Many people do not inspect what is reported before forming an opinion or accepting someone else’s opinion. The actual results are certainly worth a look.

But I think we need to consider whether the authors even were asking the right clinical question.

By narrowly construing the trial as a test of the efficacy of MDMA for PTSD, the authors may have missed some limitations. The trial is NOT primarily being a drug trial, but more properly, a trial of a drug always being delivered in conjunction with a poorly specified and unproven psychotherapy.

I have some relevant background and expertise for forming an opinion about this.

I was involved in various stages of writing and reviewing grant proposals, applications for use of human subjects, and justifications for the burden that studies place on medical patients. I was a co-principal investigator on a center grant with the responsibility of developing and implementing psychosocial interventions combined with drugs. I served on the committee monitoring the progress of a major clinical multisite trial of treatment of depression to prevent heart attacks for safety and data quality. I was an external scientific advisor conducting process evaluations that might reveal what happened in trials for anomalous results.

I have never encountered anything at all like the psychotherapy manual for the Nature Medicine trial of MDMA for PTSD.

If you like, you can wade through the actual manual here, but it is very vague and demands of your time to get to crucial details. Or you can see how promoters describe the treatment in promotional material on their websites, including graphic videos.

I am a clinical health psychologist concerned with delivering the best treatment within the limits of scarce funding. That makes me a mental health services researcher. I am deeply concerned with the lack of assurance that the same psychotherapy was delivered across settings in the trial reported in Nature Medicine.

I could imagine making a bit of a fuss if I were on a committee to evaluate ahead of time whether a major clinical trial of MDMA, a drug that was illegal and otherwise unpatentable could depend on the validity of this treatment and whether it was faithfully delivered.

Basically, investors are asking for a monopoly because they will ensure the safety and efficacy of MDMA by embedding it in a package with their psychotherapy. They claim to be so convinced by a lack of evidence that MDMA is safe or effective outside of such a package. So much so that they will not bother to gather new evidence against the null hypothesis of MDMA being unsafe and ineffective for PTSD.

In the loose, informal atmosphere that occasionally develops in closed meetings, I could imagine my younger self reading juicy sections from the manual, and insisting on playing promotional videos to the committee from the 15 sites that were available to prospective participants during recruitment.

With some degree of mock seriousness, I might have asked whether different music might have elicited a different response from patients, whether the flowers and fake artifacts were necessary.

What if a patient did not welcome what was intended to be the soothing touch of a same or different gender person while under the influence of a disorienting drug and while possibly being stimulated to sexual arousal?

I could expect blowback and protests if I raised the last point. I would come prepared with documentation that sex with a patient had occurred in at least one MAPS trial and that the unlicensed counselor had pleaded, of course, that the sex was consensual.

This claim is outrageous without substantiation. I invite you to find it here. Psychedelic therapy has a sexual abuse problem

I doubt anyone involved in reviewing the data from the trial for the US Food and Drug Administration has ever seen such psychotherapy being proposed to accompany all marketing of a drug. I would love to hear the discussion the review will generate.

Claims that findings are groundbreaking, breakthrough, or otherwise extraordinary deserve more scrutiny and maybe even skeptics thinking longer and harder about what was going on in a study.

Many on social media assume that claims that have made it into a world-class medical journal no longer need to be vetted. They believe that they can take what is said about the psychotherapy in an article in an impressive journal with their critical tools to appraise the study being left in their toolbox.

I am not one of those people. I am hoping to convince some readers that they do not want to be that kind of person either. That is generally my goal in teaching and writing about clinical trials, but I think that the Nature Medicine article is a particularly good teachable moment. The authors and their backers are screaming so loudly and incessantly that there has never before been such a study.

I am getting some pushback to my skepticism about the trial, only some of which will be disclosed here. There has been an effort to stop the publication of my critiques and remove what I have published so far. If what I have written were patently stupid, I think that would be discovered soon or later and what I have published could be left published to embarrass me.

The threshold should be high for making an article disappear, rather than simply flagging with a statement of concern or retracting it.

I first probed a fawning New York Times article about the trial with improbable claims, obviously written with the collaboration of the Nature Medicine authors. I complained that the journalist should have protected readers by getting her own experts and by providing an independent critical appraisal.

