In the largest prospective longitudinal survey to date of naturalistic psilocybin use (n=2,833 baseline; 657 at 2–3 months), participants reported sustained reductions in anxiety, depression and alcohol misuse and increases in cognitive flexibility, emotion regulation, spiritual wellbeing and adaptive personality traits after a planned psilocybin experience. A minority (11% at 2–4 weeks; 7% at 2–3 months) reported persisting negative effects such as mood fluctuations or depressive symptoms.
Introduction
The classic psychedelic psilocybin, found in some mushroom species, has received renewed interest in clinical research, showing potential mental health benefits in preliminary trials. Naturalistic use of psilocybin outside of research settings has increased in recent years, though data on the public health impact of such use remain limited.
Methods
This prospective, longitudinal study comprised six sequential automated web-based surveys that collected data from adults planning to take psilocybin outside clinical research: at time of consent, 2 weeks before, the day before, 1–3 days after, 2–4 weeks after, and 2–3 months after psilocybin use.
Results
A sample of 2,833 respondents completed all baseline assessments approximately 2 weeks before psilocybin use, 1,182 completed the 2–4 week post-use survey, and 657 completed the final follow-up survey 2–3 months after psilocybin use. Participants were primarily college-educated White men residing in the United States with a prior history of psychedelic use; mean age = 40 years. Participants primarily used dried psilocybin mushrooms (mean dose = 3.1 grams) for “self-exploration” purposes. Prospective longitudinal data collected before and after a planned psilocybin experience on average showed persisting reductions in anxiety, depression, and alcohol misuse, increased cognitive flexibility, emotion regulation, spiritual wellbeing, and extraversion, and reduced neuroticism and burnout after psilocybin use. However, a minority of participants (11% at 2–4 weeks and 7% at 2–3 months) reported persisting negative effects after psilocybin use (e.g., mood fluctuations, depressive symptoms).
Discussion
Results from this study, the largest prospective survey of naturalistic psilocybin use to date, support the potential for psilocybin to produce lasting improvements in mental health symptoms and general wellbeing.
Papers cited by this study that are also in Blossom
Leary, T., Litwin, G. H., Metzner, R. · Journal of Nervous and Mental Disease (1977)
Garcia-Romeu, A., Kersgaard, B., Addy, P. H. · Experimental and Clinical Psychopharmacology (2016)
Rucker, J., Iliff, J., Nutt, D. J. · Neuropharmacology (2017)
Griffiths, R. R., Johnson, M. W. · Journal of Psychopharmacology (2016)
Psilocybin is a naturally occurring serotonergic psychedelic found in many Psilocybe species and has a long history of ritual use. In recent decades, small clinical trials and pilot studies have suggested potential therapeutic benefits for mood, existential distress, and substance use disorders, and research in healthy volunteers has indicated possible improvements in psychological wellbeing and spiritual experiences. Concurrent cultural and policy shifts have led to increased naturalistic (non-research) use of psilocybin, but evidence on the public health impact of that use outside controlled settings remains limited. Nayak and colleagues conducted a prospective, longitudinal online survey study to add empirical data on contemporary naturalistic psilocybin use. The study aimed to characterise users and their dosing and setting, to assess prospective changes in mental health, personality, wellbeing, and functioning from before to after a planned psilocybin session, and to examine how pre-session mindset (e.g., absorption, State of Surrender, adverse childhood experiences) and elements of setting (e.g., presence of a sitter) related to acute subjective effects and persisting outcomes.
