Did boundary violations sink MDMA-assisted therapy, or was there something more? In part II of our series, we look at what else went wrong.

Publication Date: 06/17/2024

Duration: 25 minutes, 58 seconds

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report.

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

This month, an FDA panel voted to reject MDMA assisted psychotherapy for PTSD. That doesn’t mean the case is closed. The panel is an independent group of 11 scientists, clinicians, and patient advocates who advise the FDA. The FDA will make their final decision in August, and while there’s still a chance for approval we are not optimistic. 90% of the panel members voted against it, and the agency usually follows their advice.

Sexual boundary violations – which we covered last week – were one of the reasons for the fail. Last year, we warned about this potential in a special issue on psychedelics, but we didn’t anticipate it would happen under the registered eye of a clinical trial. But that was not the only problem that sank MDMA. Another was functional unblinding – which means that even though this was set up as a double blind trials, patients – and the therapists – could usually tell who got the placebo. 

CHRIS AIKEN: Imagine you sign up for an MDMA trial, and the investigator tells you you’re going to get either MDMA or a placebo. By bad luck of the draw you get the sugar pill. What are the chances that you’ll be fooled? That your mind will stir itself into an altered state and you’ll believe you got the real thing? These studies give us an answer. The chances are small, around 16% of people who got the placebo thought they got MDMA. The other 84% guessed right – and that may have changed how they experienced or even reported their symptoms. 

Now imagine you are a therapist in this trial. Would you be able to tell who got MDMA vs placebo? We opened our last episode with a recording of MDMA therapy – in both the video and audio you see facial expressions, muscle movements, a whole mental status that is unlike anything I’ve encountered in an outpatient setting. So it’s likely the blind was broken for therapists as well. Therapists might have been a little more exuberant about the therapeutic work if they knew their patient got the real thing. They might have rated their patients a little better. And they may even have asked the patients to do the same which – if we believe the anectodal reports – they did.

Some of the subjects who received MDMA said that their therapist coaxed them to report better recovery than they actually had, with the implication that they’d be helping others by getting this remarkable drug approved. 

We’re going to play an example from New York Magazine’s podcast Cover Story – it’s a great series that broke the story of the MAPS fiasco. All of the subjects they interviewed said they were told by their therapists how lucky they were to be in the MDMA trial, and how their participation would bring this remarkable treatment to the greater world. They interviewed Mel – who described how she feigned recovery so that she wouldn’t disappoint her therapists.

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KELLIE NEWSOME: Asking patients to change their answers on a rating scale is in itself a kind of boundary violation. And though it is much less harmful than the sexual violations we discussed in last weeks’ episode, it wasn’t the only boundary that was crossed in the trial. We spoke with Owen Muir shortly before the FDA decision was released. Dr. Muir is a psychiatrist who has coauthored a recent series of papers on psychedelics in the American Journal of Therapeutics. 

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CHRIS AIKEN: Functional unblinding is a problem with a lot of rapid acting drugs, including ketamine, and one way around it is to use a psychoactive drug as the “placebo” to disguise the fact that it’s a sugar pill. For example, in some ketamine trials they used a benzodiazepine as the placebo, and it’s notable that in those trials the legendary benefits of ketamine were nearly cut in half, judging by the effect size. The esketamine (Spravato) trials did not use a benzo as comparison – they used an inert placebo. 

In the case of MDMA, the FDA had advised the investigators to use an active comparator like Niacin or a low dose of MDMA, but the company declined. MDMA can be more activating in the lower dose range, and maybe the investigators were worried that this would sink their trials by introducing another variable. Psilocybin – the other psychedelic nearing the approval stage – took a different route. Most of those trials used a micro dose of the magic mushroom as the control.

KELLIE NEWSOME: The whole point of double blind placebo control is to remove bias from the clinical trial, but functional unblinding is not the only reason this trial was biased. Think about recruitment – who would be likely to sign up for an MDMA trial? Many of the subjects had tried MDMA before, and people who had bad experiences on the drug would not have volunteered to go through another bad trip. Or maybe the investigators discouraged such patients from signing up for the trials – something a report from the Institute for Clinical and Economic Review suggests they did.

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KELLIE NEWSOME: Let’s pause for a preview of the CME quiz for this episode. Earn CME credits through the link in the show notes.

