Pharmacokinetics and safety of a modified‐release psilocybin formulation: A SAD Phase I trial in normal‐weight and overweight/obese participants
Anna Signor, Stefano Comai, Gianfranco Pasut, Franco Folli, Marco Gentilucci, Negar Gharavi, Sofia Raitsin, Thuy van Nguyen, Marco Pappagallo, Andrea Mattarei, Paolo L. Manfredi, Sara de Martin
British Journal of Clinical Pharmacology September 21, 2026 DOI: 10.1002/bcp.70839 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, placebo-controlled, single ascending dose Phase I study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Healthy adults: 8 normal-weight and 32 overweight/obese |
| Dose | 0.5, 1.0, 1.5 and 2.0 mg |
| Topics | Psilocybin |
| Key points | Low-dose modified-release psilocybin (REL-P11) produced predictable, dose-proportional psilocin exposure with low interindividual variability and no measurable psychoactive effects across body weight categories. No serious adverse events or adverse events of special interest occurred, and no clinically meaningful treatment-related changes were detected on psychometric and safety assessments. The authors state these findings are preliminary and warrant further clinical study in metabolic and liver-related disorders. |
Abstract
Aims: This study aimed to evaluate the safety, tolerability and pharmacokinetics of a novel oral modified-release psilocybin formulation (REL-P11) in normal-weight and overweight/obese healthy adults and to assess its suitability for controlled, subperceptual exposure, in light of emerging evidence supporting serotonergic modulation in metabolic disorders.
Methods: Simulation-based modelling compared predicted psilocin exposure with immediate-release formulations. Then, a randomized, double-blind, placebo-controlled, single ascending dose Phase I study was conducted in eight normal-weight and 32 overweight/obese adults. Single oral doses of 0.5, 1.0, 1.5 and 2.0 mg of REL-P11 were administered. Plasma psilocin concentrations were measured using liquid chromatography-mass spectrometry, and pharmacokinetic parameters were derived using non-compartmental analysis.
Results: Simulations indicated lower peak concentrations and prolonged absorption with the modified-release formulation compared with immediate-release psilocybin. No serious adverse events or adverse events of special interest (AESIs) occurred among REL-P11-treated participants, and no clinically meaningful treatment-related changes were detected in the prespecified psychometric and safety assessments. Psilocin exposure increased proportionally with dose, with low interindividual variability. At the 2-mg dose, pharmacokinetic parameters were broadly comparable between normal-weight and overweight/obese participants, and median time to peak concentration was approximately 2 h.
Conclusions: Low-dose modified-release psilocybin provides predictable systemic exposure without measurable psychoactive effects across body weight categories. While these properties, together with preclinical evidence, are of potential interest in the context of metabolic regulation, the present findings remain preliminary. Further clinical studies are warranted to determine whether the favourable pharmacokinetic profile observed with controlled subperceptual psilocybin dosing translates into clinically relevant pharmacological and therapeutic effects in metabolic and liver-related disorders.
Comparable studies
Other randomized controlled trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Hallucinogen-naïve adults reporting regular participation in religious or spiritual... | 2006 | Double-blind study | n = 36 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
Citations in the library
Cites 15
- Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Journal of Psychopharmacology October 6, 2015
- The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act Neuropharmacology June 5, 2018
- Pharmacokinetics and Pharmacodynamics of Oral Psilocybin Administration in Healthy Participants Clinical Pharmacology & Therapeutics December 12, 2022
- The emerging science of microdosing: A systematic review of research on low dose psychedelics (1955–2021) and recommendations for the field Neuroscience & Biobehavioral Reviews May 21, 2022
- The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation Journal of Psychopharmacology 2022
and 10 more in the library