Is the New York Times a Shill for Promoters of Psychedelics?
Evidence that the newspaper is not sufficiently detached from promoters to provide an open-minded but skeptical…medium.com

Next, I limited myself to a single sentence in the abstract of the Nature Medicine article. I wondered aloud why so few “experts” were speaking out about a reporting of this study that was so wrong in so many ways.

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…medium.com

In the last installment, I focused on only the list of authors, the contributions that justified their getting authorship, and the authors’ affiliations. I concluded that there was good reason to treat the study not as strictly as a pharmacological trial but as a trial of psychotherapy in combination with either a drug or an inert pill-placebo. I proposed:

This reframing involves a very different set of criteria that could expose a different set of inadequacies in the trial of MDMA as a treatment for PTSD — such as the lack of standardization of the therapy across settings and therapists.

Surprises in the Authorship of a Paper About MDMA to Treat PTSD
Some of the 39 authors practice alternative medicine and unvalidated psychotherapies, with little research experience

I am pleased that my intuitions have generally been confirmed that there is something wrong going on with the way the study is being sold. Yet, I wince at some of the things I have written and mistakes that may have been made. Even if I have been wrong in some respects, I could be on to something. We could reach a consensus that the study is flawed, at least enough to temper the authors’ claim made in the abstract and echoed all over the world:

“We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.”

The authors and their sponsors are pushing for expedited review and approval by the US Food and Drug Administration. This was hastily done with intravenous infusion of ketamine, which — as I covered here — did not go so well.

One reader,Julian Willet, MD is unconvinced enough by what I have been writing to post a comment:

Nature Medicine is a well-respected journal and generally decently trusted (though naturally, some papers can get through the cracks). Perhaps that occurred, but I cannot say. I skimmed the paper and the results are significant/impactful, which would make it an attractive paper to publish even if there could be potential controversy.

I asked the opinion of an expert statistician who has consulted on trials of psychedelics and he replied:

*I have read the results section a few times since published (and compared) to protocol. I would say that generally it looks sound and I would guess they have a professional statistician in the team or use a consultant. That’s from what I can deduce from the paper.

His comment left me self-doubting and defensive. I went back to the Acknowledgment section of the article. I counted the number of therapists listed. I replied to him, “What if there are 40 therapists?”

Suffice to say, that reply changed his mind and got him doubting too.

Only as I sat down to write this article, did I realize the implications of what I had written to him.

The Nature Medicine article portrayed the clinical trial as evaluating whether MDMA was superior to an inert pill-placebo under tightly controlled conditions. It would be reassuring to know if the results did not vary across the clinics and providers, but we probably should not expect any surprises.

It is simple enough to standardize the providing of a pill and not expect much variation across sites and providers. Not so with psychotherapy that is so incompletely specified. I expect lots of variation in how the psychotherapy is implemented with which patient, with which therapist, in which setting.

The trial is initially blinded so that neither the clinician nor the patient knows whether the patient is assigned to get the MDMA or an inert substance in an identical capsule. The trial quickly becomes unblinded in the first half-hour of the first eight-hour session. There are three such sessions. I would be especially concerned with the improvisation that would occur once the patient and therapist knew whether the patient was getting the MDMA.

I do not have to prove my skepticism is correct. The burden is on the authors of the Nature Medicine article to prove me wrong. They are facing an evaluation by the FDA with a lot at stake.

Stay tuned and we will probe the Results section, aided by the lens I have developed in this article.

The post Before Looking at the Results of the Paper on MDMA to Treat PTSD… appeared first on Medika Life.

This author has built a reputation on his disdain for evidence-based psychotherapies. His books and workshops promote questionable psychotherapies with dubious mechanisms of mind-body interactions, backed up by dramatic anecdotes, not evidence.

Who could that be?

This revelation only encourages me to examine the trial more closely as an evaluation of psychotherapy combined with medication — not as primarily as a drug trial, as most everyone else has been doing.

This reframing involves a very different set of criteria that could expose a different set of inadequacies in the trial of MDMA as a treatment for PTSD — such as the lack of standardization of the therapy across settings and therapists.

Nature Medicine is among the most prestigious medical journals in the world. It seldom publishes clinical trials and never before has published a trial of a medication combined with psychotherapy.

I have already been discussing my concerns about this clinical trial in two Medium articles.

Is the New York Times a Shill for Promoters of Psychedelics? Evidence that the newspaper is not sufficiently detached from promoters to provide an open-minded but skeptical.