1. What best describes the problem with suicidality in the MDMA assisted therapy trials?

A. Suicidal ideation was more common in the MDMA group

B. Suicidal ideation was not measured in the trial

C. Suicidal ideation emerged as a potential risk of MDMA withdrawal

D. There were reports that cases of suicidal ideation were suppressed in the trial

There were other problems with the trials. The panel worried that many involved in the research were psychedelic advocates, who approached this work with a religious fervor. 

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CHRIS AIKEN: The FDA panel gave specific examples of how religious fervor can taint a medical treatment.

1. Dr. Doblin promoted off label use of MDMA assisted for couples therapy and for the general population. In a world where getting fired from your job is often construed as a DSM trauma, it’s easy to see how MDMA assisted therapy could spread far and wide.

2. One panelist accused Dr. Doblin of violating the Nuremberg code by proposing that MAPs enroll Ukrainians housed at refugee centers into clinical trials examining MDMA assisted group psychotherapy.

KELLIE NEWSOME: Monitoring for suicide was another setback. This may sound strange, but you might misconstrue bad outcomes as good when you believe with religious zeal that your therapy is inherently good, even when your patient becomes suicidal. One of the leaders of the MDMA trials has been quoted as saying that increases in suicidal ideation are “actually part of the process” of psychedelic therapy. Some of the founders of psychedelic therapy, like Dr. Stanislav Grof, have unconventional views on suicide, like writing that “Suicidal ideation is explained by the deep memory of prenatal suffering being terminated by release from the womb.”

In the published reports, there were suspiciously zero cases of suicidal ideation in the MDMA therapy group, but some of the MAPS therapists who spoke out anonymously painted a different picture. There was a serious suicide attempt during a dosing session that went unreported. Another patient tried to run out into traffic while on MDMA, also unreported.

CHRIS AIKEN: This isn’t unique to MDMA. I recall being at psychoanalytic case conferences where they would present patients who got worse during therapy and conclude that this was an example of the therapeutic law, “You have to get worse before you get better.” I saw similar things as a resident, in the early days of SSRIs, when doctors believed they were inherently good and did not cause mania. When we gave teens with signs of bipolar an antidepressant, they would call back anxious and agitated. The plan was usually to lower the dose and go slower – not to stop the med. The idea was that an antidepressant had to help depression. We just needed to give it more time.

CHRIS AIKEN: Then there’s the therapy itself. MAPS is not applying to get MDMA approved, but MDMA assisted psychotherapy, and so if the FDA approves this treatment they are approving the therapy along with it. That’s not something the FDA is set up to do, and these clinical trials were not set up to evaluate the efficacy of this therapy. 

So what is MAPS to do? On the one hand, they could use a standard PTSD therapy like CBT or exposure based. No controversy there, and the FDA would not feel like they are unleashing an untested therapeutic technique along with a radical new drug. MAPS did not do that. They put together a therapy. Critics say it’s an eclectic mix of a dozen different therapies loosely strung together by New Age concepts. Owen Muir points out that the manual is nearly impossible to follow in any kind of standardized way, full of poorly defined concepts like “inner healing intelligence.”

On the other hand, the therapy has face validity. It is based on the approach that therapists found most effective when they first developed MDMA assisted therapy in the 1980’s. You could argue that this therapy has a stronger empirical track record to pair with MDMA than CBT – which I don’t think has ever been combined with MDMA for PTSD. 

In the end, the FDA panel saw this novel therapy as a negative, and the fact that this approach failed to prevent boundary violations is not a ringing endorsement for its loose eclecticism. Judge for yourself. The manual is free online, google A Manual for MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder at MAPS.org. Whether or not it’s an effective therapy, it’s a good read (a rarity for therapy manuals).

KELLIE NEWSOME: The other problem with testing MDMA with a new therapy is that we don’t know if the treatment is really a major advance over existing treatments. MDMA is up for approval as a “breakthrough therapy” which means it has to move the needle further than SSRIs and exposure based treatments. The studies hint at that – most subjects had failed past treatments and the recovery rates were very high – in the 70% range – but if they had compared MDMA assisted therapy with a therapy that is known to work – like exposure therapy – we’d be more certain that it is a breakthrough. Psilocyin did just that – they paired it with an evidence based therapy for depression, acceptance and commitment therapy. And psilocybin was tested against an SSRI for depression which – incidentally – it failed to beat.

