A randomized, double-blind, placebo-controlled single-ascending-dose study to identify a non-hallucinogenic dose of psilocybin in healthy adults.

Low doses of psilocybin (0.5 to 4.0 mg) produce perceptible pharmacological effects without causing hallucinations, cognitive impairment, or increased anxiety. In a Phase 1 randomized, double-blind, placebo-controlled trial, 56 healthy adults received a single oral dose of psilocybin or placebo. No serious adverse events occurred; side effects were comparable to placebo, mainly somnolence. Psilocin appeared rapidly in the blood with dose-proportional exposure and a short half-life. Subjective drug effects were dose-related and distinguishable from placebo at or below 2.5 mg, but hallucination and altered-states scores remained low and not different from placebo.

Study at a glance

Abstract

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 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. 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. 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 at or below 2.5 mg. Peak subjective ratings increased with dose, while any signs of hallucinations or altered-states scores remained low and not different than 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. These findings indicate that the perceptible pharmacology of psilocybin can be dissociated from significant perceptual alterations and cognitive impairment at low doses. They further support controlled investigations in outpatient Phase 2 studies evaluating the safety and feasibility of repeated, self-administered low-dose psilocybin. ClinicalTrials.gov # NCT07710027