BACKGROUND: Recent studies intensively explore psilocybin's antidepressant potential, but variables like previous experience, repeated use, setting, and sex remain underexplored. This study examines acute and long-term effects of psilocybin in healthy individuals. METHODS: A double-blind, placebo-controlled, cross-over study included 40 healthy participants (20 females, mean age 38). Each received two doses of psilocybin (0.26 mg/kg) at least 56 days apart (mean 488) in two neuroimaging study arms. Nearly half had previous psychedelic experience. Acute effects were measured using the Altered States of Consciousness Scales (ASCs) and a Visual Analogue Scale (VAS) for emotional valence. The Persisting Effects Questionnaire (PEQ) assessed long-term effects. RESULTS: All results were independent of observed variables such as previous psychedelic experience, repeated use, setting, sex and occupation. Acute effects were moderate on the ASCs, with VAS ratings showing mostly pleasant or fluctuating experiences and only one unpleasant session. All experiences resolved in a positive or neutral state by the session's end. Psilocybin produced lasting positive effects across all PEQ domains, with negligible negative effects. Oceanic Boundlessness (OBN) and Visionary Restructuralization (VRS) correlated with positive outcomes, while Dread of Ego Dissolution (DED), typically associated with fear, did not predict negative effects. The nature of the acute experience (pleasant or mixed) was not linked to the direction or intensity of long-term outcomes. Peak experiences ending in a positive mood were strongly associated with favourable long-term effects. CONCLUSION: Repeated psilocybin administration in healthy individuals induces positive, lasting effects, with challenging experiences in controlled settings not causing adverse outcomes. These findings support psilocybin's psychological safety and its repeated use in clinical trials.

1st Faculty of Medicine Charles University Prague Kateřinská 32 Prague 121 08 Czechia

3rd Faculty of Medicine Charles University Prague Ruská 87 Prague 100 00 Czechia

Forensic Laboratory of Biologically Active Compounds Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Czechia

National Institute of Mental Health Topolová 748 Klecany 250 67 Czechia

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Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387:1637–48. PubMed

Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, et al. Trial of psilocybin versus Escitalopram for depression. N Engl J Med. 2021;384:1402–11. PubMed

Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30:1165–80. PubMed PMC

Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep. 2017;7:13187. PubMed PMC

Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology. 2011;218:649–65. PubMed PMC

Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006;187:268–83. PubMed

Nicholas CR, Henriquez KM, Gassman MC, Cooper KM, Muller D, Hetzel S, et al. High dose psilocybin is associated with positive subjective effects in healthy volunteers. J Psychopharmacol. 2018;32:770. PubMed PMC

Walsh Z, Mollaahmetoglu OM, Rootman J, Golsof S, Keeler J, Marsh B, et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych Open. 2021;8:e19. PubMed PMC

Yavi M, Lee H, Henter ID, Park LT, Zarate CA Jr. Ketamine treatment for depression: a review. Discov Ment Health. 2022;2:9. PubMed PMC

Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, et al. Rapid antidepressant effects of the psychedelic Ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49:655–63. PubMed PMC

Andersen KAA, Carhart-Harris R, Nutt DJ, Erritzoe D. Therapeutic effects of classic serotonergic psychedelics: a systematic review of modern-era clinical studies. Acta Psychiatr Scand. 2021;143:101–18. PubMed

Reckweg JT, Uthaug MV, Szabo A, Davis AK, Lancelotta R, Mason NL, Ramaekers JG. The clinical Pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). J Neurochem. 2022;162:128–46. PubMed PMC

O’Reilly PO, Funk A. LSD in chronic alcoholism. Can Psychiatr Assoc J. 1964;9:258–61. PubMed

Klavetter RE, Mogar RE. Peak experiences: investigation of their relationship to psychedelic therapy and self-actualization. J Humanist Psychol. 1967;7:171–7.

Pahnke WN, Kurland AA, Unger S, Savage C, Grof S. The experimental use of psychedelic (LSD) psychotherapy. JAMA. 1970;212:1856–63. PubMed

Richards W, Rhead J, DiLeo F, Yensen R, Kurland A. The peak experience variable in DPT-assisted psychotherapy with cancer patients. J Psychedelic Drugs. 1977;9:1–10.

