Multidimensional Personality Changes Following Psilocybin-Assisted Therapy in Patients With Alcohol Use Disorder: Results From a Double-Blind, Placebo-Controlled Clinical Trial

Patients with alcohol use disorder (AUD) characteristically show pathological personality traits, including elevated neuroticism and reduced conscientiousness, openness, extraversion, and agreeableness, and these trait abnormalities are theorised to contribute to the persistence and treatment resistance of AUD. Prior work links personality change to substance-use outcomes and identifies impulsiveness (a facet of neuroticism) as a particularly strong predictor of alcohol consumption and related harms. Concurrently, clinical research with serotonergic psychedelics (notably psilocybin) has reported durable shifts in core personality dimensions in healthy and clinical samples, but the downstream psychological mechanisms that connect receptor-level effects to clinical benefit remain incompletely characterised, and no randomised controlled trials had examined personality change following psychedelic-assisted therapy in a substance use disorder population prior to this study. Pagni and colleagues used data from a double-blind, placebo-controlled randomised trial of psilocybin-assisted therapy (PAT) in adults with AUD to test whether PAT normalises atypical personality trait expression. They hypothesised that, relative to an active placebo plus psychotherapy, PAT would decrease neuroticism and increase extraversion, openness, and conscientiousness; that baseline personality would predict PAT-induced trait change; and that reductions in impulsiveness would be associated with reduced alcohol consumption.

The trial randomised 95 adults with AUD to two medication sessions, four weeks apart, of either psilocybin (N=49) or an active placebo, diphenhydramine (N=46), delivered alongside a 12-week manualised psychotherapy programme. The psychotherapy combined a preparation/support/integration (PSI) model with alcohol-focused elements drawn from motivational enhancement and action-oriented cognitive–behavioural therapy, provided by trained male–female dyad therapy teams at two sites (NYU and UNM). The extracted text does not provide detailed inclusion/exclusion criteria beyond AUD diagnosis; all participants provided informed consent and the study had multi-agency regulatory approval. Personality was assessed with the 240-item NEO Personality Inventory—Revised (NEO-PI-R, Form S) at baseline (week 0, before preparatory therapy) and at the end of follow-up (week 36, about seven months after the second medication session). Drinking was measured with the Alcohol Timeline Followback (TLFB) at weeks 0, 4, 8, 12, 24, and 36. The main drinking metric used for analyses was drinks per day (DpD), calculated both as a pre-to-post change score (weeks 5–36 averaged minus weeks 0–4 averaged) and as an 8-month posttreatment average (weeks 5–36 averaged). World Health Organization (WHO) risk categories (abstinent/low, moderate, high, very high) were assigned at week 4. Of the 95 randomised participants, two were not treated and nine lacked complete pre/post NEO data, leaving 84 treated participants for the present analyses (psilocybin, N=44; placebo, N=40). The statistical plan centred on preplanned univariate ANCOVAs for each of the five trait domains (dependent variable: pre-to-post change, covariate: baseline trait score, factor: treatment group), paired t tests for within-group time effects, Pearson correlations to explore relationships between baseline traits and trait change (in the psilocybin group), and correlations between changes in impulsiveness and drinking outcomes. Secondary analyses probed facet-level change across the 30 NEO facets and exploratory subgroup analyses examined WHO risk subgroups. Multiple comparisons were controlled using the Benjamini–Hochberg false discovery rate (FDR) procedure. Effect sizes were reported as Hedges’ g (within-group time effects) and partial eta-squared (between-group effects), and analyses were conducted in SPSS v22.0. The extracted text does not state that an intention-to-treat analytic approach was used.

