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Response to Bertha Madras editorial in the New England Journal of Medicine

illustration of woman confused on a compass

Response by:

Prof David Nutt – FMedSci Imperial College London Prof Jo Neill – PhD University of Manchester On behalf of Drug Science

We read with concern the editorial by Bertha Madras that accompanied the new COMPASS Pathways trial of psilocybin in treatment-resistant depression (TRD) due to several inaccuracies and negative bias. It displayed a clear misunderstanding of which results were significant [the 25mg dose was on many measures]. A more important deficiency was the failure of the editorial to grasp the vital difference between drug efficacy measures in TRD compared with those in simple major depression, an essential distinction. These errors are particularly unfortunate and could lead the reader to misunderstand the importance of psilocybin with psychological support for TRD where patients have not responded to at least 2 courses of treatment as explained carefully in the original paper. These errors are perhaps explicable in the context of Dr Madras’ expertise as a preclinical neurobiologist with an extensive career in drug addiction rather than clinical depression research. The impact of a single 25mg treatment with psilocybin that persists for up to 12 weeks is greater than any other single-dose treatment previously tried in TRD. The fact that lower doses given with the same psychological support showed very significantly less efficacy argues against a placebo effect. This is a very important trial result for a hard-to-treat clinical condition where new treatment options are urgently needed.

This all begs the question as to why she was asked to write the editorial in the first place. Her background of a career opposing “illegal” drugs probably explains what appears to be a significant degree of bias against the study findings. This is indicated by her use of the term hallucinogen, with its connotations of adverse effects, rather than the currently accepted term psychedelic (mind-manifesting). Further her associating the risks of psilocybin with those of opioids, when the former is just used once and the latter in chronic and often increasing regimes is inaccurate and particularly concerning. Several independent systematic assessments of drug harms [e.g. Nutt et al 2010. Bonomo et al 2019] rate psilocybin as amongst the least harmful drugs overall even when used recreationally, a finding likely even more secure when just one dose is used in the clinical setting. Certain other comments such as those relating to commercial infeasibility, special FDA requirements and underground clinics, all reflect false assumptions of the harms and diversion liability of psilocybin and the costs incurred by its inappropriately high scheduling (Howard et al. 2021).

It is odd that in the many ongoing trials she has located online she fails to celebrate the ones that show similar powerful efficacy in her line of work: addiction disorders, especially alcohol and tobacco dependence (Bogenschutz et al. 2015; Johnson et al. 2017). Also, some of her criticisms will likely deter engagement by populations such as poor and racially marginalised groups she correctly complains are not being studied enough. This is a key issue that is being addressed by experts in the field (Fogg et al. 2021) and loudly acknowledged in the paper. She suggests that psychedelics’ trial reporting seeks to “minimize adverse consequences and dismiss evidence-based safety concerns”. This is clearly not the case, adverse events are discussed in depth in the original paper, and elsewhere (Schlag et al.2022; Neill et al. 2022).

In contrast to the negative bias and misreading of the trial results and their significance in this editorial, most practising clinicians will celebrate this first multi-centre dose-response RCT of psilocybin (or indeed any psychedelic) ever conducted in this very hard-to-treat population, that they meet on a daily basis. Patients will also agree that psilocybin offers hope of recovery, where there is currently none. We trust that the FDA, who gave this COMPASSPathways trial breakthrough status, will view the current trial as a success, which will encourage more such trials with other psychedelics.

Bogenschutz MP, Podrebarac SK, Duane JH, Amegadzie SS, Malone TC, Owens LT, Ross S, Mennenga SE (2018) Clinical interpretations of patient experience in a trial of psilocybin assisted psychotherapy for alcohol use disorder. Front Pharmacol 9:1–10.

Bonomo Y, Norman A, Biondo S, Bruno R, Daglish M, Dawe S, Egerton-Warburton D, Karro J, Kim C, Lenton S, Lubman DI, Pastor A, Rundle J, Ryan J, Gordon P, Sharry P, Nutt D, Castle,D.  (2019) The Australian drug harms ranking studyJOURNAL OF PSYCHOPHARMACOLOGY, Vol: 33, Pages: 759-768, ISSN: 0269-8811

Fogg C, Michaels TI, de la Salle S, Jahn SW, Williams MT (2021) Ethnoracial Health Disparities and the Ethnopsychopharmacology of Psychedelic-Assisted Psychotherapies, Experimental and Clinical Psychopharmacology, 29(5), 539–554.

Howard A, Neill JC, Schlag AK, Lennox C (2021) Schedule 1 barriers to research in the UK: an in-depth qualitative analysis. Drug Science Policy and Law, 7: 1-13.

Johnson MW, Garcia-Romeu A, Griffiths RR (2017) Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse 43:55–60.

Neill JC, Shahid M, Tarazi FI, Gittins R, Schlag AK (2022) Risks and side effects associated with the use of psychedelics In: Psychedelics as Psychiatric Medicines Editors: Nutt D and Castle D. Oxford Psychiatry Library. In press.

Nutt DJ  King LA Phillips LD (2010) Drug harms in the UK: a multicriteria decision analysis  Lancet 376: 1558-65

Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ (2022) Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. J Psychopharmacology 36(3) 258–272

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