A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study to Identify a Subperceptual Dose of...

Background/Objectives: Psilocybin shows therapeutic promise for several psychiatric disorders, but the acute perceptual and cognitive alterations produced by conventional doses (10-25 mg) require in-clinic supervision, which limits scalability. Whether the therapeutically relevant pharmacology of psilocybin can be safely separated from its hallucinogenic activity remains unresolved. To address this gap, we conducted a Phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study to characterize the safety, pharmacokinetics, and pharmacodynamics of low doses of psilocybin. Methods: Fifty-six healthy adults received a single oral dose of psilocybin (0.5, 1.0, 1.5, 2.5, 3.5 or 4.0 mg) or matching placebo across seven sequential cohorts, with each dose escalation reviewed by a Drug Safety Review Committee. All participants completed the study with no serious adverse events or discontinuations. Results: Treatment-emergent adverse events were comparable to placebo and most prominently arose as somnolence. Plasma psilocin appeared rapidly with a median time to maximum concentration <1 h with dose-proportional exposure and a short terminal half-life. Subjective drug effects were dose-related and became distinguishable from placebo at doses ≥2.5 mg. Peak subjective ratings increased with dose, while altered-state scores remained low and cognitive changes did not differ from placebo. Psychophysiological engagement was confirmed by a clear dose-dependent pupillary dilation, while cognitive performance (attention, vigilance, working memory, impulse control) showed no dose-dependent decrement, and state anxiety did not increase at any dose. Conclusions: These findings suggest that low-dose psilocybin may produce perceptible pharmacological effects without significant perceptual alterations or cognitive impairment. The results also offer preliminary support for considering controlled outpatient Phase 2 studies assessing the safety and feasibility of repeated, self-administered low-dose psilocybin. Retrospective ClinicalTrials.gov Registration on 17 July 2026 #NCT07710027.