This was a prospective longitudinal survey of English-speaking adults (≥18 years) who planned to take psilocybin outside clinical research. Recruitment occurred online between July 22, 2020 and July 14, 2022, and participants completed six automated web surveys: initial consent/demographics, ~2 weeks pre-session (baseline battery), 1 day pre-session, 1–3 days post-session, 2–4 weeks post-session, and 2–3 months post-session. The study received Institutional Review Board approval at Johns Hopkins University School of Medicine. Baseline-only measures included lifetime drug-use history, the Tellegen Absorption Scale (TAS, 0–34), and the Adverse Childhood Experience scale (ACE, 0–14). Repeated longitudinal measures administered at baseline and both follow-ups comprised a modified Beck Depression Inventory-II (BDI-II, 0–60; suicidality item removed), the Alcohol Use Disorders Identification Test (AUDIT, 0–40), the Short State-Trait Anxiety Inventory (STAI, state and trait, each 10–40), the Emotion Regulation Questionnaire (ERQ; cognitive reappraisal and expressive suppression), the Cognitive Flexibility Scale (CFS), the PROMIS-GH physical health subscale, the FACIT-Sp spiritual wellbeing scale, the Copenhagen Burnout Inventory (CBI), and the Big Five Inventory (BFI, at baseline and 2–3 months). The 1-day-pre and 1–3-day-post surveys collected planned and actual dose/form, concurrent substances, setting details (alone, with friends, with a sitter/guide), intentions, the State of Surrender (SOS) scale pre-session, and acute subjective measures post-session: the Mystical Experience Questionnaire (MEQ30) and the Challenging Experience Questionnaire (CEQ). Data analysis used linear mixed-effects models (lme4 in R) for eleven longitudinal outcomes, including baseline score and covariates (timepoint, age, sex, race, education, presence of a sitter, psilocybin dose in dried grams, prior psychedelic use, ACE, MEQ30, CEQ, SOS, TAS) and random intercepts for participants. MEQ30, CEQ, SOS, and TAS were allowed to interact with time. Five simple linear models were used for the five BFI dimensions. Correlations between ACE/TAS/SOS and MEQ30/CEQ were calculated. To control for multiple testing across 22 primary tests, a Šidák-corrected alpha of 0.0023 was applied. Two exploratory t-tests compared acute subjective effects between those reporting concurrent antidepressant use and those not; these were not included in the Šidák correction.
Survey retention declined across timepoints: N = 8,006 at consent, N = 2,833 at ~2 weeks pre-session, N = 1,551 at 1–3 days post-session, N = 1,182 at 2–4 weeks, and N = 657 at 2–3 months. The sample was majority White (81–87%), male (54–59%), US-resident (73–83%), college-educated (54–66% with bachelor’s or higher), mean age ~40 years, and highly experienced with psychedelics (mean ~16–17 prior uses). Most participants reported intentions of self-exploration (81%), mental health (71%), or therapeutic aims (48%); about 74% set a specific intention. Sessions typically occurred at home (≈70%), usually alone (43%) or with friends also using (26%); 16% had a sober sitter. The predominant reported form was dried mushrooms (≈42% whole, 19% ground), average initial dose among those reporting grams (excluding outliers) was 3.1 g (SD 2.3). Common co-used substances were cannabis (31%), caffeine (15%), and alcohol (12%); 4.6% reported concurrent antidepressant use. Acute subjective effects: mean MEQ30 total score was 0.50 (SD 0.25), with 21.6% meeting criteria for a "complete mystical experience". Mean CEQ was 0.14 (SD 0.14). MEQ30 scores predicted greater reductions in depression, personal and work burnout, and state anxiety, and greater increases in cognitive flexibility and spiritual wellbeing. CEQ did not predict linear changes in longitudinal outcomes. TAS correlated weakly with MEQ30 (r = 0.32, p < 0.001) but not CEQ; SOS correlated weakly with MEQ30 (r = 0.24, p < 0.001) and very weakly with CEQ (r = -0.10, p < 0.001). ACE scores were not significantly correlated with MEQ30 or CEQ. Adverse events and persisting negative effects were uncommon: 0.4% sought medical care and 3.4% sought psychological care within 1–3 days after the session. Persisting negative effects were reported by 7–11% across follow-ups, most commonly mood fluctuations (4.7% at 2–4 weeks, 3.0% at 2–3 months) and depressive thoughts (3.1% at 2–4 weeks, 1.7% at 2–3 months). Primary longitudinal outcomes showed statistically significant improvements from baseline to follow-ups after covariate adjustment. Modified BDI-II mean scores fell from 15.3 (SD 11.2) at baseline to 6.4 (8.3) at 2–4 weeks and 7.5 (8.9) at 2–3 months. Covariate-adjusted standardised mean differences (SMD; interpretable as adjusted Cohen’s d) for BDI were -0.71 [95% CI -0.79, -0.63] at 2–4 weeks and -0.58 [-0.66, -0.50] at 2–3 months (both p < 0.001), indicating moderately large reductions in depressive symptoms. AUDIT scores decreased slightly (SMD -0.06 [-0.10, -0.02] at 