Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression
Aaronson, S. T., Alvarez, O., Arden, K., Baker, A., Bennett, J. C., Bird, C., Blom, J. D., Brennan, C., Brusch, D., Burke, L., Campbell-Coker, K., Carhart-Harris, R. L., Cattell, J. P., Daniel, A., Debattista, C., Dunlop, B. W., Eisen, K., Feifel, D., Forbes, M. K., Goodwin, G. M., Haumann, H. M., Hellerstein, D. J., Hoppe, A. I., Husain, M. I., Jelen, L. A., Kamphuis, J., Kawasaki, J., Kelly, J. R., Key, R. E., Kishon, R., Knight, G., Koolen, M. H. B., Lean, M., Licht, R. W., Malievskaia, E., Maples-Keller, J. L., Mars, J., Marwood, L., McElhiney, M. C., Miller, T. L., Mirow, A., Mistry, S., Mletzko-Crowe, T., Modlin, N. L., Nielsen, R. E., Nielson, E. M., O’Keane, V., Offerhaus, S. R., Páleníček, T., Peck, S. K., Printz, D., Rademaker, M. C., Reinholdt, F., Repantis, D., Rucker, J., Rudow, S., Ruffell, S. G. D., Rush, A. J., Schoevers, R. A., Seynaeve, M., Shao, S., Soares, J. C. K., Somers, M., Stansfield, S., Sterling, D., Strockis, A., Tsai, J., van Reemst, A., Visser, L., Wahba, M., Williams, S., Young, A. H., Ywemba, P., Zisook, S.
This double-blind active-placebo controlled trial (n=233) tested the effect of a single dose of psilocybin (25/10/1mg) with supportive therapy for treatment-resistant depression. The primary endpoint at three weeks finds a significant reduction in depressive symptoms (MADRS, 12-point drop from baseline of 32) that was significantly greater in the 25mg group vs the 1mg (placebo) group (6.6 points larger drop). The response (>50% drop in MADRS score) in the 25mg group dropped from 37% at 3 weeks to 20% at 12 weeks.
Abstract
Background Psilocybin is being studied for use in treatment-resistant depression.Methods In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin [COMP360] at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary endpoint was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary endpoints included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).Results A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were −12.0 for 25 mg, −7.9 for 10 mg, and −5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P<0.001) and between the 10-mg group and 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P=0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.Conclusion In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder.