Summary
Background Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent
studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety,
obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we
aimed to investigate the feasibility, safety, and effi cacy of psilocybin in patients with unipolar treatment-resistant
depression.
Methods In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar,
treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a
supportive setting. There was no control group. Psychological support was provided before, during, and after each
session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin’s eff ects. Patients
were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up.
Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the
16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary effi cacy outcome. This trial is
registered with ISRCTN, number ISRCTN14426797.
Findings Psilocybin’s acute psychedelic eff ects typically became detectable 30–60 min after dosing, peaked 2–3 h
after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0–1 scale)
was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well
tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we
noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients),
mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive
symptoms were markedly reduced 1 week (mean QIDS diff erence –11·8, 95% CI –9·15 to –14·35, p=0·002, Hedges’
g=3·1) and 3 months (–9·2, 95% CI –5·69 to –12·71, p=0·003, Hedges’ g=2) after high-dose treatment. Marked and
sustained improvements in anxiety and anhedonia were also noted.
Interpretation This study provides preliminary support for the safety and effi cacy of psilocybin for treatment-resistant
depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of
this approach.
Funding Medical Research Council. Copyright © Carhart-Harris et al. Open Access article distributed under the terms of CC BY.
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