2–4 weeks and -0.09 [-0.13, -0.05] at 2–3 months; p < 0.001), reflecting small reductions in alcohol misuse. State and trait anxiety showed reductions (details partially fragmented in extraction but reported as decreased). Cognitive reappraisal (ERQ) increased with SMD 0.19 [0.11, 0.27] at 2–4 weeks and 0.24 [0.16, 0.32] at 2–3 months (p < 0.001), while expressive suppression showed no consistent change. Cognitive flexibility (CFS) increased with SMD 0.23 [0.15, 0.31] at 2–4 weeks and 0.22 [0.15, 0.30] at 2–3 months (p < 0.001). Personal burnout decreased (CBI personal SMD -0.33 [-0.37, -0.29] at 2–4 weeks and -0.36 [-0.42, -0.31] at 2–3 months; p < 0.001); work-related burnout decreased significantly only at 2–3 months (SMD -0.19 [-0.25, -0.12], p < 0.001). No significant change was observed in self-reported physical health (PROMIS-GH). Personality measures showed small but significant increases in extraversion (from 3.12 to 3.17, p < 0.001) and decreases in neuroticism (from 2.88 to 2.81, p < 0.001); openness, agreeableness, and conscientiousness did not change significantly. Set and setting variables: prior psychedelic experience and presence of a sitter/guide did not significantly predict longitudinal outcomes. Higher MEQ30 scores were associated with greater improvements on several outcomes. In exploratory analyses, concurrent antidepressant use (n = 72) was associated with lower acute MEQ30 (mean 0.40 vs 0.51, p = 0.0007) and CEQ (0.10 vs 0.15, p = 0.001) scores, indicating attenuated acute subjective effects among this subgroup. At follow-ups, 29–36% rated the session among the 10 most personally meaningful or spiritually significant experiences of their lives, and most respondents (84–89%) reported positive changes in wellbeing and life satisfaction attributable to the experience. Approximately half reported improved relationships and substantial proportions reported other positive behavioural changes (increased exercise, improved work life, better diet).
Nayak and colleagues interpret these results as supportive of persisting improvements in mental health, wellbeing, and psychological functioning following naturalistic psilocybin use in this convenience sample. The longitudinal reductions in depressive symptoms, anxiety, and alcohol misuse, together with increases in cognitive flexibility, cognitive reappraisal, spiritual wellbeing, and reductions in burnout, are presented as broadly consistent with prior clinical and epidemiological findings. The authors note the moderately large adjusted effect sizes for depression (SMD ≈ 0.58–0.71) and emphasise that mystical-type acute experiences (MEQ30) were associated with greater persisting improvements across several domains. The discussion contrasts acute subjective effects observed here with those from laboratory studies, noting lower proportions of "complete mystical experiences" and lower mean MEQ30 scores in this naturalistic sample, which likely relates to lower average doses and heterogeneous contexts in non-research settings. The authors highlight that challenging acute experiences were low on average and did not predict longitudinal outcomes, suggesting that while such challenges may pose acute risk, they did not on average predict therapeutic benefit in this dataset. The exploratory finding of attenuated acute subjective effects among participants concurrently taking antidepressants is noted and compared with mixed evidence from small experimental studies; the authors call for targeted research on interactions between psilocybin and psychiatric medications. Several limitations acknowledged by the investigators temper interpretation. These include a self-selected, predominantly White and well-educated sample that limits generalisability; anonymous, self-report data that cannot be externally verified; attrition across follow-ups that may bias results; possible confounding from concurrent substance use; and the fact that many participants took additional psilocybin doses after the reference experience (26% at 2–4 weeks and 50% at 2–3 months), complicating attribution of persisting effects to a single session. The authors also note the small absolute rates of acute medically significant reactions but caution that individuals with severe adverse events may have been less likely to complete follow-ups. Finally, the investigators suggest set and setting variables still play an important role in acute and persisting effects and that therapeutic contexts may leverage these factors to boost outcomes beyond pharmacological effects alone. Overall, the authors conclude that their large prospective dataset aligns with a growing body of evidence indicating potential therapeutic and wellbeing-related benefits of psilocybin, while underscoring the need for further targeted, controlled, and more demographically diverse research to clarify causal mechanisms, optimal dosing regimens, and safety in the context of concurrent medications and varied real-world settings.
