Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

Robin L Carhart-Harris,Mark Bolstridge,James Rucker,Camilla M J Day,David Erritzoe,Mendel Kaelen,Michael Bloomfield,James A Rickard,Ben Forbes,Amanda Feilding,David Taylor,Steve Pilling,Valerie H Curran,David J Nutt

doi:10.1016/s2215-0366(16)30065-7

Abstract

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 efficacy of psilocybin in patients with unipolar treatment-resistant depression. 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 effects. 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 efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. Psilocybin's acute psychedelic effects 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 difference -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. This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. Medical Research Council.

Highlights

Psilocybin is a naturally occurring plant alkaloid found in the Psilocybe genus of mushrooms
Depressive symptoms were markedly reduced 1 week and 3 months (–9·2, 95% CI –5·69 to –12·71, p=0·003, Hedges’ g=2) after high-dose treatment
Interpretation This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach

Summary

Introduction

Psilocybin is a naturally occurring plant alkaloid found in the Psilocybe genus of mushrooms. Psilocybe mushrooms have been used for millennia for healing purposes, but were only discovered by modern science in the late 1950s.1,2. Psilocybin is a prodrug of psilocin (4-hydroxy-dimethyltryptamine), a serotonin receptor agonist and classic psychedelic drug whose principal psychoactive effects are mediated by serotonin 2A (5-HT2A) receptor agonism.[3] Psilocybin has a novel pharmacology in the context of currently available antidepressant medications, because selective serotoninreuptake inhibitors are not direct 5-HT2A receptor agonists. Enhanced cognitive flexibility,[4] associative learning,[5] cortical neural plasticity,[6] and antidepressant responses have been reported with 5-HT2A receptor agonism in animals,[7] and increased and sustained improvements in wellbeing[8] and optimism[9] have been observed after psychedelic experiences in human beings. Data obtained from large-scale population studies have recently challenged the view that psychedelics negatively affect mental health,[11,12,13] with one study’s findings showing lower rates of psychological distress and suicidality among people who had used

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