MacLean KA, Johnson MW, Griffiths RR. Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol. 2011;25:1453–61. PubMed PMC

Garcia-Romeu A, Johnson M, Griffiths R. Examining the psychological mechanisms of psilocybin-assisted smoking cessation treatment: a pilot study. Drug Alcohol Depend. 2014;140:48–55.

Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30:1181–97. PubMed PMC

Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29:289–99. PubMed

Roseman L. Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol. 2018;8:974. PubMed PMC

Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013;34:287–93. PubMed

Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse. 2017;43:55–60. PubMed PMC

Olson DE. Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics. J Exp Neurosci. 2018;12:1179069518800508. PubMed PMC

Glue P, Medlicott NJ, Surman P, Lam F, Hung N, Hung CT. Ascending-dose study of controlled-release ketamine tablets in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability. J Clin Pharmacol. 2020;60:751–7. PubMed

Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed Esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176:428–38. PubMed

Glue P, Medlicott NJ, Neehoff S, Surman P, Lam F, Hung N, Hung CT. Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Ther Adv Psychopharmacol. 2020;10:2045125320922474. PubMed PMC

Reif A, Bitter I, Buyze J, Cebulla K, Frey R, Fu DJ, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;389:1298–309. PubMed

Vasiliu O. Esketamine for treatment-resistant depression: a review of clinical evidence. Exp Ther Med. 2023;25:111. PubMed PMC

Maslow AH. Cognition of being in the peak experiences. J Genet Psychol. 1959;94:43–66. PubMed

Stace WT. Mysticism and philosophy. London: Macmillan and Co.; 1960.

Pahnke WN, Richards WA. Implications of LSD and experimental mysticism. J Relig Health. 1966;5:175–208. PubMed

MacLean KA, Leoutsakos JM, Johnson MW, Griffiths RR. Factor analysis of the mystical experience questionnaire: a study of experiences occasioned by the hallucinogen psilocybin. J Sci Study Relig. 2012;51:721. PubMed PMC

Davis AK, Barrett FS, So S, Gukasyan N, Swift TC, Griffiths RR. Development of the psychological insight questionnaire among a sample of people who have consumed psilocybin or LSD. J Psychopharmacol. 2021;35:437–46. PubMed PMC

James E, Robertshaw TL, Hoskins M, Sessa B. Psilocybin occasioned mystical-type experiences. Hum Psychopharmacol. 2020;35:e2742. PubMed

Ko K, Knight G, Rucker JJ, Cleare AJ. Psychedelics, mystical experience, and therapeutic efficacy: a systematic review. Front Psychiatry. 2022;13:917199. PubMed PMC

Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A. 2012;109:2138–43. PubMed PMC

Smigielski L, Scheidegger M, Kometer M, Vollenweider FX. Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage. 2019;196:113700. PubMed

Kuypers KP, Riba J, de la Fuente Revenga M, Barker S, Theunissen EL, Ramaekers JG. Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking. Psychopharmacology. 2016;233:3395–403. PubMed PMC

Davis AK, Barrett FS, Griffiths RR. Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety. J Contextual Behav Sci. 2020;15:39. PubMed PMC

Hendricks PS. Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy. Int Rev Psychiatry. 2018;30:331–42. PubMed

Carhart-Harris RL, Leech R, Hellyer PJ, Shanahan M, Feilding A, Tagliazucchi E, et al. The entropic brain: a theory of conscious States informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci. 2014;8:20. PubMed PMC

Carhart-Harris RL. The entropic brain – revisited. Neuropharmacology. 2018;142:167–78. PubMed

Studerus E, Gamma A, Kometer M, Vollenweider FX. Prediction of psilocybin response in healthy volunteers. PLoS ONE. 2012;7:e30800. PubMed PMC

Haijen ECHM, Kaelen M, Roseman L, Timmermann C, Kettner H, Russ S, et al. Predicting responses to psychedelics: a prospective study. Front Pharmacol. 2018;9:897. PubMed PMC

Pahnke W. Drugs and mysticism: an analysis of the relationship between psychedelic drugs and the mystical consciousness. Cambridge: Harvard Univ.; 1963.

Rick D. Pahnke’s Good Friday Experiment: a long-term follow-up and methodological critique. 1991. (Není uveden oficiální zdroj – doporučuji doplnit vydavatele nebo médium.).

