Patterns of Internalizing Problems, Substance Use and Cognitive Flexibility Before and After Naturalistic Psilocybin Use: A Repeated Measures Latent Profile Analysis

Psilocybin is attracting renewed interest in both naturalistic and clinical settings, but longitudinal evidence on how its use relates to internalising problems, substance use and cognitive flexibility remains limited. The paper notes that prior observational studies have generally suggested possible benefits, particularly in supportive or treatment-oriented contexts, but that findings are heterogeneous and some users report adverse psychological outcomes. The authors also frame depression, anxiety and substance use as overlapping but distinct dimensions, and suggest that cognitive flexibility may be a transdiagnostic mechanism relevant to change across these domains. Richard and colleagues therefore aimed to examine patterns of change in depression, anxiety, substance use problems and cognitive flexibility before and after naturalistic psilocybin use. Rather than focusing only on average change across the whole sample, they sought a person-centred analysis to identify subgroups with different trajectories and to test whether those subgroups differed in sociodemographic factors, personality, prior psilocybin experience, preparation, setting and acute subjective effects.

The study was a prospective longitudinal online survey of English-speaking adults aged 18 years or older who were planning to take psilocybin outside a clinical research setting. Recruitment took place online through social media and word of mouth, and the study ran from July 2020 to July 2022. Participants completed six web-based surveys through Qualtrics XM. An initial survey at Time 1 collected consent and sociodemographic data from 8,006 respondents, and later surveys were scheduled relative to the planned psilocybin experience: 2 weeks before (Time 2), 1 day before (Time 3), 1-3 days after (Time 4), 2-4 weeks after (Time 5), and 2-3 months after (Time 6). The extracted text reports that 2,850 completed Time 2, 1,551 completed Time 5, and 657 completed Time 6. The authors describe several safeguards against fraudulent online participation, including unique participant IDs, email-linked survey links, IP tracking, a ballot-stuffing prevention feature, and prorated compensation. They also removed duplicate emails and excluded implausible psilocybin dose reports below 0.1 g or above 15 g, as well as responses judged inconsistent or unreliable. Measures included demographic variables, the 44-item Big Five Inventory at Time 2, depression and anxiety measures at Time 2, Time 5 and Time 6, alcohol and drug use measures at the same time points, the Cognitive Flexibility Scale, and psilocybin-related variables such as prior lifetime use, psychological surrender before the session, dose, setting, and subsequent psilocybin use. Acute subjective effects were assessed 1-3 days after use with the Mystical Experiences Questionnaire, Challenging Experiences Questionnaire and Awe Experience Scale. The main analysis was a repeated measures latent profile analysis using 15 continuous indicators across Time 2, Time 5 and Time 6: depression, trait anxiety, cognitive flexibility, alcohol use and drug use scores. Missing data were handled with full information maximum likelihood under a missing-at-random assumption. Model selection relied on fit indices, likelihood ratio tests and entropy, alongside clinical interpretability. After identifying the best-fitting profile solution, the authors used descriptive statistics, one-way analysis of variance and chi-square tests to compare profiles on baseline characteristics, preparation and acute experience variables, with Bonferroni correction for multiple comparisons.

