Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

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; Ekaterina Malievskaia

doi:10.1056/NEJMoa2206443

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

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 ForbesHannah 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, Ekaterina Malievskaia

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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 treatmentresistant 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). 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. CONCLUSIONS 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.

Original language	English
Pages (from-to)	1637-1648
Number of pages	12
Journal	New England Journal of Medicine
Volume	387
Issue number	18
DOIs	https://doi.org/10.1056/NEJMoa2206443
Publication status	Published - 3 Nov 2022

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Single-Dose Psilocybin for a Treatment-Resistant Episode of Major DepressionFinal published version, 642 KB

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Goodwin, G. M., Aaronson, S. T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J. C., Bird, C., Blom, R. E., Brennan, C., Brusch, D., Burke, L., Campbell-Coker, K., Carhart-Harris, R., Cattell, J., Daniel, A., DeBattista, C., Dunlop, B. W., Eisen, K., Feifel, D., ... Malievskaia, E. (2022). Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine, 387(18), 1637-1648. https://doi.org/10.1056/NEJMoa2206443

@article{21d08a874c0746deb380c6221f851abd,

title = "Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression",

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 treatmentresistant 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-{\AA}sberg 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). 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. CONCLUSIONS 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.",

author = "Goodwin, {Guy M.} and Aaronson, {Scott T.} and Oscar Alvarez and Arden, {Peter C.} and Annie Baker and Bennett, {James C.} and Catherine Bird and Blom, {Renske E.} and Christine Brennan and Donna Brusch and Lisa Burke and Kete Campbell-Coker and Robin Carhart-Harris and Joseph Cattell and Aster Daniel and Charles DeBattista and Dunlop, {Boadie W.} and Katherine Eisen and David Feifel and MacKenzie Forbes and Haumann, {Hannah M.} and Hellerstein, {David J.} and Hoppe, {Astrid I.} and Husain, {Muhammad I.} and Jelen, {Luke A.} and Jeanine Kamphuis and Julie Kawasaki and Kelly, {John R.} and Key, {Richard E.} and Ronit Kishon and {Knatz Peck}, Stephanie and Gemma Knight and Koolen, {Martijn H.B.} and Melanie Lean and Licht, {Rasmus W.} and Maples-Keller, {Jessica L.} and Jan Mars and Lindsey Marwood and McElhiney, {Martin C.} and Miller, {Tammy L.} and Arvin Mirow and Sunil Mistry and Tanja Mletzko-Crowe and Modlin, {Liam N.} and Nielsen, {Ren{\'e} E.} and Nielson, {Elizabeth M.} and Offerhaus, {Sjoerd R.} and Veronica O{\textquoteright}Keane and Tom{\'a}{\v s} P{\'a}len{\'i}{\v c}ek and David Printz and Rademaker, {Marleen C.} and {van Reemst}, Aumer and Frederick Reinholdt and Dimitris Repantis and James Rucker and Samuel Rudow and Simon Ruffell and Rush, {A. John} and Schoevers, {Robert A.} and Mathieu Seynaeve and Samantha Shao and Soares, {Jair C.} and Metten Somers and Stansfield, {Susan C.} and Diane Sterling and Aaron Strockis and Joyce Tsai and Lucy Visser and Mourad Wahba and Samuel Williams and Young, {Allan H.} and Paula Ywema and Sidney Zisook and Ekaterina Malievskaia",

note = "Funding Information: Supported by COMPASS Pathfinder . Publisher Copyright: Copyright {\textcopyright} 2022 Massachusetts Medical Society.",

