March 18, 2026

expert reaction to two papers looking at 1) a phase 2b trial of psilocybin for treatment resistant depression and 2) the role of blinding in psychedelic therapy, as published in JAMA Psychiatry

experts comment on two papers in JAMA Psychiatry, 1) a phase 2b trial of psilocybin for treatment resistant depression and 2) the role of blinding in psychedelic therapy

Prof Hamish McAllister-Williams, Professor of Affective Disorders at Newcastle University and Deputy Medical Director for Research and Innovation at Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, said:

“The Mertens team al. Study is of interest, particularly in the light of the recent press releases regarding the results of the COMPASS phase III studies.  While the Meerten’s study is smaller (n=144) one differences from the COMPASS studies was that the patients included had not responded to more antidepressants effort taking part in the study.  This is important since this probably is more representative of the type of patients who might receive psilocybin in clinical practice in the UK, though including such participants might be expected to lead to a smaller effect of psilocybin.  Another difference is that the participants in the Mertens et al. Study appear to have received more psychotherapy alongside the psilocybin than in the COMPASS study – something that might lead to a larger effect of psilocybin.  While the primary outcome in the Merten’s study was negative, there were statistically significant, and clinically meaningful, greater benefits of psilocybin compared to the placebo (nicotinamide).  In addition, the benefits appeared to be larger after a second dose given 6 weeks after the first.  Overall, the magnitude of effect appears similar to that seen in the COMPASS studies.From a safety point of view, most side effects were transitory, but the treatment is not devoid of adverse effects.

“The Williams et al. Meta-analysis is of interest, since it suggests that some of the benefit seen with psychedelics in studies is due to participants being aware of whether they are taking the active drug or placebo due to the acute side effects they experience.  This has always been a potential concern for these studies.It does mean that there needs to be caution in interpretation of effect sizes in psychedelic studies, and there remains some concern that the effects seen may be driven by a placebo effect to a greater or lesser extent.However, it should be born in mind that in clinical practice treatments are not administered “blind” – patients know what treatment they are receiving. 

“Taken together, these two studies provide further support for psilocybin leading to clinically meaningful benefits in patients with treatment resistant depression.However, the treatment is not a panacea with many patients not achieving at least a 50% improvement in symptoms, and there remain concerns about how much of the effect seen may be driven by a placebo response.  Ultimately, the most important question remains – how long do the benefits seen last for?If the effects are sustained over time, then the question of placebo response becomes more of a mute point.”

Prof David Owens, Professor Emeritus of Clinical Psychiatry, University of Edinburgh, said:

“Both these studies are of considerable interest as, in different ways, they address perhaps THE outstanding issue in the assessment of psilocybin and other hallucinogens as therapeutic tools in treatment-resistant depression – blinding. 

“The RCT was, in my view, well-planned and executed with attempts made at ‘triple blinding’ (unusual in work in ‘depression’) but even this was, at the end of the day, not entirely successful. The meta-analysis came to the conclusion that in work published so far, which has largely been positive, non-blinding has been an inevitability. 

“The increasing exploration of these ‘psychedelics’ (a term I do not like – they do not ‘expand’ the mind but create a highly unphysiological state that no matter how much you like it or may benefit from it, is not a version of ‘normality’!) is important as their novel pharmacologies opens up new approaches to therapy and, if anything more importantly, new ways of conceptualising the disorders in which they are being tried, which replace theories that have long-since reached the end of their roads! However, the ‘relief’ at finding potentially new ways forward and the clinical enthusiasm that ensues, mustn’t be allowed to blind us to the challenges inherent to proving their therapeutic place – or otherwise. I think both these studies, especially the RCT, keep the project alive, but appropriately temper that unwarranted enthusiasm to which clinicians are so prone!”

Dr James Rucker, Consultant Psychiatrist & Senior Clinical Lecturer in Psychopharmacology, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London (KCL), said:

(on Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions) “This well conducted systematic review coalesces data from numerous trials to show that depression scores are no different for participants in trials of psychedelic assisted therapy when compared to participants in trials of antidepressants, if the participant is aware they are getting an antidepressant. In some ways this is reassuring, as it reconfirms that psychedelic therapy probably does have a true antidepressant effect. On the other hand, it also suggests that a significant part of this effect is mediated by a positive expectancy effect derived from a participant knowing that they are receiving treatment. Thus, at the same time as highlighting the limitations of the RCT paradigm for evaluating the effects of psychiatric drugs, this study also highlights what most clinicians and patients already know – that being an active part of a treatment decision is a therapy in itself.” 

