• Guy M Goodwin, Scott T Aaronson, Oscar Alvarez, Peter C Arden, Annie Baker, James C Bennett, Catherine Bird, Renske E Blom, Christine Brennan, Donna Brusch, Lisa Burke, Kete Campbell-Coker, Robin Carhart-Harris, Joseph Cattell, Aster Daniel, Charles DeBattista, Boadie W Dunlop, Katherine Eisen, David Feifel, MacKenzie Forbes, Hannah M Haumann, David J Hellerstein, Astrid I Hoppe, Muhammad I Husain, Luke A Jelen, Jeanine Kamphuis, Julie Kawasaki, John R Kelly, Richard E Key, Ronit Kishon, Stephanie Knatz Peck, Gemma Knight, Martijn H B Koolen, Melanie Lean, Rasmus W Licht, Jessica L Maples-Keller, Jan Mars, Lindsey Marwood, Martin C McElhiney, Tammy L Miller, Arvin Mirow, Sunil Mistry, Tanja Mletzko-Crowe, Liam N Modlin, René E Nielsen, Elizabeth M Nielson, Sjoerd R Offerhaus, Veronica O'Keane, Tomáš Páleníček, David Printz, Marleen C Rademaker, Aumer van Reemst, Frederick Reinholdt, Dimitris Repantis, James Rucker, Samuel Rudow, Simon Ruffell, A John Rush, Robert A Schoevers, Mathieu Seynaeve, Samantha Shao, Jair C Soares, Metten Somers, Susan C Stansfield, Diane Sterling, Aaron Strockis, Joyce Tsai, Lucy Visser, Mourad Wahba, Samuel Williams, Allan H Young, Paula Ywema, Sidney Zisook, and Ekaterina Malievskaia.
• From COMPASS Pathfinder (G.M.G., J.C.B., L.M., S.M., S.C.S., J.T., S.W., E.M.), the Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (C. Bird, L.A.J., G.K., L.N.M., F.R., J.R., S. Ruffell, M. Seynaeve, A.H.Y.), the National Institute for Health and Care Research Clinical Research Facility, King's College Hospital NHS Foundation Trust (K.C.-C., J.C., A.D.), and South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital (L.A.J., L.N.M., J.R., A.H.Y.), London, and the Cumbria, Northumberland, Tyne and Wear Foundation Trust and Newcastle University, Newcastle (M.W.) - all in the United Kingdom; the Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Baltimore (S.T.A., M.F., T.L.M., S. Rudow); Sant Joan de Déu Hospital and the Sant Joan de Déu Research Foundation, Barcelona (O.A.); SUNY Downstate College of Medicine (P.C.A.), the New York State Psychiatric Institute (D.J.H., R.E.K., R.K., M.C.M., E.M.N.), and the Department of Psychiatry, Columbia University (D.J.H., R.K., M.C.M., E.M.N.) - all in New York; the Department of Psychiatry, Trinity Centre for Health Sciences, Tallaght University Hospital, Dublin (A.B., C. Brennan, L.B., J.R.K., V.O.); the Department of Psychiatry, University Medical Center (UMC) Utrecht Brain Center, University Medical Center Utrecht, Utrecht (R.E.B., H.M.H., A.I.H., M.H.B.K., S.R.O., M.C.R., A.R., M. Somers, L.V., P.Y.), the Research Department, GGz Centraal Innova, Amersfoort (R.E.B.), and the Department of Psychiatry, UMC Groningen, Groningen (J. Kamphuis, J.M., R.A.S.) - all in the Netherlands; the Department of Psychiatry, University of California San Diego (D.B., J. Kawasaki, S.K.P., D.P., S.S., A.S., S.Z.), and Kadima Neuropsychiatry Institute (D.F., S.K.P., A.M., D.S.), La Jolla, the Weill Institute for Neurosciences, University of California San Francisco, San Francisco (R.C.-H.), and the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford (C.D., K.E., M.L.) - all in California; the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (B.W.D., J.L.M.-K., T.M.-C.); the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, and the Department of Psychiatry, University of Toronto, Toronto (M.I.H.); the Department of Psychiatry, Aalborg University Hospital, and the Department of Clinical Medicine, Aalborg University, Aalborg, Denmark (R.W.L., R.E.N.); the National Institute of Mental Health, Klecany, Czech Republic (T.P.); Charité-Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Berlin (D.R.); Duke University School of Medicine, Durham, NC (A.J.R.); and the University of Texas (UT) Harris County Psychiatric Center and the UT Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, UT Houston Medical School, Houston (J.C.S.).
• N. Engl. J. Med. 2022 Nov 3; 387 (18): 163716481637-1648.

BackgroundPsilocybin is being studied for use in treatment-resistant depression.MethodsIn 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 at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point 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 end points 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).ResultsA 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.ConclusionsIn 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. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).Copyright © 2022 Massachusetts Medical Society.

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