The analysed sample (N=84) had long-standing AUD (mean years dependent 31.56, SD=11.47), met on average 5.25 of seven dependence criteria (SD=1.22), had a mean Short Index of Problems (SIP) score of 20.42 (SD=9.03), and averaged 52.57% heavy drinking days in the past month (SD=30.32). The cohort was predominantly white (about 77%) and relatively affluent (mean incomes reported as psilocybin $266.7K, placebo $147.7K). At baseline the groups were similar on neuroticism, extraversion, and agreeableness, while the psilocybin group had higher conscientiousness and the placebo group had higher openness. Primary between-group analyses showed that, relative to active placebo plus psychotherapy, PAT produced significant decreases in neuroticism and significant increases in extraversion and openness; these three effects survived FDR correction. No significant treatment effects were found for agreeableness or conscientiousness. Within the psilocybin group, paired tests indicated decreases in neuroticism and increases in extraversion and openness; an increase in conscientiousness was observed within-group but did not survive FDR correction. The placebo group showed no significant within-group changes across the five traits. Comparisons with normative NEO scores suggested that PAT-induced trait shifts generally moved participants toward population norms, except that openness was already above normative levels at baseline and increased further. Facet-level analyses identified that reductions in neuroticism were driven by significant decreases in the facets depression, impulsiveness, and vulnerability; these three facet changes survived FDR correction. Increases in openness were driven by increases in the facets fantasy and feelings, both of which survived correction. An increase in the extraversion facet positive emotions was observed but did not survive FDR correction. No facet changes within agreeableness reached significance. Within the psilocybin group, baseline trait levels predicted trait change: greater baseline neuroticism correlated with larger neuroticism reductions (r=-0.32, p=0.03), and lower baseline extraversion and conscientiousness were associated with larger increases in those domains (extraversion r=-0.52, p<0.001; conscientiousness r=-0.44, p<0.01). Across the full sample (N=84), decreases in the impulsiveness facet correlated with lower posttreatment DpD (r=0.25, p=0.02, pFDR=0.04), although impulsiveness change did not correlate with pre-to-post change in DpD. The correlation confined to the psilocybin group alone was not statistically significant (N=44; r=0.27, p=0.07). In exploratory subgroup analyses among psilocybin-treated participants who remained at or above moderate WHO risk at week 4, correlations between impulsiveness change and posttreatment drinking were larger (moderate+ risk N=17, r=0.50, p=0.04; high-risk N=11, r=0.70, p=0.02; very-high-risk N=4, r=0.91, p=0.09), but these subgroup findings did not survive FDR correction and sample sizes were small. The extracted text reports exploratory sex effects: females showed increases in conscientiousness and openness, while males showed an increase in extraversion.

Pagni and colleagues interpret their findings as evidence that psilocybin-assisted therapy can elicit durable, clinically relevant personality change in patients with AUD, specifically reductions in neuroticism and increases in extraversion and openness, with facet-level decreases in depression, impulsiveness, and vulnerability and increases in openness to feelings and fantasy. They position these results within a growing literature showing psychedelic-associated shifts in personality, noting that prior work has largely been open-label or observational and that the present study is the first double-blind, randomised, placebo-controlled trial to examine personality change in a substance use disorder. The investigators highlight two mechanistic possibilities suggested by the data: first, that PAT might directly reduce impulsiveness and thereby contribute to drinking reductions; second, that individuals with more abnormal baseline personality profiles may be more likely to show larger trait changes and clinical benefit. They also raise the hypothesis, informed by preclinical literature, that psychedelics could reopen developmental ‘‘critical periods’’ and thereby catalyse maturation or reorganisation of personality domains that alcohol exposure has stunted. The authors recommend that future trials include more frequent personality assessments to characterise temporal dynamics and to determine whether trait shifts precede, follow, or covary with changes in drinking. Several limitations are acknowledged. The sample was relatively small and homogeneous (high average income, majority white) and excluded many patients with common psychiatric comorbidities, which limits generalisability. Personality was measured only at baseline and at week 36, so temporal and causal inferences are constrained. Functional unblinding was a major concern—about 94% of participants in the parent trial correctly guessed treatment assignment—and expectancy or reporting biases may have influenced self-reported personality change. Baseline group differences in some traits (higher conscientiousness in the psilocybin group, higher openness in the placebo group) raise the possibility of ceiling effects, regression to the mean, or other biases despite the use of baseline covariates. The subgroup correlations relating impulsiveness change to drinking were based on small samples and did not survive correction for multiple comparisons, so they are presented as preliminary. Clinically, the authors suggest that PAT-induced personality normalisation may be relevant to AUD treatment and to comorbid conditions that share atypical personality structure, and that targeting personality domains such as impulsiveness might be one of several psychological mechanisms mediating benefit. They caution that further, larger and more diverse trials are needed to replicate these findings, to probe neurobiological substrates, and to determine whether personality change contributes causally to improved clinical outcomes or is an epiphenomenon of other therapeutic effects.

In this double-blind, randomised, placebo-controlled trial of psilocybin-assisted therapy for AUD, treatment with PAT—but not active placebo plus psychotherapy—was associated with attenuation of personality abnormalities, characterised principally by decreases in neuroticism and increases in extraversion and openness. Facet-level changes implicated reductions in depression, impulsiveness, and vulnerability and increases in openness to feelings and fantasy. Associations between decreases in impulsiveness and lower posttreatment alcohol consumption suggest a possible psychological pathway for clinical improvement, but these relationships are preliminary. The authors conclude that further PAT studies are required to clarify the links between personality change and AUD outcomes, to identify underlying neurobiological mechanisms, and to test generalisability to other clinical populations.