non‑responders), and changes in emotion by 13/29 (some reporting reduced negative affect, others increased positive affect). Regarding durability, 27/29 referenced longevity of effects: 15/29 described short‑term changes (hours or days), while 24/29 reported some change lasting ≥3 weeks (some up to 8 weeks at the time of interview). Expectations and future‑treatment views were also prominent: 17/29 reported expectations entering the study, and 22/29 reported increased hope about future treatments after participation; increased willingness to try treatments was more common in responders (17/18) than non‑responders (5/11). Responder vs non‑responder trends: Numbers were insufficient for formal subgroup statistics, but the authors report trends: body‑distortion was more common in responders (~70%) than non‑responders (~36.6%); auditory pseudo‑hallucinations and loss of control were also more frequent among responders, while negative experiences (anxiety) were not clearly enriched in non‑responders. The authors emphasise these trends require replication with larger samples.

Sumner and colleagues interpret their findings as preliminary evidence that elements of a mystical‑like or peak psychedelic experience during ketamine infusion—specifically spirituality, unity and insight—are associated with greater short‑term antidepressant response. The 11D‑ASC correlations were supported and enriched by qualitative themes from the acute interviews, which captured experiential detail beyond standard dissociation/psychotomimesis scales. The authors note emerging evidence for phenomena akin to emotional breakthrough—intense relief or emotional release linked to addressing personal challenges—which has been associated with therapeutic benefit in psilocybin research. The discussion emphasises the importance of set and setting: although participants experienced ketamine in a constrained MRI environment without formal psychological preparation or integration, many still reported meaningful peak and afterglow effects. This suggests ketamine can produce clinically relevant experiential changes even absent a classic psychedelic therapy model, but it raises the possibility that therapeutic integration (ketamine‑assisted psychotherapy) could enhance or prolong benefit. The authors point out that randomised trials testing psychotherapeutic augmentation of ketamine are lacking. On durability and mechanisms, the authors describe qualitative evidence for a psychedelic afterglow and longer‑term shifts in perspective and decentring, which may reduce ruminative self‑focus and increase capacity and motivation to engage with psychological therapies. They propose a potential synergistic relationship whereby ketamine's short‑term opening of cognition could improve subsequent psychotherapy outcomes. Mechanistically, the discussion contrasts ketamine's glutamatergic NMDA antagonism and HCN1 effects with the serotonin‑centred action of classic psychedelics, noting both pathways may converge on enhanced plasticity; existing theoretical models such as REBUS are serotonin‑focused and do not directly incorporate ketamine, but ketamine may nonetheless produce related changes in prediction error sensitivity and network dynamics. Strengths and limitations are highlighted: the combination of 11D‑ASC and in‑depth qualitative methods is a strength, and the MRI context allowed integration with broader imaging work; however, sample size limited the reliability of correlations and subgroup comparisons. The MRI environment itself constrained aspects of the acute experience (for example, hallucination content linked to the fixation cross and scanner sounds) and may have limited set‑and‑setting effects. Finally, the authors note ethical considerations around participant expectations and the post‑trial availability of ketamine, and they call for future research that centres qualitative inquiry, avoids MRI interference where appropriate, and evaluates the added value of psychotherapeutic integration.

The authors conclude that sub‑anesthetic ketamine administered for depression produces hallmark features of a psychedelic experience and that certain elements of the peak experience and afterglow may contribute to its antidepressant properties. They suggest there is a rationale for incorporating psychotherapeutic guidance and careful attention to context when delivering ketamine for major depressive disorder, because qualitative interviews revealed experiential and perspective changes not captured by depression rating scales alone.