In spite of the study’s limitations, the authors conclude that findings from this large prospective naturalistic cohort are consistent with prior clinical and epidemiological work, indicating that psilocybin use in non-research settings was associated with lasting improvements in several domains of mental health and wellbeing. They present these results as supportive of psilocybin’s broad therapeutic potential while noting the need for further rigorous research to address remaining questions about safety, optimal use conditions, medication interactions, and generalisability.
Descriptive statistics including means, SD, and ranges were performed for demographic variables. For longitudinal measures, linear mixed models using the lme4 package (50) in R were used with the following covariates: baseline score of each measure, time (2-weeks prior to session, 2-4 weeks after the session, or 2-3 months after), age, sex, race (White or non-White), education level, the presence of a sitter, dose of psilocybin mushroom in dried grams, whether the participant had ever taken a psychedelic before, ACE score, MEQ30 score, CEQ score, State of Surrender score, and TAS score. MEQ30, CEQ, State of Surrender, and TAS also included interactions with time, and models included random intercepts for participant to account for repeated measures. Eleven such models were used for the following outcomes, which were assessed 2-weeks prior to the session, 2-4 weeks after and 2-3 months after: BDI, AUDIT, STAI-Trait, STAI-State, CFS, PROMIS-GH physical health, FACIT-Sp, the expressive suppression and cognitive reappraisal subscales of the ERQ, and the personal and work burnout subscales of the CBI. Model results for individual regression parameters are reported as beta regression coefficients (β) and p-values. p-values for categorical demographic variables with more than 2 levels (Education and Sex) were calculated using type II Wald Chi-square tests using the Anova function of the car package. This is an omnibus test performed on the regression model that allows for a single p-value for categorical variables with multiple levels. Effects on longitudinal measures are presented as covariate-adjusted mean differences between timepoints-both unstandardized and standardized mean differences (SMD). These SMDs are interpretable as covariate-adjusted Cohen's d's. SMDs reflecting changes between timepoints were calculated as follows: first, linear mixed-models were performed with the outcome variables Z-scored. Then, covariateadjusted contrasts were calculated between each follow-up timepoint and baseline using the emmeans function of the emmeans package. For the five dimensions of the Big Five Inventory, simple linear models were performed with time as the predictor of interest and baseline score as a covariate. Additionally, correlations between adverse childhood experience (ACE) scores and subjective drug effects (MEQ30 and CEQ) were calculated using Kendall correlations. Similarly, correlations between Tellegen Absorption Scale (TAS) and State of Surrender (SOS) scores were performed with subjective drug effects measures (MEQ30 and CEQ) using Pearson correlations. Eleven mixed models for longitudinal variables, 5 linear models total for the Big Five Inventory, and 6 correlations total 22 statistical significance tests. The Šidák correction was used with an unadjusted alpha of 0.05 and 22 tests for a corrected alpha threshold of 0.0023. Two additional exploratory analyses were included to examine the effects of concurrent antidepressant use on acute subjective effects of psilocybin. Means and standard deviations for MEQ30 and CEQ were calculated for those endorsing antidepressant use of any kind (this was not differentiated by antidepressant drug class) during the psilocybin experience. These scores were compared with MEQ30 and CEQ ratings of individuals who were not taking an antidepressant during their psilocybin experience using independent samples t-tests. As exploratory measures, these were not included in the calculation of the Šidák correction above.