CHRIS AIKEN: People who disagree with the panel’s decision might be thinking that the panel didn’t understand how serious PTSD is. But that doesn’t seem to be the case. Among the “no’s” were the deputy director for research at the National Center for PTSD. 

In fairness, you might argue that the problem of unblinding affects other drugs as well – many have argued that unblinding inflated the effect size of antipsychotics in mood disorders, especially those with known sedative side effects like olanzapine and quetiapine. And most companies that submit their data to the FDA don’t even bother to check if the blind was broken. Psychedelics are being singled out here, and maybe they should be – after all, people don’t seek out antipsychotics as recreational drugs, prison populations aside. But from a patient’s perspective, antipsychotics have nearly a dozen black box warnings, while a few doses of a psychedelic didn’t raise any medical red flags.

Here’s the bottom line. Science tries to take bias out of the trial, through randomization and blinding, but those methods failed here, and the researchers had strong biases – both commercial and ideological – to favor the medication. Everyone was influenced by the hype around this drug. The question that remains is: Was all this bias based on legitimate benefits of MDMA? Maybe patients expect to get a lot of benefit out of MDMA because it’s a uniquely effective drug. If it is, let’s get it approved and start the healing, but first let’s go through the more mundane motions of proving that the excitement is real even when the blinds are in place.

There is also a risk of abuse and diversion. Although we didn’t see that in the trials, they enrolled a select population, and they didn’t look as hard for drug misuse as the FDA would have liked. There were no ratings of liking or euphoria on MDMA.

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MDMA can also have dangerous side effects like psychosis and mania. In the 1980’s, MDMA pioneers spoke of how the drug sometimes brought out a dark, shadowy side in people who took it. They tried to construe this in terms of Jungian mystic dualism, but what if it was just psychosis they were seeing? 

In New York Magazine’s Cover Story podcast, subjects tell of psychotic like experiences after taking MDMA that they either withheld from the investigators so as not to spoil the chance of approval, or once they did tell the investigators were told it was part of the healing process. 

Just as dangerous is the risk of boundary violations, problems that will end this therapy if they are not kept in check. And they are difficult to keep in check because therapists are likely to take the drug themselves. Imagine seeing powerful transformations in patients, working day after day with a drug that takes away not just PTSD but the self-conscious, inhibited anxieties that we all struggle with. The temptation for clinicians to try MDMA would be a strong one, and once people take it their own sense of boundaries and even morality can start to shift. We saw this play out in Timothy Leary’s failed experiments, and it goes back before then. When Leary began studying psilocybin he early 1960’s, researchers at NIMH reached out to warn him that similar experiments went awry at the NIMH when the investigators started taking the drug themselves. It’s a bit like the curse of the Hope Diamond.

If MDMA is approved, it will likely involve tight restrictions, with use in approved health care settings, close monitoring of patients and diligent reporting of adverse events. And that will mean a very expensive drug. With 2 therapists at each session, I estimate that the 12 session therapy takes up about 75 hours of therapists time, which could cost anywhere from 10,000 to 20,000 for a 3 month treatment. And this means we’ll need to be much more careful in assessing who is a good candidate for the treatment.

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KELLIE NEWSOME: For now, MDMA remains an illegal drug in the US, schedule I, which means the DEA considers it to have no accepted medical use and a high potential for abuse. But MDMA assisted therapy is approved in Australia, and other countries like Switzerland, Canada, and Israel are exploring limited compassionate use. And for patients who are determined to find it, MDMA assisted psychotherapy is conducted underground in the US and legally in countries like Jamaica and Costa Rica.

And while the FDA grapples with questions of addiction and bias, patients with PTSD await the kind of recovery that those who’ve gone through MDMA assisted therapy testify to. A woman with PTSD from sexual assault testified that “What used to feel like a tsunami of overwhelming panic was now merely a puddle at my feet.” In the words of a military veteran, since MDMA “I have been allowed to live, to truly live.” 

Owen Muir, MD, is an interventional psychiatrist in New York City and the editor of the Frontier Psychiatrists newsletter which you can find on Substack. His recent articles there were among the sources for this podcast.

The Carlat Podcast team is now on video. Find monthly episodes of Carlat Psychiatry News on the Carlat YouTube channel or under webinars on the Carlat webpage. This month features research on TMS for Teens, Olanzapine Serum Levels, a prazosin-combo pill for alcohol, how to switch sleep meds, lithium, omega-3’s, and caffeine. 

The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.