Effects of psilocybin therapy on personality structure

Major depressive disorder is common, causes substantial individual and societal burden, and a sizeable fraction of cases are treatment-resistant (treatment-resistant depression, TRD), defined here as poor response to two adequate trials of different antidepressant classes. Given TRD’s poor prognosis and high cost, alternative therapeutic strategies have been sought. Interest in classic serotonergic psychedelics such as psilocybin has re-emerged, and small pilot studies suggest psychedelic-assisted therapy can produce durable clinical benefits across conditions including addiction, obsessive–compulsive disorder, end-of-life distress, major depression, and TRD. One intriguing observation from prior work is that therapeutic effects often outlast the acute pharmacological presence of the compounds, and that psychedelic-occasioned ‘‘peak’’ or ‘‘mystical-type’’ experiences—characterised by ego-dissolution, unity, insight and connectedness—may be linked to longer-term change. Mm and colleagues set out to examine whether psilocybin with psychological support modulates personality structure in patients with TRD, whether any personality changes relate to the subjective quality of the psychedelic experience, and whether such changes might help explain the durability of psychedelic-assisted therapy. The study therefore investigated pre-to post-treatment change in the five NEO-PI-R personality domains and their facets, and explored associations between personality change, clinical response, and measures of the acute psilocybin experience.

This was an open-label feasibility study conducted with regulatory and ethics approvals in the UK. Twenty patients meeting criteria for unipolar major depression of at least moderate severity (HAM-D ≥17) and having failed at least two pharmacologically distinct antidepressant trials in the current episode were enrolled. Key exclusions included a current or past psychotic disorder or a first-degree relative with psychosis. Five participants reported prior psychedelic use; most participants had previously received psychological therapy. After telephone prescreening and an in-person screening with medical and psychiatric assessment (including MINI-5), baseline measures were obtained including the NEO-PI-R personality inventory and the QIDS-SR16 for depressive symptoms. Eligible participants attended a preparation visit and then two dosing sessions one week apart: 10 mg psilocybin in the first session and 25 mg in the second. During dosing, participants lay with eyes closed listening to a music playlist while two therapists provided a non-directive, supportive presence. Integration visits occurred one day and one week after the 25 mg session; personality was reassessed at 3 months. Primary personality outcomes were the five NEO-PI-R domains (Neuroticism, Extraversion, Openness, Conscientiousness, Agreeableness) and their facets, scored as T-scores (M = 50, SD = 10). The acute subjective experience was measured with the altered states of consciousness questionnaire (ASC), whose subfactors include insightfulness, blissful state, experience of unity, and spiritual experience. Depression severity was measured with the QIDS-SR16. Analyses compared baseline to 3-month NEO-PI-R scores with two-tailed paired t-tests and applied false discovery rate correction (FDR) at 0.05. Cohen’s d effect sizes were calculated from raw scores. Treatment response was defined as ≥50% reduction in QIDS from baseline; exploratory Pearson bivariate correlations tested associations among ASC subfactors, personality change, and depressive symptom change. Correlation analyses were not corrected for multiple comparisons and are presented as exploratory.

