Mystical Experience Induced by Esketamine Treatment: A Real-World Observational Study

Treatment-resistant depression is common and difficult to manage, and ketamine and esketamine have emerged as fast-acting antidepressant options. Most attention has focused on dissociation as the main acute subjective effect, but earlier research suggested that this does not reliably explain antidepressant response. At the same time, studies of classic psychedelics have shown that mystical-type experiences, such as feelings of unity, insight, spirituality, bliss, transcendence and ineffability, can be associated with clinical improvement. For (es)ketamine, evidence for similar experiences existed but was limited, inconsistent, and often based on sparse or single-time-point assessments. Mallevays and colleagues aimed to determine whether established psychedelic experience questionnaires can capture esketamine-induced effects in routine care, to describe the frequency and phenomenology of mystical experiences during treatment, and to examine whether these acute subjective effects are associated with antidepressant outcomes. They also explored whether baseline spirituality and personality traits predicted either mystical experiences or treatment response. The study was designed as a real-world, longitudinal observational investigation across the full induction phase of esketamine treatment in patients with treatment-resistant depression.

This was a prospective naturalistic observational study conducted in two clinical centres over the induction phase of esketamine treatment. The follow-up lasted four weeks, with the option to extend to five weeks if induction was prolonged, and participants were assessed at each administration, which occurred twice weekly. Fifty-seven patients were recruited and 12 were excluded, leaving 45 participants in the final sample. Sociodemographic and clinical characteristics, treatment resistance history, and the indication for esketamine were collected from the clinical team and patient interviews. Depressive symptoms were measured with the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) and the self-report Quick Inventory of Depressive Symptomatology (QIDS-SR16). Suicidality at baseline was assessed with the Columbia-Suicide Severity Rating Scale. Baseline MADRS, QIDS-SR16 and C-SSRS were completed before treatment started, while MADRS was repeated before each session and a final MADRS and QIDS-SR16 assessment was completed within one week after the induction phase. Change in depression was defined primarily as baseline MADRS minus post-treatment MADRS. Acute subjective effects were measured after each session using the Mystical Experience Questionnaire (MEQ-30), completed within 24 hours. The authors used a threshold of MEQ-30 ≥ 60 at least once during treatment to define participants as having experienced a mystical experience. In sessions with MEQ-30 scores above 45, the Five-Dimensional Altered States of Consciousness scale (5D-ASC) was added for a more detailed characterisation. Visual analogue scales were introduced partway through recruitment to capture affective valence and other non-mystical subjective effects, and clinician-rated dissociation scores were taken retrospectively from the medical record; available dissociation ratings from sessions 1 and 2 included the CADSS and a clinician-rated 0–5 dissociation intensity score. Spiritual wellbeing was measured at baseline and after induction using the WHOQOL-SRPB, and personality with the Big-Five Inventory-45. Because the subjective effect scales were not validated specifically for esketamine, the researchers used principal component analyses on MEQ-30 and VAS items to identify data-driven dimensions of the acute experience. Statistical analyses were conducted in R, with correction for multiple comparisons using Bonferroni or Benjamini-Hochberg procedures where appropriate. The authors also used Bayesian statistics to assess null findings. Analyses of variance controlling for age, sex, diagnosis, and treatment centre tested whether subjective effects predicted antidepressant response and whether baseline spirituality and personality predicted response or mystical experiences. Pearson correlations examined relationships between subjective-effect measures, and t-tests assessed pre-to-post changes in spirituality and personality.

