A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin.
Marlene Tai, Balázs Szigeti, Amanda E. Downey, Jacob S. Aday, Lisa Fredenburg, Kimberly Sakai, Cesar Molina, Gisele Fernandes-Osterhold, Ellen Bradley, Madeline M. Pantoni, Ryan Moss, B. Lightburn, Franziska Plessow, Aoife O’donovan, J. Woolley
Journal of Psychopharmacology August 29, 2026 DOI: 10.1177/02698811261478603 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, within-subject, crossover trial Peer reviewed |
|---|---|
| Sample size | 20 |
| Population | Healthy adults (10 men, 10 women; mean age 40.1 ± 5.9 years) |
| Interventions | Psilocybin Psilocin Sublingual psilocin |
| Dose | oral psilocybin 25 mg; oral psilocin 17.5 mg; sublingual psilocin 2.18, 4.36, or 8 mg |
| Topics | Psilocybin |
| Registration | NCT05317689 |
| Key findings | 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 lower achieved drug exposure limited comparability to oral administration. |
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.