Moderating factors in psilocybin-assisted treatment affecting mood and personality: A naturalistic, open-label investigation

Psychedelic-assisted therapy, using agents such as psilocybin alongside psychological support, has re-emerged as a potentially effective adjunct for mood and trauma-related disorders. Earlier clinical work showed rapid and sometimes durable reductions in depression and anxiety after one or two psilocybin sessions, and some studies reported shifts in personality traits such as reduced neuroticism and increased openness. Investigators have also highlighted the likely importance of extra‑pharmacological factors—'set', 'setting', and the subjective quality of the acute experience (for example mystical-type experiences or emotional breakthrough)—in shaping longer-term outcomes. This study, led by Irrmischer and colleagues, set out to examine which demographic and subjective factors moderate acute and longer-term changes in depression, anxiety, PTSD and selected personality traits following an individual, naturalistic psilocybin-assisted treatment programme. The primary aim was exploratory: to test whether baseline characteristics, facets of the acute mystical experience, measures of emotional breakthrough and post‑session interpretations of growth were associated with changes on standard clinical and personality measures over time.

This investigation used an open‑label, naturalistic design. Data were gathered from 83 self‑referred participants (46 females, mean age 42.3 years) who enrolled in an individual psilocybin-assisted programme delivered with a standardised protocol. Participants were not recruited for a specific clinical trial and were a highly educated, predominantly employed sample; about 45% had a prior or current psychiatric diagnosis and 36% had ever used psychiatric medication. Baseline screening and intake questionnaires were evaluated by a psychiatrist and psychologist against inclusion/exclusion criteria (details reportedly in an appendix). The intervention comprised an intake, preparatory sessions (one 1 h online and two in‑person sessions totalling about 3 h of preparation), a single high‑dose psilocybin dosing session administered as fresh truffle sclerotia equivalent to 25 mg psilocybin with a facilitator present all day, plus integration therapy (a 2 h in‑person session the day after dosing and a 1 h online session one week later). Across the programme each participant received approximately 6 h of psychotherapist contact and roughly 9–10 h of facilitator contact according to the extracted text (the document contains slightly inconsistent reporting on exact facilitator contact hours). Outcome measures were collected at baseline, shortly after dosing and at a 3‑month follow‑up. Primary clinical measures were the Patient Health Questionnaire‑9 (PHQ‑9), Generalized Anxiety Disorder‑7 (GAD‑7) and PTSD Checklist for DSM‑5 (PCL‑5). Personality was measured with the NEO‑FFI‑3 (neuroticism, extraversion, openness, agreeableness, conscientiousness). Additional instruments included the Mystical Experience Questionnaire (MEQ‑30; completed 1 day post dose), the Posttraumatic Growth Inventory (PTGI; completed 1 week post dose) and the Emotional Breakthrough Inventory (EBI; added later and thus completed by a smaller subgroup). Some post‑session questionnaires were voluntary, producing missing data that the authors characterise as random. Statistical analysis relied principally on mixed‑effects linear models using maximum likelihood estimation to examine change over time and test moderator effects. The authors conducted a priori power calculations indicating that a sample of about 28 participants would give 0.81 power to detect a medium repeated‑measures effect; actual analyzable sample sizes varied by measure (see Results). Moderators were tested in stages: demographic factors present before the session, acute subjective measures during dosing (ability to surrender, emotional experience, and MEQ‑30 facets), and post‑session growth interpretations (PTGI facets). Model fit was assessed with the Akaike information criterion (AIC) and p values were adjusted for multiple comparisons using the Benjamini‑Hochberg false discovery rate.