This study presents the largest prospective, longitudinal dataset on naturalistic psilocybin use published to date. Similar to cross-sectional data on naturalistic psilocybin use, relatively few medically significant acute reactions (<4%) or persisting negative effects (<5%) were reported here. Nevertheless, some non-trivial issues were reported in a small minority of respondents, indicating a need for ongoing caution among both naturalistic users and clinical researchers to avoid negative outcomes such as mania or psychosis, which have been previously reported. Positive behavioral changes were more frequently reported after psilocybin use than negative ones, with improved relationships being most commonly endorsed (~50% of respondents), and about 23% reporting no notable behavioral changes after their experience. In retrospect, most participants (>90%) viewed their naturalistic psilocybin use positively, and more than 80% attributed desirable changes in wellbeing and life satisfaction to their experience. Overall, data support prior evaluations of psilocybin as reasonably safe and non-toxic compared to other commonly used substances, with the caveat that individuals who experienced particularly difficult reactions or significant adverse events may not have been able or willing to respond to follow-up surveys as described in the study limitations. Subjective effects data found low challenging experience scores on average and moderately high mystical experience scores, with roughly one fifth of the sample meeting a priori criteria for a "complete" mystical experience. Interestingly, acute challenging experiences were only weakly related to State of Surrender before the session and did not significantly predict any changes in longitudinal variables, suggesting that challenging experiences may pose acute risk but that they may not on average predict therapeutic outcomes. These data also indicate a need for better characterization of challenging psychedelic experiences and their potential relationship to persisting effects. Subjective effects ratings were lower and yielded a smaller proportion of "complete" mystical experience than those found in laboratory research administering 20 mg/70 kg or 30 mg/70 kg psilocybin. At follow-up surveys roughly 2 weeks and 2 months after the reference experience, between a quarter and a third of respondents considered the experience among the 10 most meaningful or spiritually significant of their lives, exhibiting lower rates of personal meaning and spiritual significance than both healthyand clinical populationsadministered psilocybin in laboratory settings. However, the doses used in the present study are likely lower than those typically used in clinical research and previous studies have shown ratings of personal meaning, spiritual significance, and mystical-type effects of psilocybin, as well as related subjective effects such as oceanic boundlessness, to be dose dependent. Longitudinal data indicate that among the convenience sample reported here, naturalistic use of psilocybin mushrooms was associated with significant improvements in mental health, wellbeing, and psychological functioning when controlling for demographic variables, in line with initial hypotheses. Persisting reductions in depression, state and trait anxiety, and alcohol misuse were found after psilocybin use, congruent with clinical studies showing similar results. Moreover, a moderately large effect size (SMD = 0.58-0.71) was observed for reductions in depression, providing additional support for psilocybin as a potential antidepressant treatment. However, it is notable that a substantial proportion of the current sample (>40%) met BDI-II criteria for depression at baseline and that the majority (>85%) had prior experience using psilocybin an average of 16-17 times before joining the study. These findings suggest psilocybin may have a time-limited window of antidepressant effects, consistent with clinical trial data, and imply that some individuals may require repeated psilocybin dosing for continued antidepressant benefits. Future research should examine methods for identifying such individuals, and the optimal interval and dosing regimen to be used in these cases. In exploratory analyses, we found weaker acute subjective effects of psilocybin (i.e., mystical-type and challenging effects) among those concurrently taking antidepressants. This is consistent with similar survey findings of attenuated psychedelic response in individuals on antidepressants. Although antidepressants were not differentiated by drug class in the present survey, it is likely the majority were serotonergic. Given the heterogeneous clinical presentation and small number of individuals taking antidepressants in the current study, impact of antidepressant use on enduring outcomes was not possible to adequately assess. However, it is possible that diminished subjective effects may not necessarily equate to reduced clinical efficacy in patient populations. Of note, a recent study found pre-treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram produced no difference in positive mood effects of psilocybin (25 mg) in healthy individuals (n = 23), but did elicit less bad drug effect, anxiety, and