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

Oral psilocin was associated with a lower burden of adverse events than oral psilocybin in a small randomized crossover study

In a small randomized crossover study of healthy, psychedelic-experienced adults, oral botanical psilocin (17.5 mg) produced acute psychological and physiological effects broadly comparable to 25 mg oral botanical psilocybin, while producing a lower overall burden of adverse events. Sublingual psilocin was well tolerated but produced substantially weaker effects at the doses tested, limiting conclusions about the potential advantages of sublingual delivery.

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.

Tai ML, Szigeti B, Downey AE, et al. A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin. Journal of Psychopharmacology. 2026;0(0). Read Paper

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