JAMES COYNE'S COLUMN

The MDMA-Assisted Therapy for PTSD Study. What You’ll Get Wrong

Seldom have so many experts had such strong opinions about an open-access drug trial they did not read carefully, thanks to a well-orchestrated publicity campaign by the study’s funders?

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Recently I complained that coverage in the New York Times of a high-profile study of MDMA (ecstasy)-assisted therapy for severe post-traumatic stress disorder (PTSD) lacked the objectivity that we would have expected from this prestigious newspaper.

The tip-off started with the impressive staged photos that the NYT commissioned for the article. Each of the photos was formatted to fill the entire screen of a monitor when a reader scrolled through the article on a desktop computer.

The photos in the NY Times article displayed authors of the study and actual patients in contrived settings. The captions of the photos of the patients provided glowing testimonials about how the treatment they received in the study miraculously changed their lives.

Other sources quoted as experts in the article conveyed an enthusiasm for the breakthrough nature of the study. The tone was more consistent with the article being an infomercial for the treatment being evaluated in the study, rather than a detached, open-minded, but skeptical probing of the actual quality of the science of the study.

The NY Times article represented more of an active collaboration between the newspaper and the publicity campaign for the trial than what happened with many other media sources. Lazy journalists simply drew on a press kit provided by the study’s funders. However, there was a remarkable consistency in the adulating, highly redundant coverage of the story.

“Readers, including even experts, are falling for a hard sell job by venture capitalists who launder their funding of the study through a nonprofit foundation and seek not legalization of psychedelics and related illegal drugs but lucrative control over their use for therapeutic and recreational use.”

The actual Nature Medicine paper is available here.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

The fog rolls in when the title gets elaborated in the second sentence of its abstract:

We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma.

“Double-blind” is not true of the patients or therapist/coaches for very long.

The study was unblinded within minutes of the administration of the active MDMA or inert pill. The difference in subjective reaction was obvious, especially since the patients’ expectations that they should experience a strong effect have been shaped in the therapist/guides and confirmed or disconfirmed in no more than 20 minutes.

The patients’ reports of subjective reactions continue to be shaped in the coaching during the three administrations of the drug and in “integration” sessions afterward, including one after the last administration of the drug or inert pill, just before the outcome assessment.

“Placebo-controlled” is only true in the trivial sense that the patients receive either MDMA or an inert substance in a capsule carefully constructed to be indistinguishable without the patient ingesting it.

The stronger, more appropriate technical sense of “placebo” is the total of the expectancies and support patients receive in the course of the study and the broader context of the setting and what they are told in advertisements encouraging enrollment in the study.

Patients seeking enrollment in the study have strong expectations of a positive experience with trained experimenters and therapists/counselors unlikely to be available elsewhere legally and with the assurance of the purity of the drug.

That goal may even distort their reports of symptoms in the baseline assessment to ensure that they can get into the study. That is a problem that is familiar to trialists who recruit from the community.

That the trial is “multisite” might seem to encourage confidence in the broad generalizability or validity of the findings, but…

The clinical trial conducted in multiple sites or “nesting” must be taken into account in any analyses of the primary outcome. Analyses should consider whether there was variation between sites in the difference in outcomes obtained by MDMA versus placebo. It is a challenge to ensure that procedures are identical across settings. Sometimes the differences between settings in how the study was implemented can dwarf or explain away any overall differences between active treatment and placebo.

A dive into the details of the article and supplementary materials reveals that there were 15 clinical sites in diverse jurisdictions and cultures. In a study with only 42 patients assigned to MDMA and 39 assigned to placebo, it is impossible to separate the effects of the site from the effects of patients getting MDMA or placebo across those sites.

Unconvinced that this is important? In a devastating commentary on the FDA approval of ketamine for treatment-resistant depression, Erick Turner noted that positive results were entirely due to the inclusion of one outlier site in Poland, where there was 100% relapse in the placebo group.”

The trial has a registration with the US government, but there is another registration of the study elsewhere…

The trial registration number provided in this article (NCT03537014) checks out at ClinTrials.Gov. It identifies the primary outcomes reported in this paper. However, it is unnerving to discover in a press release from the Imperial College, London, that the study is registered elsewhere with neuroscience outcomes. Consent and recruitment to a study involving MRI assessments of the brain present very different nonspecific (placebo) conditions for the subsample of patients participating in the trial who get the brain scans. This is a crucial concern for an area of study with so much hype about MDMA opening or changing the brain. The entire sample is too small to take such factors into account. The study is undoubtedly too underpowered to be talking about effects on the brain, anyway.

This is just a probing of one sentence in the abstract, but it should motivate interested readers to probe further, especially the figures and tables and the strength of evidence for claims made in the discussion.

But I am posing a broader issue. I have growing, nagging concerns that readers, including even experts, are falling for a hard sell job by venture capitalists who launder their funding of the study through a nonprofit foundation and seek not legalization of psychedelics and related illegal drugs but lucrative control over their use for therapeutic and recreational use.

Why are so few “experts” speaking out about a reporting of this study that is so wrong in so many ways? Why the silence?

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James Coynehttp://www.coyneoftherealm.com
James C. Coyne is Professor Emeritus of Psychology in Psychiatry at the University of Pennsylvania where he was Director of Behavioral Oncology at the Abramson Family Cancer Center and Senior Fellow, Leonard Davis Institute of Health Economics. He also was Professor of Health Psychology at the University of Groningen, the Netherlands, and has been on the faculties of University of Michigan School of Medicine and University of California, Berkeley. He received a BA in Psychology from Carnegie Mellon in 1969 and a Ph.D. in Clinical Psychology from Indiana University in 1975. Professor Coyne was the 2015 Carnegie Centenary Visiting Professor at the University of Stirling. He is the author of over 400 articles and chapters and has been designated one of the most influential psychologists of the second half of the twentieth century. His diverse interests have included clinical health psychology, mental health services research, and evaluation of depression screening and suicide prevention programs. As a blogger at Science-Based Medicine and Mind the Brain, Dr. Coyne is known for skeptical appraisals of advice gurus misleading consumers with hype and hokum. His activism with colleagues concerning undisclosed conflicts of interest has yielded dozens of corrections to published papers, a few retractions, and the Bill Silverman Prize from the Cochrane Collaboration.

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JAMES COYNE, PHD

James C. Coyne is Professor Emeritus of Psychology in Psychiatry at University of Pennsylvania where he was Director of Behavioral Oncology at the Abramson Family Cancer Center and Senior Fellow, Leonard Davis Institute of Health Economics. He also was Professor of Health Psychology at University of Groningen, the Netherlands and has been on the faculties of University of Michigan School of Medicine and University of California, Berkeley. He received a BA in Psychology from Carnegie Mellon in 1969 and a PhD in Clinical Psychology from Indiana University in 1975.

Professor Coyne was the 2015 Carnegie Centenary Visiting Professor at the University of Stirling. He is the author of over 400 articles and chapters and has been designated one of the most influential psychologists of the second half of the twentieth century. His diverse interests have included clinical health psychology, mental health services research, and evaluation of depression screening and suicide prevention programs. As a blogger at Science-Based Medicine and Mind the Brain,

Dr. Coyne is known for skeptical appraisals of advice gurus misleading consumers with hype and hokum. His activism with colleagues concerning undisclosed conflicts of interest has yielded dozens of corrections to published papers, a few retractions, and the Bill Sliverman Prize from the Cochrane Collaboration.

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