year = "2022",

month = nov,

day = "3",

doi = "10.1056/NEJMoa2206443",

language = "English",

volume = "387",

pages = "1637--1648",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "18",

}

Goodwin, GM, Aaronson, ST, Alvarez, O, Arden, PC, Baker, A, Bennett, JC , Bird, C, Blom, RE, Brennan, C, Brusch, D, Burke, L, Campbell-Coker, K, Carhart-Harris, R, Cattell, J, Daniel, A, DeBattista, C, Dunlop, BW, Eisen, K, Feifel, D, Forbes, M, Haumann, HM, Hellerstein, DJ, Hoppe, AI, Husain, MI , Jelen, LA, Kamphuis, J, Kawasaki, J, Kelly, JR, Key, RE, Kishon, R, Knatz Peck, S, Knight, G, Koolen, MHB, Lean, M, Licht, RW, Maples-Keller, JL, Mars, J, Marwood, L, McElhiney, MC, Miller, TL, Mirow, A, Mistry, S, Mletzko-Crowe, T, Modlin, LN, Nielsen, RE, Nielson, EM, Offerhaus, SR, O’Keane, V, Páleníček, T, Printz, D, Rademaker, MC, van Reemst, A, Reinholdt, F, Repantis, D, Rucker, J, Rudow, S, Ruffell, S, Rush, AJ, Schoevers, RA, Seynaeve, M, Shao, S, Soares, JC, Somers, M, Stansfield, SC, Sterling, D, Strockis, A, Tsai, J, Visser, L, Wahba, M, Williams, S , Young, AH, Ywema, P, Zisook, S & Malievskaia, E 2022, 'Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression', New England Journal of Medicine, vol. 387, no. 18, pp. 1637-1648. https://doi.org/10.1056/NEJMoa2206443

TY - JOUR

T1 - Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

AU - Goodwin, Guy M.

AU - Aaronson, Scott T.

AU - Alvarez, Oscar

AU - Arden, Peter C.

AU - Baker, Annie

AU - Bennett, James C.

AU - Bird, Catherine

AU - Blom, Renske E.

AU - Brennan, Christine

AU - Brusch, Donna

AU - Burke, Lisa

AU - Campbell-Coker, Kete

AU - Carhart-Harris, Robin

AU - Cattell, Joseph

AU - Daniel, Aster

AU - DeBattista, Charles

AU - Dunlop, Boadie W.

AU - Eisen, Katherine

AU - Feifel, David

AU - Forbes, MacKenzie

AU - Haumann, Hannah M.

AU - Hellerstein, David J.

AU - Hoppe, Astrid I.

AU - Husain, Muhammad I.

AU - Jelen, Luke A.

AU - Kamphuis, Jeanine

AU - Kawasaki, Julie

AU - Kelly, John R.

AU - Key, Richard E.

AU - Kishon, Ronit

AU - Knatz Peck, Stephanie

AU - Knight, Gemma

AU - Koolen, Martijn H.B.

AU - Lean, Melanie

AU - Licht, Rasmus W.

AU - Maples-Keller, Jessica L.

AU - Mars, Jan

AU - Marwood, Lindsey

AU - McElhiney, Martin C.

AU - Miller, Tammy L.

AU - Mirow, Arvin

AU - Mistry, Sunil

AU - Mletzko-Crowe, Tanja

AU - Modlin, Liam N.

AU - Nielsen, René E.

AU - Nielson, Elizabeth M.

AU - Offerhaus, Sjoerd R.

AU - O’Keane, Veronica

AU - Páleníček, Tomáš

AU - Printz, David

AU - Rademaker, Marleen C.

AU - van Reemst, Aumer

AU - Reinholdt, Frederick

AU - Repantis, Dimitris

AU - Rucker, James

AU - Rudow, Samuel

AU - Ruffell, Simon

AU - Rush, A. John

AU - Schoevers, Robert A.

AU - Seynaeve, Mathieu

AU - Shao, Samantha

AU - Soares, Jair C.

AU - Somers, Metten

AU - Stansfield, Susan C.

AU - Sterling, Diane

AU - Strockis, Aaron

AU - Tsai, Joyce

AU - Visser, Lucy

AU - Wahba, Mourad

AU - Williams, Samuel

AU - Young, Allan H.

AU - Ywema, Paula

AU - Zisook, Sidney

AU - Malievskaia, Ekaterina

PY - 2022/11/3

Y1 - 2022/11/3

N2 - BACKGROUND Psilocybin is being studied for use in treatment-resistant depression. METHODS In this phase 2 double-blind trial, we randomly assigned adults with treatmentresistant 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). 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. CONCLUSIONS 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.

AB - BACKGROUND Psilocybin is being studied for use in treatment-resistant depression. METHODS In this phase 2 double-blind trial, we randomly assigned adults with treatmentresistant 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). 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. CONCLUSIONS 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.

UR - http://www.scopus.com/inward/record.url?scp=85141170646&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa2206443

DO - 10.1056/NEJMoa2206443

M3 - Article

SN - 0028-4793

VL - 387

SP - 1637

EP - 1648

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 18

ER -

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

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