Background:
Psilocybin has demonstrated apparent antidepressant effects in pilot studies with depressed patients, but RCT evidence for its effect in treatment-resistant depression has been lacking. Treatment resistance is common, carries significant morbidity and next step treatments are often unsatisfactory.

Methods:
We performed a double-blind, parallel-group trial to evaluate the safety and efficacy of psilocybin in adults with treatment-resistant major depressive disorder, randomized 1:1:1 to a single dose of psilocybin (25mg, 10mg, 1mg), with psychological support.

Results:
A total of 79 patients were assigned to psilocybin 25mg, 75mg, 10mg, and 79 to 1 mg. Mean week 3 change in the MADRS for psilocybin 25 mg and 10 mg dose groups versus 1 mg were – 12.0 and -7.9 versus -5.4 points (least-squares mean difference for the 25 mg and 10 mg doses versus the 1 mg dose was -6.6 points: 95% CI, -10.2 to 2.9, P<0.001; and -2.5 points, 95% CI, -6,2 to 1.2; not significant). Sustained response rates at week 12 were 34.8% for psilocybin 25mg, 9.1% for 10 mg, and 18.2% for 1 mg. The number of patients discontinuing due to an adverse event on psilocybin 25 mg, 10 mg and 1 mg was n=2,2, and 4, respectively. The relationship between positive psychedelic experience and clinical outcomes supports the dose-related effect seen in the primary analysis.

Conclusions:
The efficacy and acceptability demonstrated in this Phase IIb trial support the further development of psilocybin for treatment-resistant depression. The proposed phase 3 clinical programme will be described.