Psilocybin with psychological support for treatment-resistant depression

Background: Psilocybin is a serotonin receptor agonist that occurs naturally in some species of mushrooms. Recent studies have evaluated the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and tobacco and alcohol dependence, with promising preliminary results. Here, our goal was to investigate the feasibility, safety, and efficacy of psilocybin in patients with treatment-resistant unipolar depression.

Methods: In this open-label feasibility study, 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 viability was the patient-reported intensity of the psilocybin effects. Patients were monitored for adverse reactions during dosing sessions and subsequent clinical and remote follow-up. Depressive symptoms were assessed using standard assessments from 1 week to 3 months after treatment, with the 16-item Rapid Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This test is registered with the ISRCTN, number ISRCTN14426797.

Discoveries: The acute psychedelic effects of psilocybin generally become detectable 30-60 minutes after dosing, peak 2-3 hours after dosing, and diminish to negligible levels at least 6 hours after dosing. The self-assessed mean intensity (on a scale of 0-1) 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 patients and no serious or unexpected adverse events occurred. The adverse reactions we observed were transient anxiety during the onset of the drug (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Compared to baseline, depressive symptoms were markedly reduced at 1 week (mean difference in QIDS -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 treatment with high doses. Marked and sustained improvements in anxiety and anhedonia were also observed.

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.

Financing: Medical Research Council.