adverse effects compared to pre-treatment with placebo. Similarly, novel data showed 25 mg of psilocybin exhibited clinically meaningful antidepressant effects lasting up to 3 weeks in individuals with treatment resistant-depression (n = 19) who were concurrently maintained on an approved SSRI medication. Future targeted research on interactions between psilocybin and common psychiatric medications will be highly valuable to inform clinical practice. In addition to psychiatric constructs such as depression and anxiety, psilocybin also impacted broader areas related to emotion, Frontiers in Psychiatry 16 frontiersin.org mental health symptoms such as anxiety and depression (13), as well as racial trauma among black, indigenous, and people of color. Similarly, the psychedelic ayahuasca has been found to increase cognitive flexibility and mindfulness in the period immediately following use, and psilocybin has also shown enhancement of cognitive flexibility in neuropsychological testing up to 4 weeks after drug administration in individuals with major depression. However, improvements in cognitive flexibility and reductions in depression were not directly correlated, suggesting an important, but nuanced role for cognitive flexibility in mediating mental health benefits of psychedelics. Personal burnout showed significant reductions at both 2-4 weeks and 2-3 months after psilocybin use, and work-related burnout showed significant reductions at the 2-3 month follow-up only. To our knowledge, these are the first data showing psychedelic-associated reductions in burnout as a specific construct, which is characterized by fatigue and exhaustion in relation to high-stress work or living environments. No changes were found in self-reported physical health from before to after psilocybin use, suggesting minimal impact of naturalistic psilocybin use on physical health factors such as activities of daily living (e.g., walking), and providing a useful positive control for longitudinal data. However, significant and persisting increases in spiritual wellbeing after psilocybin use were observed in the present study, consistent with clinical trials administering highdose psilocybin to cancer patients with anxiety and depressed mood. Finally, regarding personality, only two dimensions showed significant changes after psilocybin use, with increases in extraversion and decreases in neuroticism observed, but no changes in openness, which has previously been reported to increase after psilocybin administration. Several hypotheses were tested in the current study. The first was borne out by longitudinal data showing general improvements across multiple domains of mental health and wellbeing. Regarding elements of mindset and their influence on subjective drug effects, consistent with previous findings, we found significant associations between absorption and State of Surrender before the psilocybin experience, and mystical-type effects during psilocybin use. State of Surrender was weakly negatively correlated with challenging experience scores, and absorption showed no relationship to challenging experiences. History of adverse childhood experiences (ACE) was not significantly associated with either mystical or challenging subjective drug effects, contrary to initial hypotheses. However, greater baseline ACE scores were associated with decreased depression and personal burnout at follow-up and increased spiritual wellbeing at follow-up. Contrary to expectations, greater State of Surrender was not associated with outcomes other than lower depression overall and less decrease in depression at the 2-4 week timepoint. The latter finding could be related to regression toward the mean. Greater TAS was not associated with outcomes other than decreased cognitive reappraisal at both follow-up time points, decreased spiritual wellbeing at 2-4 weeks, and increased expressive suppression at 2-4 weeks. The origin and nature of these relationships remain somewhat unclear and may benefit from additional investigation. Consistent with prior research, mystical-type effects were associated with persisting improvements in mood, anxiety, cognitive flexibility, and spiritual wellbeing. Additionally, novel findings presented here suggest mystical-type effects of psilocybin were associated with ongoing and significant reductions in personal burnout, an area that requires further study. Finally, presence of a sitter during psilocybin use was not associated with any persisting benefits, contrary to previous findings and our initial hypotheses, although such a finding does not preclude the idea that a sitter may reduce the likelihood of adverse events or risky behavior. Taken together, these findings indicate set and setting variables contribute strongly to perceived drug effects acutely as well as persisting effects, consistent with research showing notable placebo responses in carefully designed experimental environments. In therapeutic settings, it is likely that these factors can be leveraged to enhance mental health outcomes over and above drug effects alone via additive and dynamic social processes such as psychological support and intentional meaning-making.
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