The sample was predominantly White (81.4%), male (54%), and well educated, with a mean age of 39.77 years. At baseline, common weekly substance use included cannabis (53.4%), alcohol (36.7%) and tobacco (22.7%), and the average lifetime psilocybin use was 17.11 prior uses. The repeated measures latent profile analysis supported a four-profile solution. The four groups were labelled: Improved Mental Health with Low Substance Use (30.25%), Stable Mental Health with Low Substance Use (53.12%), Persistent Mental Health Symptoms with Persistent Substance Use (8.84%), and Improved Mental Health with Persistent Substance Use (7.79%). The model showed good classification accuracy, with average latent profile probabilities around 0.86-0.91. The Improved Mental Health with Low Substance Use profile showed moderate depression and anxiety at Time 2, followed by marked improvements in internalising problems and a slight increase in cognitive flexibility after psilocybin use, while substance use stayed relatively low. The Persistent Mental Health Symptoms with Persistent Substance Use profile began with severe internalising problems and low cognitive flexibility, improved somewhat after psilocybin but remained in the moderate range for depression and anxiety, and continued to show problematic substance use, especially weekly benzodiazepine use. The Improved Mental Health with Persistent Substance Use profile also improved in depression, anxiety and cognitive flexibility, but had the highest rates of substance use in the sample, including the greatest alcohol and tobacco use; its alcohol-related problems remained high and drug-related problems, although reduced, stayed in the problematic range. The Stable Mental Health with Low Substance Use profile had low symptom levels across all time points and only minor changes over time. Between-profile comparisons showed that the Stable Mental Health with Low Substance Use profile was older, more educated than the Persistent Mental Health Symptoms with Persistent Substance Use profile, had the most adaptive personality profile, and reported the highest psychological surrender before the session. The Persistent Mental Health Symptoms with Persistent Substance Use profile had the highest proportion of women and the most maladaptive personality profile, with higher neuroticism and lower scores on the other Big Five traits. The Improved Mental Health with Persistent Substance Use profile had the highest proportion of men. The Persistent Mental Health Symptoms with Persistent Substance Use profile also reported the lowest mystical experience and awe scores, and lower psychological surrender than the Stable Mental Health with Low Substance Use profile. Challenging experience scores were lower in the Stable Mental Health with Low Substance Use profile than in the Improved Mental Health with Low Substance Use and Persistent Mental Health Symptoms with Persistent Substance Use profiles. There were no significant differences in reported setting or in the number of additional psilocybin uses after the target session.

The authors interpret the findings as showing that naturalistic psilocybin use is associated with more than one pattern of response rather than a single uniform trajectory. Most participants were in profiles characterised by low symptom burden or by improvement in depression, anxiety and cognitive flexibility, but two smaller profiles had persistent substance use problems after psilocybin use. The authors emphasise that the profile with the greatest psychological vulnerability before use also had the least favourable acute experience profile, including lower mystical and awe experiences, lower pre-session surrender and higher challenging experiences, which they suggest may be linked to less benefit afterwards. Richard and colleagues position their results alongside earlier research suggesting that psychedelic experiences can be associated with positive mental health changes and that subjective mystical-type experiences often correlate with better outcomes. At the same time, they note that their findings extend prior work by showing heterogeneity at the individual level, including profiles in which internalising symptoms improved but substance use remained largely unchanged. They argue that this is particularly relevant because earlier work has not always separated these response patterns. The discussion suggests that baseline characteristics such as age, gender, education, personality and pre-session mindset may help explain who falls into different response patterns. The authors also raise the possibility that some participants with persistent substance use may have been using psilocybin in a self-medication framework, rather than with clear intentions to change substance use. They suggest that substance-use change may depend on more than mystical experience alone, and may also involve intention, preparation, setting and integration. Although no setting differences were detected here, the authors note that few participants used psilocybin in treatment or religious/spiritual contexts, limiting conclusions about context. The paper acknowledges several limitations: the lack of a non-psilocybin comparison group, small sample sizes for two profiles, self-selection and response bias, attrition, reliance on self-report, possible underestimation of substance use, and a sample that was mostly White and relatively highly educated. The authors conclude that the findings are preliminary and that larger, more diverse studies are needed, especially to clarify how intention, setting and other contextual factors shape outcomes after psychedelic use.

The authors conclude that four distinct response patterns emerged around internalising problems, substance use and cognitive flexibility after naturalistic psilocybin use. They state that while many participants showed psychological stability or sustained improvement, others had persistent substance use problems and, in one subgroup, greater psychological vulnerability with less benefit. They further conclude that the broader effects of psilocybin on substance use remain unclear, and that preparation, clarified intentions and post-session integration may be important for maximising benefit and reducing potential longer-term harms.