Of 20 enrolled patients, 19 provided complete follow-up personality data (6 females, 13 males; mean age 44.7 ± 10.9 years, range 27–64). At baseline, 18 participants met criteria for severe or very severe depression (QIDS-16 ≥16), and two were in the moderate range. Comparing baseline to 3-month follow-up, three of the five NEO-PI-R domains changed significantly. Neuroticism decreased (T-score change −5.7, P = 0.002), while Extraversion increased (T-score change +6.5, P < 0.001) and Openness increased (T-score change +4.9, P = 0.012). Conscientiousness showed a borderline increase (+3.2 T-score points, P = 0.086) and Agreeableness did not change. Eleven facet scores changed significantly, ten of which survived FDR correction. Cohen’s d effect sizes were reported in the paper’s tables (not fully reproduced in the extracted text). When participants were divided by clinical response at 3 months (responders n = 7; non-responders n = 12), responders showed a larger reduction in Neuroticism (mean change −23 ± 17 vs −6 ± 8; P = 0.038) and a larger increase in Conscientiousness (15 ± 11 vs 0 ± 12; P = 0.017) than non-responders. Responders and non-responders did not differ significantly in changes in Openness (11 ± 21 vs 7 ± 6, P = 0.623), Agreeableness (−1 ± 7 vs 1 ± 8, P = 0.577) or Extraversion (17 ± 10 vs 9 ± 11, P = 0.105). In exploratory correlation analyses, none of the five domain changes correlated significantly with change in QIDS or BDI scores at 3 months; there were trend-level associations between decreases in Neuroticism and QIDS decreases (r = 0.41, P = 0.080) and between increases in Extraversion and QIDS decreases (r = −0.42, P = 0.071), but these did not reach conventional significance. Analyses relating the acute experience to personality change found that higher insightfulness during the 25 mg session correlated with greater reduction in Neuroticism (r = −0.47, P = 0.043) and a greater increase in Extraversion (r = 0.54, P = 0.017). Spiritual experience correlated positively with increased Extraversion (r = 0.47, P = 0.048). Baseline Openness showed a borderline association with blissful state (r = 0.43, P = 0.063); at the facet level, Openness to Fantasy correlated with blissful state (r = 0.50, P = 0.030) and Openness to Aesthetics showed a trend (r = 0.45, P = 0.054). Several other facet-level associations with aspects of the peak experience were at trend level. Baseline Neuroticism correlated negatively with improvement in depression at trend level (r = −0.42, P = 0.075), indicating higher baseline Neuroticism tended to predict smaller clinical gains, although responders and non-responders did not differ on baseline domain scores.

Mm and colleagues interpret their findings as evidence that psilocybin therapy for treatment-resistant depression is accompanied by measurable changes in personality structure at 3 months: decreases in Neuroticism, increases in Extraversion and Openness, and a trend-level increase in Conscientiousness, with no change in Agreeableness. Ten facet-level changes survived correction for multiple comparisons. The authors note this is the first report of personality change following psychedelic-assisted therapy in a clinical depressed sample and that the pattern of change overlaps substantially with personality shifts reported after conventional antidepressant treatment, in particular reductions in Neuroticism and increases in Extraversion and Conscientiousness. Where the present results differ, the researchers highlight larger effect sizes for Openness and Extraversion in this psilocybin-treated sample compared with pooled effect sizes from several antidepressant trials, a finding they suggest could indicate an effect more specific to psychedelic therapy. They caution, however, that differences in follow-up timing across studies and limited sample size make direct comparisons tentative. The authors also discuss the possibility that the observed changes are not merely transient state effects: durability at 3 months and prior reports of long-lasting increases in Openness after single-dose psilocybin in healthy volunteers argue that at least some changes may reflect enduring trait modification. Associations between acute experience and personality change were reported chiefly for insightfulness predicting decreased Neuroticism and increased Extraversion, and spiritual experience predicting increased Extraversion. The authors emphasise these correlation analyses were exploratory and uncorrected for multiple comparisons. They acknowledge important limitations: the open-label design, small sample size (especially for subgroup analyses), lack of a placebo or active comparator, and the resulting limited statistical power. These constraints prevent strong causal inference and mandate replication in larger, randomised, controlled trials. Neurobiological mechanisms remain speculative; the paper discusses serotonin 2A receptor links to Neuroticism and proposes further work to probe receptor-level and other neural correlates of personality change. In conclusion, the study reports that psilocybin-assisted therapy was associated with several personality changes at 3 months in patients with TRD, that some of these changes aligned with clinical improvement while others (notably increased Openness) appeared independent of symptom change, and that facets of the acute psychedelic experience—particularly insight—may help predict which personality domains change. The authors call for future controlled trials and mechanistic studies to confirm and extend these observations.