Open Psilocybin Project

Using open science practices to assess the effects of psilocybin on the brain, the body and self-perception

Background

Psilocybin is currently one of the most intensively studied psychoactive compounds, yet the evidence base rests on shaky methodological ground. Small samples, functional unblinding, placebo effects, a proliferation of poorly validated scales, heterogeneous analysis pipelines and a scarcity of open data and preregistrations jointly threaten the internal, external, construct and statistical conclusion validity of the field. These threats are synergistic: together they cast doubt on the conclusions currently drawn about how psychedelics work.

Aim

The OPS addresses these challenges by conducting a high-powered, within-subjects study of the pharmacological, neurocognitive and psychological mechanisms of psilocybin in healthy volunteers. Our central hypothesis, derived from the REBUS model and the predictive-processing framework, is that psilocybin (1) reduces top-down neural signalling and amplifies bottom-up prediction-error signalling, (2) thereby loosening perceptual priors about the body and the self, and (3) that this mechanism underlies psychedelic-induced changes in self-perception and subjective experience.

The primary endpoint is resting-state functional connectivity measured with fMRI: we test whether increasing doses of psilocybin increase between-network and reduce within-network connectivity. Secondary objectives span task-based fMRI (somatotopic mapping, category selectivity), EEG (resting-state qEEG, roving mismatch negativity, self–other face processing), behavioural paradigms (implicit body perception, explicit sense of control, heart-rate discrimination, mind-wandering), pharmacokinetics/pharmacodynamics, and validated self-report measures of subjective effects and well-being. A further set of objectives targets the field itself: quantifying functional unblinding, isolating the contribution of expectancy and placebo effects, and demonstrating what fully open psychedelic research can look like.

Design

Participants receive placebo and two doses of oral psilocybin across separate occasions in a randomised, double-blind, placebo-controlled within-subjects crossover design. Each occasion combines fMRI, EEG, behavioural testing, blood sampling for PK modelling, and questionnaire and experience-sampling measures of acute and short-term sustained effects. All hypotheses, outcomes and analysis plans are preregistered before data collection begins.

Open science

The OPS is built around open science from the outset. Hypotheses, primary outcomes and analysis plans are frozen and preregistered on the Open Science Framework; protocols, data and analysis code are shared openly; and the robustness of findings is stress-tested through multiverse analyses and a many-analyst approach in which independent teams analyse the same dataset.

Collaboration with CHDR

The OPS is conducted jointly by the PRSM lab at Leiden University’s Faculty of Social and Behavioural Sciences and the Centre for Human Drug Research (CHDR) in Leiden. CHDR oversees the clinical conduct of the trial, bringing its established infrastructure for early-phase clinical pharmacology, its experience with psychedelic compounds, and its expertise in PK/PD modelling and neurocognitive profiling. MRI data are acquired at the Leiden University Medical Center (LUMC), in collaboration with the Leiden Institute for Brain and Cognition (LIBC). T
Funding

The OPS is funded by a grant from the Norrsken Mind Foundation (Psychedelic Science Initiative Fund) to Michiel van Elk (project RG25-0002, SEK 4,770,018 / approx. €427,000), awarded to Leiden University as administering organisation.

Team

Michiel van Elk (PI, PRSM lab, Leiden University) · Gabriël Jacobs (PI Psychiatry, CHDR) · Josephine Marschall and Xaver Funk (postdoctoral researchers, PRSM lab) Lukas Heinrich (PhD candidate, INTEGRATE ITN) with the project and clinical operations teams at CHDR.