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expert reaction to Phase IIb Clinical Trial of Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

Results from the Phase IIb clinical trial of single-dose psilocybin for treatment-resistant depression have been published in The New England Journal of Medicine.

This Roundup accompanied an SMC Briefing.


Professor Anthony Cleare, Professor of Psychopharmacology, King’s College London, said:

“This is the largest study to date on the use of psilocybin for treatment resistant depression.

“Given that patients had not responded to between two and four other treatments, it is a very encouraging finding that nearly 4 in 10 showed a clear response to a single dose of psilocybin.

“It is also notable how rapid in onset the treatment effects were, with the maximum effect seen the day after receiving the treatment. This contrasts with standard antidepressants, which take several weeks to reach maximum effect.

“However, there are several issues that need further study before this can become part of regular clinical practice. The effects did start to wear off by three months, and we need to know how best to prevent the depression returning. This might involve adding in other treatments, such as psychological therapies, or repeating the psilocybin treatment periodically.

“There is also concern that because of the relatively small number of patients studied so far we don’t yet know enough about potential side effects, particularly whether some people may experience a worsening of some symptoms. While the safety profile seems encouraging overall, great care is obviously needed when using psychoactive substances such as psilocybin.

“Larger studies are on the way that we hope will help answer these issues.”


Professor Andrew McIntosh, Head of Division of Psychiatry, University of Edinburgh, and member of the MQ Mental Health Research Science Council:

“This new trial greatly improves our understanding of whether psilocybin could potentially help depressed people when conventional treatments have failed. The study appears well-conducted and suggests that 3 weeks after people were given a single 25mg dose of psilocybin, they had lower levels of depressive symptoms than people treated with lower doses (1mg or 10mg). Participants were not asked if they could guess whether they were in the arm of the study that received a higher dose of the psychedelic. This is important, because psilocybin is associated with euphoria and changes in perception that may reveal that they are in an higher-dose or ‘more active’ treatment arm. People who believe they are in a higher-dose treatment group are potentially more likely to report treatment benefits, regardless of whether the intervention works, undermining the double-blind design. Nevertheless, this study is an advance on previously published work in smaller numbers of people that reported efficacy based on depression scales that were not intended to be the main measure of treatment benefit. It is the strongest evidence so far to suggest that further, larger and longer randomised trials of psychedelics are justified and that psilocybin may (one day) provide a potential alternative to antidepressants that have been prescribed for decades.”


Prof David Nutt, The Edmond J Safra Chair and Head of the Centre for Neuropsychopharmacology, Imperial College London, said:

“This study is important for several reasons. First it replicates our earlier study in treatment-resistant depression with 25mg of psilocybin [Carhart-Harris – et al lancet psychiatry 2016], thus solidifying confidence in the general principle. Second it shows a dose-response relationship with doses of 10 and 1 mg [sub-psychedelic doses] showing less efficacy than the 25 mg dose which further supports the theory that a psychedelic trip itself plays a significant role in the therapeutic outcome. Thirdly it shows the robustness of the psilocybin effect. Even though the trial was conducted in many centres in multiple countries the effects were clinically significant, suggesting that the therapy is likely to be effective in a wider role out across the world.”


Dr Ravi Das, Associate Professor, University College London, said:

Background: Goodwin and colleagues examined whether a single dose of 25mg psilocybin (the active ingredient in magic mushrooms) could reduce depressive symptoms vs. a 1mg ‘control dose’.  The study had a large sample size for the psychedelics literature, but not what would be considered a large sample for a clinical trial in the medical literature. It was more robustly designed than many prior studies of psilocybin interventions for depression, although the period over which it followed participants was still far too short; a common problem in the psychedelic medicine field.

“Please note: There are important aspects of the statistical analysis that I am unable to evaluate, because the key parameter estimates and model fit from the primary mixed model analysis are not reported in the paper I was sent.  The following this therefore based on the less-than-ideal least squares estimates reported in the main paper.

Findings: The findings were positive, but not what I could call ‘spectacular’. The study found that the highest dose (25mg) of psilocybin produced a large reduction in depressive symptoms versus the control group of very low-dose psilocybin (1mg) at 3 weeks. However, a lower dose (10mg), did not produce a significantly greater reduction.  However, there were an uneven number of severely depressed patients in each group; with significantly fewer severely depressed people in the apparent ‘effective’ (25mg) dose group. This does not appear to be acknowledged in the paper. Severe depression is harder to treat and this may explain why the high-dose psilocybin appeared more effective.  There is some evidence for greater incidence of adverse events, including a troubling three instances of suicidal behaviour in the 25mg group. These effects will be important to monitor in future studies. 

“While 3-week changes in depression might be important, the effect is already starting to reduce at just 12 weeks; with the 12 week response-rate at only 20% in the high-dose group, versus 10% in the control group. This is not a spectacular response rate for a psychiatric treatment, or in comparison to ketamine, for example and we would only expect this to worsen over a longer follow-up period.  Furthermore, there is evidence for significant levels of further treatment-seeking at 12 weeks (around a third in the 25mg group). If people are seeking further treatment, clearly their depression is not in remission. Depression can be a long-lasting problem and much longer follow-up periods than 12 weeks should be used.

Risk of bias: The study was designed and run by Compass pathways. This is a for-profit company who own the patent on the psilocybin preparation used in the study. They were able to review the statistical analysis prior to publication. The trial was registered on, which is good practice for adhering to the study protocol. However, the analysis plan is not pre-registered, as far as I can see.  The primary outcome measure on the registration is given as MADRS depression rating score up to 12 weeks. This given certain degrees of freedom and it is unclear why 3 weeks is specified in the paper as the primary end point. The study aimed to be ‘double blind’, however this is very hard to achieve with a psychoactive drug like psilocybin and it was not checked whether participants had actually guessed their treatment. Given these factors, the risk of bias in the study is fairly high.

“Please note: As the supplementary materials were not available, there was a lot of information I was unable to review. This comment is based on the information available in the main paper itself.”



Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression’ by Guy Goodwin et al. will be published in The New England Journal of Medicine at 21:00 UK time Wednesday 2 November 2022.

DOI: 10.1056/NEJMoa2206443



Declared interests

Prof David Nutt is a scientific adviser to and grant recipient from COMPASSPathways. He also advises several other companies working in the psychedelic space though not with psilocybin.

Dr Ravi Das: “I declare no conflicts of interest in reviewing this paper. I am an academic researcher in the field.”

Prof Anthony Cleare: In the last three years, AJC has received honoraria for educational activities and consulting from Janssen and Medscape, and research grant support from the Medical Research Council (UK), Wellcome Trust (UK), the National Institute for Health Research (UK) and Protexin Probiotics International Ltd. He is involved in several research studies involving psychedelic treatments but receives no funding or payment for these. Prof Cleare treats patients with depression within the NHS.

For all other experts, no reply to our request for DOIs was received.

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