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

The Nature Medicine article is available open access, meaning you can view it for free.

Mitchell, Jennifer M., et al. “MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.” Nature Medicine (2021): 1–9

Clicking on the link takes you to the article on the website, where you can also download a free PDF. However, if you just read the article on the website, the authors are listed like this:

Click on the […] at the website and it expands to the full list of 39 authors.

That number of authors in itself is mindboggling, especially when you consider that 39 is the number of patients assigned to pill placebo who completed the trial. That ratio of authors to patients in a clinical trial is extraordinary.

Check out the list of authors’ affiliations and their specific contributor statements available in the article that justified awarding authorship. You will find some real surprises.

I will touch on some of these details before ending with a bombshell revelation that changed my thinking about this study, raised my already high level of skepticism about it, and pointed me in some new directions in probing the study.

The 39 authors list 25 different affiliations, of which seven are academic medical settings with research capacity. Authors’ academic degrees are not listed in the article, but a Google search reveals few MDs and fewer psychiatrists. Only a few of the MDs list university medical affiliations.

Four authors list the same academic setting as their affiliation. One is the Ph.D. neuroscientist who is the first author. The other authors in that setting are the Ph.D. regulatory affairs coordinator and an internist and an assistant professor MD Ph.D. who is in residence at a nearby Veterans Administration Hospital.

Beyond the other six academic medical settings that are each listed by one author, there are some interesting affiliations.

The largest number of authors (12) are with the MAPS Public Benefit Corporation, San Jose, California. The for-profit corporation will manage sales for prescription MDMA when it is approved by the Food and Drug and Administration. For now, the corporation provides training for therapists as well as:

A team of wonderful night attendants who stay with study participants at the clinic during the required overnight stay following MDMA sessions. The night attendants continue the care and support of participants by delivering or preparing dinner and breakfast, setting up their sleeping arrangements, and remaining available throughout the night should participants need anything at all. During this time, the therapy team and study physician remain on call should there be any problems or concerns.

Most affiliations are for only one or two authors and seem to be private practice settings awaiting approval of psychedelics by the FDA. Their names are suggestive of particular kinds of mystical spa experiences: Zen Therapeutic Solutions, Fluence (defined as a mysterious, magical, or hypnotic power), Nautilus Sanctuary, Wholeness Center, and the San Francisco Insight and Integration Center.

Some of these settings currently — or will in the future — offer spa experiences for people without requiring a diagnosis of a psychiatric disorder. At Aguazul-Bluewater, Inc, one of the authors of the Nature Medicine article offers Rolfing Structural Integration sessions.

In the relaxed biographic sketches provided at their affiliations, a number of authors express the intention to use prescription MDMA not as a formal mental health treatment, but for wellness treatments administered in spa settings specializing in alternative medicine.

Some of the authors of the Nature Medicine articleespouse the use of psychedelics as a transformative experience conceived as an integration of mysticism and neuroscience that is decidedly outside the range of testable and disprovable scientific explanation.

Many of the authors are clinical psychologists who are not quantitative research scientists, but who instead dabble in impressionistic qualitative or mixed-method research related to psychedelics.

I did not see or endorsements of conventional, evidence-based therapies in any of the authors’ personal statements. I found abundant references to the view of personal change as a mystical or spiritual experience somehow involving neuroscience and the brain, but not really spelled out in conventional scientific terms.

It is safe to say that these clinical psychologists do not confine the psychotherapy they offer for PTSD to the manualized treatments with the strongest scientific support, exposure, and cognitive reprocessing therapy. That would be just too stifling and downright boring, especially given the exciting transformative experience that psychotherapy is supposed to provide.

What does it mean to be listed as an author on an article in a highly selective, prestigious medical journal like Nature Medicine?

It is generally understood that authorship on scientific papers requires an intellectual contribution to the conduct of research. In addition, an author must take responsibility for the final version of the paper that will appear in the journal.

I am “only” a clinical psychologist, and I do not have an M.D. Critics might say I am hypocritically pretending to be more scientific than these authors in calling for a more rigorous, i.e., medical approach to this treatment.

The Nature Medicine article presents the case that MDMA is an amazingly effective treatment for PTSD, yet also that it is potentially so dangerous and subject to abuse that it must remain a prescription-only drug delivered under the supervision of a physician.