Dittrich A. Zusammenstellung eines Fragebogens (APZ) Zur erfassung abnormer psychischer zustände [Construction of a questionnaire (APZ) for assessing abnormal mental states]. Z Klin Psychol Psychiatr Psychother. 1975;23:79–112.

Dittrich A, Lamparter D, Maurer M. 5D-ABZ: Fragebogen Zur erfassung außergewöhnlicher bewusstseinszustände (5D-ASC). PSIN PLUS; 2010.

Bodmer I, Dittrich A, Lamparter D. The measurement of altered States of consciousness using the APZ questionnaire. In: Hofmann A, Leuner H, editors. Welten des bewusstseins. Volume 3. Göttingen: Verlag für Experimentelle Psychologie, Neurobiologie und Chemie; 1994. pp. 45–8.

Tylš F, Páleníček T, Kadeřábek L, Lipski M, Kubešová A, Horáček J. Sex differences and serotonergic mechanisms in the behavioural effects of Psilocin. Behav Pharmacol. 2016;27:309–20. PubMed

Butcher JN, Graham JR, Fowler RD. Special series: the MMPI-2. J Pers Assess. 1991;57:203–4. PubMed

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33. quiz 34–57. PubMed

Bravermanová A, Viktorinová M, Tylš F, Novák T, Androvicová R, Korčák J, et al. Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing—study on P300 and mismatch negativity in healthy volunteers. Psychopharmacology. 2018;235:491–503. PubMed

Gren J, Tylš F, Lasocik M, Király C. Back from the rabbit hole: theoretical considerations and practical guidelines on psychedelic integration for mental health specialists. Front Psychol. 2023;14:1054692. PubMed PMC

Viktorin V, Griskova-Bulanova I, Voicikas A, Dojcanova D, Zach P, Bravermanova A, et al. Psilocybin-mediated Attenuation of gamma band auditory steady-state responses (ASSR) is driven by the intensity of cognitive and emotional domains of psychedelic experience. J Pers Med. 2022;12:1004. PubMed PMC

Fredrickson BL, Kahneman D. Duration neglect in retrospective evaluations of affective episodes. J Pers Soc Psychol. 1993;65:45–55. PubMed

Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol. 2008;22:621–32. PubMed PMC

Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, et al. Pharmacokinetics of escalating doses of oral psilocybin in healthy adults. Clin Pharmacokinet. 2017;56:1543–54. PubMed

Garcia-Romeu A, Barrett FS, Carbonaro TM, Johnson MW, Griffiths RR. Optimal dosing for psilocybin pharmacotherapy: considering weight-adjusted and fixed dosing approaches. J Psychopharmacol. 2021;35:353–61. PubMed PMC

MacCallum CA, Lo LA, Pistawka CA, Deol JK. Therapeutic use of psilocybin: practical considerations for dosing and administration. Front Psychiatry. 2022;13:1040217. PubMed PMC

Cavanna F, Muller S, de la Fuente LA, Zamberlan F, Palmucci M, Janeckova L, et al. Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study. Transl Psychiatry. 2022;12:307. PubMed PMC

Golden TL, Magsamen S, Sandu CC, Lin S, Roebuck GM, Shi KM, Barrett FS. Effects of setting on psychedelic experiences, therapies, and outcomes: a rapid scoping review of the literature. Curr Top Behav Neurosci. 2022;56:35–70. PubMed

Carbonaro TM, Bradstreet MP, Barrett FS, MacLean KA, Jesse R, Johnson MW, Griffiths RR. Survey study of challenging experiences after ingesting psilocybin mushrooms: acute and enduring positive and negative consequences. J Psychopharmacol. 2016;30:1268–78. PubMed PMC

Barber G, Nemeroff CB, Siegel S. A case of prolonged mania, psychosis, and severe depression after psilocybin use: implications of increased psychedelic drug availability. Am J Psychiatry. 2022;179:892–6. PubMed

Bremler R, Katati N, Shergill P, Erritzoe D, Carhart-Harris RL. Case analysis of long-term negative psychological responses to psychedelics. Sci Rep. 2023;13:15998. PubMed PMC

Muthukumaraswamy SD, Forsyth A, Lumley T. Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Rev Clin Pharmacol. 2021;14:1133–52. PubMed