Predicting the Intensity of Psychedelic-Induced Mystical and Challenging Experience in a Healthy Population: An Exploratory Post-Hoc Analysis

Psychedelics are being actively investigated in clinical research, and during acute administration users commonly report profound subjective effects that investigators label as mystical and/or challenging experiences. Mystical experience (ME) is characterised by features such as ineffability, deeply felt positive mood, sacredness and a sense of unity; oceanic boundlessness (OBN) on the 5D-ASC is a quantitative measure closely related to ME. Challenging experiences include physiological arousal and psychological distress, and the dread of ego dissolution (DED) subscale of the 5D-ASC captures aspects of this domain. Previous studies and systematic reviews have linked ME to therapeutic benefit in multiple psychiatric contexts, but evidence around how ME and challenging experience predict clinical outcomes is mixed and the predictors of the intensity of these acute states remain incompletely established. Ko and colleagues set out to explore clinical predictors of the intensity of psilocybin-induced mystical and challenging experiences by analysing data from an existing Phase I randomised, double-blind, placebo-controlled trial. The investigators examined dosage, five-factor personality traits, baseline affect, and individual variables (age, biological sex, prior psilocybin exposure) as potential predictors of OBN (mystical-like experience) and DED (challenging experience). A set of directional hypotheses was specified for dose, age, prior experience, sex, personality dimensions (notably openness and neuroticism), and positive/negative affect.

This was a post hoc exploratory analysis of data from a Phase I, randomised, double-blind, placebo-controlled, between-groups clinical trial (EudraCT 2018-000978-30). Eighty-nine healthy volunteers were randomised to a single oral dose of placebo, 10 mg psilocybin, or 25 mg psilocybin (COMP360, a proprietary pharmaceutical-grade synthetic psilocybin formulation), with 12 weeks of follow-up in the parent trial. The present analysis used data collected before and immediately after the dosing session. Inclusion criteria allowed adults aged 18–65 who could complete study instruments in English; exclusion criteria included current or past psychiatric disorder (or first‑degree family history), recent psychiatric medication, substance dependence (excluding nicotine), specified medical conditions (cardiovascular disease, diabetes, seizure disorder), pregnancy, or concurrent trial participation. The extracted text indicates four withdrawals occurred, all from the placebo arm; the analysis sample comprised the 85 participants who completed the trial. Predictor variables were personality (NEO‑FFI; five‑factor model: openness, neuroticism, extraversion, agreeableness, conscientiousness), affect (PANAS: Positive and Negative Affect Schedule), individual characteristics (age, biological sex, prior psilocybin experience) and psilocybin dose. Outcome variables were the oceanic boundlessness (OBN) and dread of ego dissolution (DED) subdimensions of the 5D‑ASC, administered immediately after the 6–8 hour dosing session. Baseline PANAS and NEO‑FFI were completed one day prior to dosing. Statistical analyses were exploratory and conducted in IBM SPSS Statistics v28. Pearson correlations were used to assess associations between personality/affect and OBN/DED, stratified by dose group. The same correlation approach was applied to individual variables within control and treatment groups. Analysis of variance (ANOVA) tested the relationship between dose and the continuous outcomes OBN and DED with pairwise comparisons between placebo and 10 mg and between placebo and 25 mg; mean differences were to be presented with 95% confidence intervals. The investigators stated the study was not powered for definitive hypothesis testing and did not correct for multiple testing due to its exploratory post‑hoc nature.

Eighty-nine participants were randomised to 25 mg (n=30), 10 mg (n=30) or placebo (n=29). Four participants withdrew (all from placebo) and were excluded from the modified intent‑to‑treat population, leaving 85 completers. Participants were aged 20–59 (mean 36.1, SD 9.06); 48 (53.9%) were male and 41 (46.1%) female. Thirty‑three participants (37.1%) reported prior psilocybin experience, distributed unevenly across arms (placebo 24.1%, 25 mg 36.7%, 10 mg 50%). Dose was associated with both mystical and challenging experience: ANOVA indicated higher psilocybin dose corresponded to greater OBN and greater DED. The extracted text states the intensity of both OBN and DED was strongly associated with higher dosage, and that residuals approximated normality, but the specific mean differences and full test statistics for OBN and DED pairwise comparisons are not clearly reported in the extracted material. Among individual variables, age showed a nominally significant negative correlation with DED when data from the 10 mg and 25 mg groups were analysed together (Pearson r = -0.28, 95% CI -0.50 to -0.03, p = 0.03), indicating higher age was associated with lower intensity of challenging experience. Biological sex did not correlate with either OBN or DED. Personality findings were largely null. Openness showed no correlation with OBN or DED. Extraversion, agreeableness and conscientiousness were not significant predictors of either outcome. Neuroticism demonstrated a positive correlation with intensity of challenging experience at the higher dose (25 mg) according to the authors, but the extracted text does not provide the exact correlation coefficient or p‑value for this subgroup finding. Baseline affect, measured by PANAS (positive and negative affect), did not predict OBN or DED in the analyses presented. Prior psilocybin experience was not significantly associated with intensity of mystical or challenging experience; the authors note that very recent prior use was an exclusion criterion and may have influenced this result.

Ko and colleagues interpret their findings as evidence that psilocybin dose predicts the intensity of both mystical‑like (OBN) and challenging (DED) acute experiences in healthy volunteers, which aligns with several prior studies. They emphasise, however, that the escalation in intensity with dose appeared greater for challenging experience than for mystical experience, suggesting higher doses may disproportionately increase acute difficulty without a commensurate increase in mystical phenomena. The authors note that duration of a challenging episode may be clinically important, but their dataset captured intensity rather than duration and therefore cannot address this point. The negative association of age with intensity of challenging experience is presented as consistent with earlier work and interpreted as possibly reflecting psychological or biological changes with age (for example, improved coping skills) rather than a direct causal effect of age per se. Biological sex showed no relationship with the outcomes, in line with previous reviews. Regarding personality, the authors report no association for openness but a dose‑specific positive association between neuroticism and challenging experience at 25 mg, suggesting neuroticism might help identify individuals at greater risk of an intense acute challenge; the extracted text does not provide detailed subgroup statistics for this effect. Limitations are acknowledged: this was a post hoc, exploratory analysis that was not pre-registered and for which the parent trial was not designed; therefore the study may be underpowered and susceptible to both false‑positive and false‑negative findings. Selective analysis and lack of multiple testing correction are noted; the authors recommend replication in larger datasets. They propose alternative, economical data sources such as national surveys and citizen science projects to examine these relationships, and recommend future studies assess duration as well as intensity, include measures such as emotional excitability, and directly compare healthy and clinical populations. The authors caution that these findings have limited clinical applicability at present and cannot be straightforwardly extrapolated to patient populations; even if age or personality predicted adverse acute responses, ethical considerations would affect any policy about excluding patients from treatment.

In this post hoc analysis of a Phase I trial, the investigators found that higher psilocybin dose was associated with greater intensity of both mystical‑like and challenging acute experiences in healthy volunteers. Additional indications were observed for age (older participants experienced less intense challenging effects) and for neuroticism (higher trait neuroticism associated with greater challenging experience at the higher dose). The authors conclude that replication using larger samples—potentially via national surveys or citizen science—is warranted, and that while these findings are primarily of relevance to healthy populations at present, further study including clinical groups is needed before any clinical implications can be drawn.