Of the 45 included participants, antidepressant improvement was evident during the induction phase: 49% of patients responded, and symptoms improved within the first week after two sessions, with a mean MADRS change of -6.45 ± 6.16 (t(43) = -6.95, p < 0.001). Early improvement at one week also predicted the overall response. The paper reports that esketamine had clear antidepressant effects in this sample. Mystical experiences were common and variable. Using the MEQ-30 threshold, mystical experiences occurred in 58% of patients, with substantial inter- and intra-individual variability in intensity, frequency and phenomenology across sessions. Principal component analysis supported the use of the MEQ-30 for esketamine by identifying three components that mapped onto the questionnaire’s established domains: a core mystical component with partial loadings on transcendence of time and space, ecstasy and awe; a component reflecting ineffability plus transcendence of time and space; and a positive mood component. Mean MEQ dimension scores were significantly higher in the mystical than the non-mystical group for all dimensions, after Bonferroni correction. Among the 21 participants who had at least one session with MEQ-30 > 45 and completed the 5D-ASC, the overall 5D-ASC score averaged 38.45/100 and the peak score averaged 45.68/100. The strongest 5D-ASC dimension was vigilance reduction, and within oceanic boundlessness the most prominent subdimensions were unity and insightfulness. Anxious ego dissolution was driven mainly by disembodiment rather than anxiety, and visual restructuring was present to a lesser extent, mainly as changes in imagery rather than complex hallucinations. Visual analogue scale data were available for 29 participants. These ratings did not differ significantly between the mystical and non-mystical groups. PCA of VAS items produced three dimensions: positive emotional and social effects, ego dissolution with stimulation and fear, and cognitive slowing with reduced sociality. Dissociation scores from the first week were available for 30 participants, with a mean of 3.32/5. Across measures, positive mood was the clearest overlapping feature: MEQ positive mood correlated strongly with the VAS positive-emotion/sociality component (r = 0.66, BH-corrected p < 0.001). VAS ego dissolution also correlated with MEQ ineffability (r = 0.67) and transcendence of time and space (r = 0.68). Other MEQ dimensions did not correlate meaningfully with VAS components. The main clinical finding was that mystical experience intensity predicted antidepressant improvement. Higher peak MEQ scores predicted greater MADRS reduction across treatment, and the same was true for mean MEQ scores, even after adjusting for age, sex, diagnosis and treatment centre. Among participants who experienced mysticism at least once, the frequency of mystical sessions did not significantly relate to MADRS change, suggesting that cumulative frequency was less important than intensity. First-week MEQ scores also predicted end-of-induction improvement, indicating an early association with later clinical response. However, mystical experience intensity did not predict immediate improvement after the first week, and similar results were seen for QIDS-SR16. When individual MEQ dimensions were examined, positive mood was associated with antidepressant improvement, whereas transcendence of time and space and ineffability were not clearly predictive in the text provided. In the smaller 5D-ASC subgroup, neither total score nor individual 5D-ASC dimensions predicted MADRS change. Likewise, VAS components and dissociation measures did not significantly predict clinical improvement. Baseline spirituality did not change from before to after treatment, but higher baseline WHOQOL-SRPB spirituality scores predicted both greater MADRS reduction and higher peak MEQ scores in the first week. Baseline spirituality was not associated with baseline depression severity, VAS components, or dissociation. Baseline Big Five personality scores did not predict antidepressant response, mystical experiences, dissociation or VAS scores. After treatment, agreeableness and neuroticism decreased modestly.

Mallevays and colleagues interpret the findings as evidence that esketamine can induce psychedelic-like mystical experiences in routine clinical care, and that these experiences may matter clinically. They argue that the results challenge the usual framing of acute esketamine effects as merely dissociative side effects, because mystical-type experiences were frequent, measurable with psychedelic-oriented instruments, and associated with later antidepressant improvement. The authors emphasise that the relationship was seen for mystical intensity and positive mood dimensions, not for dissociation or general psychoactive intensity. They place their findings in the context of earlier work suggesting that mystical or awe-related experiences may accompany therapeutic benefit in both classic psychedelic therapy and (es)ketamine studies, while noting that previous ketamine findings have been inconsistent. They suggest that their repeated-measures design across the whole induction phase may have captured effects that single-session assessments missed, and they interpret the lack of association with immediate one-week response as consistent with a possible delayed contribution of mystical experiences to antidepressant benefit. The authors also highlight baseline spirituality as a predictor of both mystical experience intensity and clinical response. They interpret this as consistent with previous research on intrinsic spirituality, meaning-centred coping, and resilience in depression. Several limitations are acknowledged. The study was observational and unblinded, so expectancy, self-selection, and suggestibility biases cannot be ruled out. Assessments were collected in routine care and were therefore not fully standardised. Dissociation data were incomplete and partly merged across non-identical measures, making those analyses exploratory. Concomitant antidepressant treatments were not controlled. The sample was small for some measures, especially the VAS and 5D-ASC subgroups, which limited statistical power. The authors also note that the role of the treatment setting remains unresolved. In terms of implications, the paper suggests that clinical administration of (es)ketamine may benefit from greater attention to subjective experience, including the possibility of adapting the setting and exploring combinations with psychotherapy. The authors also call for further work on the neurobiological mechanisms and longer-term psychological effects of mystical experiences during ketamine treatment.

The authors conclude that mystical-type experiences induced by esketamine are frequent in patients with treatment-resistant depression, can be captured with existing psychedelic research scales, and are associated with antidepressant effects alongside baseline spirituality. They state that these findings support considering such experiences when administering esketamine and point to the need for further research on mechanisms, long-term effects, and the possible role of clinical setting.