Sample and questionnaire completion varied by measure. All 83 participants completed baseline GAD‑7, PHQ‑9 and PCL‑5; however, the numbers with post‑dosing and follow‑up data were smaller (44 post dosing and 37 at 3 months for the primary mood measures). NEO‑FFI‑3 data were available for 41 at baseline, 35 post dosing and 34 at follow‑up. MEQ‑30 was completed by 36 participants, PTGI by 44 and EBI by 23. Baseline comparisons with reference populations indicated that this sample had higher mean scores on depression (PHQ‑9 M = 4.52 versus population M = 2.91, p = 0.0003), PTSD symptoms (PCL‑5 M = 12.43 versus population M = 5.8, p < 0.0001), anxiety (GAD‑7 M = 4.62 versus population M = 2.95, p = 0.0001) and neuroticism (NEO neuroticism M = 27.05 versus population M = 20.8, p = 0.0001). Openness and extraversion were also higher than the reference sample, while agreeableness and conscientiousness did not differ significantly. Mixed‑model analyses showed significant changes over time on the primary mood measures and neuroticism. PHQ‑9 scores fell from 4.52 ± 4.0 at baseline to 2.39 ± 2.9 post dosing (p < 0.001) and were 3.55 ± 3.0 at 3 months; scores at 3 months remained significantly lower than baseline (p = 0.001) though higher than immediate post dosing (p = 0.019). PCL‑5 scores decreased from 12.43 ± 11.4 at baseline to 6.11 ± 7.3 post dosing (p < 0.001) and were 7.63 ± 8.5 at follow‑up; follow‑up remained significantly lower than baseline (p < 0.001) and did not differ from the immediate post dose value. GAD‑7 scores decreased from 4.62 ± 3.6 to 2.82 ± 3.2 post dosing (p = 0.001) and were 3.79 ± 2.9 at 3 months; the follow‑up was not significantly different from the immediate post dose score and trended toward being lower than baseline (p = 0.057). Neuroticism declined from 27.05 ± 9.0 at baseline to 24.17 ± 9.8 post dosing and 23.68 ± 9.0 at 3 months, with significant reductions from baseline both after dosing (p = 0.003) and at follow‑up (p = 0.001). Openness and conscientiousness showed pre‑to‑post increases (openness p = 0.028; conscientiousness p = 0.018) but did not show a significant interaction with time across the three assessments. Extraversion and agreeableness did not change significantly. On acute and interpretive measures, participants reported substantial mystical and emotional experiences. Mean total MEQ‑30 score was 90 ± 32.2 (about 60% of the maximum), a level the authors characterise as qualifying as 'mystical'. MEQ facets with the highest percentages were Ineffability (70%), Transcendence (63%) and Positive Mood (63%). PTGI total averaged 63 ± 18.6 out of 105, with highest facet scores for Appreciation of Life and Personal Strength. EBI averaged 71 ± 26.3 out of 100, which the authors note is higher than an online sample mean of 43 ± 31.5 (p < 0.0001). Self‑rated ability to surrender to the experience and personal significance were high (mean surrender 82.4 ± 16.0; personal significance 85.9 ± 13.4). Exploratory moderation analyses identified several factors associated with differential outcomes. Among pre‑session demographics, lower alcohol intake was associated with larger reductions in symptoms and with higher openness; younger age interacted with time such that younger participants showed greater anxiety reductions. Prior high‑dose psilocybin experience and low alcohol intake were associated with higher openness. Conscientiousness was higher in older participants, those with a diagnosis, and those who drank less. Subjective measures during dosing improved model fit substantially over time‑only models. Self‑reported ability to surrender and rating the session as emotional moderated improvement across depression, PTSD, anxiety, neuroticism and openness (but not conscientiousness). MEQ‑30 facets showed differential moderation: Transcendence moderated changes in depression, anxiety, openness and conscientiousness; Positive Mood moderated PTSD, openness and conscientiousness; Mysticism moderated depression, neuroticism and openness; Ineffability moderated anxiety and neuroticism. Post‑session interpretations (PTGI facets) also improved model fit. 'Personal strength' moderated changes in PTSD, anxiety and depression. 'Appreciation for life' moderated PTSD, depression and openness. 'Seeing new possibilities' and 'Spiritual change' additionally moderated openness.

Irrmischer and colleagues interpret their findings as supportive of a beneficial effect of a single high psilocybin dose given with preparatory and integrative psychological support on symptoms of depression, anxiety and PTSD, and on the personality trait neuroticism, with many changes maintained at 3 months. Small increases in openness and conscientiousness were observed after treatment. The authors note these outcomes are consistent with prior clinical studies and that similar positive effects were replicated in this open‑label, naturalistic context. The discussion emphasises the role of extra‑pharmacological factors. Participants commonly reported mystical‑type experiences, strong emotional breakthrough and marked post‑session personal significance; facets of the MEQ‑30 and PTGI as well as the ability to surrender to and experience emotion during dosing were associated with larger improvements. The authors argue that transcendent, emotional and growth‑related interpretations after the session may facilitate reduced experiential avoidance, enhanced psychological flexibility and increased self‑efficacy—mechanisms that could support symptom reduction and personality change. Several limitations are acknowledged. The sample was self‑selected and not representative of the general population: participants sought out the public provider, were motivated and relatively affluent, and many had prior psychological complaints. The naturalistic open‑label design precludes causal attribution to psilocybin alone because there was no comparator arm (therapy‑only or drug‑only). Missing data arose because some post‑session questionnaires were voluntary and some therapists did not send questionnaires; the authors report this missingness as essentially random and thus argue mixed‑model analyses remain robust. Expectancy effects cannot be excluded; therapists' intake assessments provided only a rough measure of conscious expectancy and subconscious expectancy was not measurable. The authors contend that high self‑reported surrender reduces the likely influence of expectancy, but they present this as an interpretation rather than proof. Finally, the investigators discuss practical implications suggested by the moderation findings: lower alcohol use, presence of a supportive personal system, preparation to enable surrender and emotional engagement during dosing, and fostering post‑session personal growth may be important factors to consider when designing therapeutic protocols and integration plans. The authors position these results as exploratory and recommend further controlled research to clarify causal mechanisms and generalisability.