In a naturalistic, open‑label study a single high dose of psilocybin with psychotherapy produced sustained reductions in depression, anxiety, PTSD symptoms and neuroticism, and increases in openness and conscientiousness at three months. The size of these benefits was moderated by participants’ subjective dosing experiences (mystical‑type experiences, emotional breakthrough and post‑treatment growth) and demographic factors, highlighting variables that may help optimise psilocybin‑assisted treatment.
Papers cited by this study that are also in Blossom
Agin-Liebes, G. I., Zeifman, R. J., Luoma, J. B. et al. · Journal of Psychopharmacology (2022)
Rationale
Psychedelic-assisted therapy is increasingly applied within mental health treatment.
Objectives
This study focused on factors moderating changes in the acute and long-term effects of an individual psilocybin-assisted program on depression, anxiety, PTSD and personality structures by including demographic factors, subjective experience and degree of mystical type experiences during the dosing, as well as emotional breakthrough and personal growth after the program.
Methods
At baseline, 1 week and 3 months after the psilocybin program participants completed the Generalized Anxiety Disorder Assessment (GAD-7), Patient Health Questionnaire (PHQ-9), PTSD Checklist for DSM-5 (PCL-5) and NEO Five-Factor Inventory-3 (NEO-FFI-3). In addition, after the dosing the Mystical Experiences Questionnaire (MEQ-30), Posttraumatic Growth Inventory (PTGI) and Emotional Breakthrough Inventory (EBI) were administered. Moderation effects were established using linear mixed-model analysis.
Results
A single high dose of psilocybin in combination with therapy was found to lower symptoms of anxiety, depression, PTSD and neuroticism over a period of 3-months. Scores on openness and conscientiousness increased after the treatment only. Participants reported mystical type experiences, emotional breakthrough and personal growth. These subjective experiences together with demographic factors were moderating the observed positive changes.
Conclusions
Findings indicate that individual psilocybin-assisted therapy has the potential for beneficial effects on mood and personality characteristics. Moreover, the study highlights the importance of subjective experiences and demographic factors in moderating this effect. This study adds to the ongoing research on psilocybin-assisted therapy by investigating contributing factors for optimizing this evolving type of therapy.
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.
First, to ascertain that the smallest measurement (34 participants) provided enough power to detect the hypothesized effects, we conducted a power analysis for repeated measures ANOVA using the program G*Power 3.1.9.4). After applying a medium effect size η 2 = 0.13 (similar to f = 0.25), correlation = 0.5 and 3 measurements, the obtained power was 0.81 for a sample size of 28. Baseline analyses of the GAD-7, PHQ-9, PCL-5 and the NEO-FFI-3 facets (neuroticism, extraversion, openness, agreeableness and conscientiousness) were performed by adding the total score and then comparing them with representative samples of the general population using between group t-tests. To investigate the outcome of the treatment on the MEQ-30, PTGI & EBI the average scores for each were calculated by adding the total scores and comparing them to other treatment outcomes from literature, using between group t-tests. For the MEQ-30 the total scores were also calculated as % of total (h score/30; positive mood score /30; ineffability score/15; mystical score /75; total score/150). Additionally, single word qualitative descriptions of the experience were collected which will be reported in % averages. To examine the long-term effects of the treatment on the outcome of the GAD-7, PHQ-9, PCL-5 and NEO-FFI-3 facets, the average scores were calculated and analyzed for the three time points (before dosing session, after dosing session, follow-up) using a basic mixed-effects linear model analysis for each with time included as a factor. To explore possible moderating factors on the treatment outcome over time, each of the basic models were extended with variables available from the intake and additional questionnaires (see Table& description of questionnaires). In this exploratory analysis, first the influence of demographic moderators (gender, age, alcohol intake, diagnosis, 'years of having complaints', reported abuse, support system and 'prior experience with psilocybin') present before the session were tested. Then measures of subjective experience ('Ability to Surrender', 'Emotional experience' and the 4 facets of the MEQ-30) during the experience, and last changes after the experience (5 facets of the PTGI). The reasoning behind testing multiple models (before, during and after) lies in feasibility of applying the available data in a comprehensive and meaningful way without overloading the model with too many variables. The reasoning behind testing each facet of the MEQ-30 and PTGI lies in the exploratory nature of this study, to gain more nuanced insight. The models were tested for main effects of the moderators and their interaction effects with time. For openness and conscientiousness only main effects, and no interaction with time, were included due to the lack of significance of time in the basic model (for the mixed-effects linear model formula see section supplemental material). The model fit was tested using the Akaike information criterion (AIC). Results were tested at a significance level of p < 0.05 and corrected for multiple comparisons using the Benjamini Hochberg false discovery rate (FDR, 0.05) correction method. Data was analyzed using IBM SPSS Statistics (version 28) (IBM 2021).
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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.
To gain the most comprehensive account of the subjective experience after the session from our data we used the 5 facets of the PTGI: 'Appreciation for life', 'Personal strength', 'Relating to others', 'Seeing new possibilities' and 'Spiritual change' as possible moderators of the effect. Including these interpretations of growth after the treatment gave a better model fit compared to the basic model which only includes the effect of time (depression: ∆ AIC= -205, PTSD: ∆ AIC = -301, anxiety: ∆ AIC = -208, neuroticism: ∆ AIC = -455, openness: ∆ AIC = -389, conscientiousness ∆ AIC = -395). 'Personal strength' was the most important, moderating the change in PTSD (F(1, 46.0) = 4.5, p = 0.039), anxiety (F(45.3, 1) = 5.0, p = 0.031) and depression (F(1, 44.1) = 4.8, p = 0.034). 'Appreciation for life' is moderating the change in PTSD (F(1, 45.5) = 4.3, p = 0.044), depression (F(1, 43.5) = 4.5, p = 0.040) and openness (F(1, 14.8) = 5.7, p = 0.031). Further, openness was also moderated by 'Seeing new possibilities' (F(, 13.9) = 5.4, p = 0.036) and 'Spiritual change' (F(1, 11.9) = 7.5, p = 0.018).