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Peer-reviewedCC BY-NC 4.0Journal of Psychopharmacology (Oxford, England)

A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin

  • Marlene L. Tai1,2
  • Balázs Szigeti1
  • Amanda E. Downey1,3
  • Jacob S. Aday1,4
  • Lisa Fredenburg1
  • Kimberly Sakai1
  • Cesar Molina1
  • Gisele Fernandes-Osterhold1
  • Ellen R. Bradley1,5
  • Maddie Pantoni1
  • Ryan Moss6
  • Benjamin Lightburn6
3 more authors
  • Franziska Plessow1
  • Aoife O’Donovan1,2
  • Josh D. Woolley1,2
6 affiliations
  1. 1Department of Psychiatry and Behavioral Sciences, Translational Psychedelic Research (TrPR) Program, Weill Institute for Neurosciences, University of California, San Francisco, USA
  2. 2San Francisco Veterans Affairs Medical Center, CA, USA
  3. 3Department of Pediatrics, University of California, San Francisco, USA
  4. 4Department of Anesthesiology, University of Michigan, Ann Arbor, USA
  5. 5Parkinson’s Disease Research, Education, and Clinical Center, San Francisco Veterans Affairs Medical Center, CA, USA
  6. 6Filament Health Corp., Burnaby, BC, Canada
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Abstract

Background:: Psilocybin, a serotonergic psychedelic found in hallucinogenic mushrooms, is metabolized to psilocin, the compound responsible for its psychoactive effects. Psilocybin has demonstrated therapeutic potential for neuropsychiatric conditions. While recent trials have primarily used orally administered synthetic psilocybin, alternative formulations and delivery methods may offer therapeutic advantages, yet the effects of these approaches remain poorly characterized.

Aims:: To compare the pharmacodynamic profiles and tolerability of oral psilocybin, oral psilocin, and sublingual psilocin derived from whole-mushroom extracts in healthy adults.

Methods:: In this randomized, within-subject, crossover trial, 20 healthy adults (10 men, 10 women; mean age 40.1 ± 5.9 years) completed up to four drug administration sessions involving botanical oral psilocybin (25 mg), oral psilocin (17.5 mg), or sublingual psilocin (2.18, 4.36, or 8 mg). All sessions included therapeutic support and pre- and post-dose psychotherapy. Acute effects were assessed using vital signs and subjective ratings of drug intensity and psychedelic experience.

Results:: Oral psilocin produced a similar temporal and subjective profile to oral psilocybin, with a lower burden of adverse effects. Sublingual psilocin was well tolerated, though the apparently lower achieved drug exposure limited comparability to oral administration.

Conclusions:: Oral psilocin may offer tolerability advantages over oral psilocybin. Sublingual psilocin was well tolerated at the dosages tested. Further studies are needed to evaluate botanical formulations and optimize delivery approaches.

Clinical trial registration: https://clinicaltrials.gov/study/NCT05317689

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Cite

BibTeXRIS
BibTeX
@article{tai2026randomized,
  title = {{A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin}},
  author = {Marlene L. Tai and Balázs Szigeti and Amanda E. Downey and Jacob S. Aday and Lisa Fredenburg and Kimberly Sakai and Cesar Molina and Gisele Fernandes-Osterhold and Ellen R. Bradley and Maddie Pantoni and Ryan Moss and Benjamin Lightburn and Franziska Plessow and Aoife O’Donovan and Josh D. Woolley},
  journal = {Journal of Psychopharmacology (Oxford, England)},
  year = {2026},
  month = aug,
  doi = {10.1177/02698811261478603},
  url = {https://doi.org/10.1177/02698811261478603},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin
AU  - Marlene L. Tai
AU  - Balázs Szigeti
AU  - Amanda E. Downey
AU  - Jacob S. Aday
AU  - Lisa Fredenburg
AU  - Kimberly Sakai
AU  - Cesar Molina
AU  - Gisele Fernandes-Osterhold
AU  - Ellen R. Bradley
AU  - Maddie Pantoni
AU  - Ryan Moss
AU  - Benjamin Lightburn
AU  - Franziska Plessow
AU  - Aoife O’Donovan
AU  - Josh D. Woolley
PY  - 2026
DA  - 2026/08/29
JO  - Journal of Psychopharmacology (Oxford, England)
DO  - 10.1177/02698811261478603
UR  - https://doi.org/10.1177/02698811261478603
AB  - Background:: Psilocybin, a serotonergic psychedelic found in hallucinogenic mushrooms, is metabolized to psilocin, the compound responsible for its psychoactive effects. Psilocybin has demonstrated therapeutic potential for neuropsychiatric conditions. While recent trials have primarily used orally administered synthetic psilocybin, alternative formulations and delivery methods may offer therapeutic advantages, yet the effects of these approaches remain poorly characterized.  Aims:: To compare the pharmacodynamic profiles and tolerability of oral psilocybin, oral psilocin, and sublingual psilocin derived from whole-mushroom extracts in healthy adults.  Methods:: In this randomized, within-subject, crossover trial, 20 healthy adults (10 men, 10 women; mean age 40.1 ± 5.9 years) completed up to four drug administration sessions involving botanical oral psilocybin (25 mg), oral psilocin (17.5 mg), or sublingual psilocin (2.18, 4.36, or 8 mg). All sessions included therapeutic support and pre- and post-dose psychotherapy. Acute effects were assessed using vital signs and subjective ratings of drug intensity and psychedelic experience.  Results:: Oral psilocin produced a similar temporal and subjective profile to oral psilocybin, with a lower burden of adverse effects. Sublingual psilocin was well tolerated, though the apparently lower achieved drug exposure limited comparability to oral administration.  Conclusions:: Oral psilocin may offer tolerability advantages over oral psilocybin. Sublingual psilocin was well tolerated at the dosages tested. Further studies are needed to evaluate botanical formulations and optimize delivery approaches.  Clinical trial registration: https://clinicaltrials.gov/study/NCT05317689
SN  - 0269-8811
SN  - 1461-7285
ER  -