(on Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression) “This well conducted clinical trial lends more tentative support to the notion that high doses of psilocybin have antidepressant effects, albeit relatively temporary in most cases. As with all treatments, there are also risks, but this study did not highlight significant new risk concerns. As more and more clinical trial evidence around psilocybin accumulates it highlights the limitations of the RCT paradigm in unpicking the undoubted expectancy effects that come with a drug like psilocybin from the more biological effects we are used to from more traditional antidepressants like SSRIs. However, since both are important in the treatment of depression, psilocybin therapy represents an increasingly intriguing option.”

Prof Anthony Cleare, Professor of Psychopharmacology,  Institute of Psychiatry, Psychology & Neuroscience, King’s College London, said:

(on Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions ) “This new study shows that psychedelics do work for many people with depression, but that the underlying antidepressant effects of psychedelics are similar in size to taking traditional antidepressant tablets. The reason that the effects of psychedelics appear larger in many trials is that with psychedelics, first, people can much more easily guess what treatment they are taking compared to a dummy treatment, and second, if they are given the dummy treatment there is a so-called “know-cebo” effect in which the disappointment at not getting the psychedelic treatment actually makes people worse.

“We have long known that people taking psychedelics can guess whether they are having real or dummy treatments, but this is the first time the impact this has on treatment response has been clearly shown. 

“On the other hand, in real world practice outside of research studies, patients always know what treatment they are being given, and so it is the overall benefit that matters most.

“We should not take this as suggesting psychedelics are not going to be a useful treatment option for some people – the emerging data suggest they will – but we should avoid the temptation to overstate their likely impact.”

Prof Robin Carhart-Harris, Ralph Metzner Distinguished Professor, University of California San Francisco, said:

“I think the assumption that “unblinding” or “unmasking” activates an expectancy bias for psychedelic therapy is flawed. I’ve seen in my psilocybin therapy trial data and others that pre-trial expectations are a very poor predictor of therapeutic response to psychedelic therapy. I believe the senior author has also been this in his own work. In one trial, our head-to-head with escitalopram, we found that those with higher pre-trial expectations for psilocybin actually did worse with that intervention, whereas those with low expectations did the best. In comparison, response to escitalopram, an SSRI, was clearly driven by an expectation effect. Regarding this specific paper, cross comparison work suffers from an absence of experimental control and standardization of variables. It’s proposed as comparing apples with apples when it is more like comparing apples with oranges. Direct head-to-head trials of psilocybin versus current treatments are the most valid way to compare treatments. I would therefore advise against drawing conclusions from the results of this meta-analysis. It asks for inference via extrapolations that aren’t justified.”

* ‘Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions – A systematic Review and Mata-Analysis’ by Zachary Williams,et al. was published in JAMA Psychiatry at 15:00 UK time March 18^th March.

DOI: 10.1001/jamapsychiatry.2025.4809

 ‘Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression The EPISODE Randomized Clinical Trial’ by Lea J. Mertens et al. was published in JAMA Psychiatry at 15:00 UK time on Wednesday 18 March

DOI: 10.1001/jamapsychiatry.2026.0132

Declared interests

Dr James Rucker: James Rucker leads commercially and publicly funded clinical trials using psychedelics, alongside other trials in mood disorders, within these institutions. 

Prof Anthony Cleare: In the last 3 years, AJC has received grant funding from the UK MRC, ADM Protexin Ltd, UK NIHR, European Union Horizon Europe/Innovate UK, Beckley Psytech Ltd, and Wellcome Trust, has received payment or honoraria for presentations and/or consulting from Janssen, Otsuka, COMPASS Pathways Plc., UCB, Viatris and Medscape, and is President of the International Society for Affective Disorders (unpaid).

Prof Robin Charhart-Harris: Robin is scientific advisor to Otsuka, Entropy Neurodynamics, Red Light Holland and Atai-Beckley.