MDMA has been around for a while and cannot be patented. The Nature Medicine clinical trial tests a packaged delivery system in which the drug augments or facilitates psychotherapy that is said to dramatically reduce the suffering and burden of PTSD.

No one is claiming that taking MDMA by itself is effective in treating PTSD. There is ample evidence to the contrary. So, what is the nature of the psychotherapy that is presumed to allow MDMA to achieve its therapeutic effect?

The psychotherapy offered in this trial is not presumed to be effective in treating PTSD by itself, without MDMA. There is no prior evidence that the particular psychotherapy administered as part of this trial as effective for any clinical problem in any situation.

Although it has been given little attention in the enormous press coverage that has been given to the trial reported in the Nature Medicine paper, a lot depends on the credibility of the psychotherapy provided in the trial. At stake are hundreds of millions of dollars already invested in what is expected to be the multibillion-dollar business of marketing prescription psychedelics plus psychotherapy in a package ensuring their safety and effectiveness as mental health treatment and pleasurable spa experiences.

If MDMA is not patentable, why not patent the package of the drug plus less expensive psychotherapy with greater evidence of efficacy as a mental health treatment, like a modified version of exposure therapy?

Enter the mastermind behind the psychotherapy being offered in this trial

The intellectual responsibility for this parrticular psychotherapy as it is described in the Nature Medicine article largely depends on the nineteenth author, psychiatrist Bessel van der Kolk.

According to the author-contribution statement, Bessel can de Kolk (KvdK) has unrivaled contributions to the article.

BvdK was among the four authors having full access to all of the data in the study and taking responsibility for the integrity of the data and the accuracy of the data analysis. Other contributions attributed to him include the basic design of the study. He was among the authors who collected the data and carried out sponsor oversight of data collection. He was part of the group that carried out statistical analysis and interpretation of data.

He was among the four authors who drafted the original paper. He was a member of the larger group critically revising the paper for important intellectual content.

The two contributions not listed for BvdK are obtaining funding and carrying out supervision and training.

Outside of this trial, BvdK has an enormous following among credentialed and non-credentialed therapists and counselors, as well as a substantial proportion of laypersons who believe their lives have been impacted in a profound way by adversity and trauma. He has sold millions of copies of popular books worldwide, his workshops draw large crowds, and his videos get huge traffic on YouTube.

Yet, many research-oriented mental health professionals consider BvdK a popularizer, not a research-oriented clinician-scientist. Many of us experience enormous frustration with his talks and writing. He promises too much from unproven psychotherapies. Lasting change does not necessarily come with such theatrics as he suggests.

BvdK denigrates scientific evidence and well-established evidence-based therapies. At the same time, he presents unproven somatic therapies and discredited therapies such as tapping and emotional freedom techniques in vivid anecdotes in which miraculous results never fail to be achieved in dramatic, sudden moments of therapist intervention.

BvdK’s best-selling books, like The Body Has its Reasons, present discredited theories like Polyvagal Theory and Mirror Neuron Theory in simplistic terms. Rebuttal and refutation by experts would require long technical explanations that would bore lay audiences to tears and put them to sleep.

Not everyone would agree with me, and certainly not even all evidence-based clinician-researchers. Yet, I think I could muster a considerable consensus that BvdK’s depictions are not to be trusted of the research status of psychotherapies and the scientific status of their presumed basic mechanisms of change.

Such skepticism is just a useful starting point. We might have to revise our opinion with a closer look at the Nature Medicine article, its supplementary materials, and the enormous publicity its authors have so skillfully orchestrated.

Regardless, there are big questions:

How can a drug which is ineffective when simply taken by itself be combined with a psychotherapy without evidence of effectiveness as a standalone treatment to yield results in the treatment of PTSD that have never before been seen?

And

What if the FDA approval of the marketing of the previously illegal street drug Ecstasy as a treatment for PTSD is restricted excuslively to the drug being delivered with a psychotherapy that was developed under the supervision of Bessel van der Kolk?

That would be very strange, but there is a lot of startup funding betting on that possibility. The Franchising of specialty clinics has already begun.

We will have to see how FDA grapples with whether to tie the marketing of a drug to a specific psychotherapy — or is open to continued experimentation with other packages, breaking the monoply of MAPS.

The post Surprises in the Authorship of a Paper About MDMA to Treat PTSD appeared first on Medika Life.