Decoding the FDA Committee's Decision to Reject MDMA-Assisted Therapy With Andrew Penn, MS, PMHNP

Andrew Penn, MS, PMHNP, a clinical professor at the University of California, San Francisco, in the school of nursing, and a member of the Psych Congress steering committee, discusses the recent vote by the US Food and Drug Administration’s (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) against a midomafetamine (MDMA)-based therapy for the treatment of post-traumatic stress disorder (PTSD) in adults. Penn explores the research behind this controversial treatment, the committee's concerns, and the potential implications for future PTSD therapies. This interview sheds light on what the decision means for the future of PTSD treatment and the ongoing quest for better mental health solutions.

Stay tuned for part 2, where Penn will delve into the strategies that could help alleviate issues in these clinical trials, the crucial steps for integrating psychedelic treatments into mainstream health care, and the impact of the FDA committee's decision on the future direction of PTSD treatment options.

To read more about the committee meeting, read: FDA Advisory Committee Rejects First MDMA Treatment for PTSD.

Read the transcript:

Andrew Penn, MS, PMHNP: Hi, I'm Andrew Penn. I'm a psychiatric nurse practitioner, a clinical professor at UC San Francisco in the School of Nursing, and a member of the Psych Congress Steering Committee.

Meagan Thistle, Senior Managing Editor, Psych Congress Network: Can you give a brief overview and background into why MDMA-assisted therapy research was pursued?

Penn: This has been an interesting topic of research for over 15 years now. Midomafetamine, which is also known as MDMA or methylinedioxymethamphetamine, is a drug that has been under investigation, coupled with psychotherapy as a treatment for PTSD, which as we well know, is a difficult to treat and increasingly problematic condition for those of us in the mental health field, particularly, post-COVID-19.

This has been an area of inquiry run by an organization called MAPS, or the Multidisciplinary Association for Psychedelic Studies, which is unusual in drug development in that it's a nonprofit. In more recent years, a pharmaceutical branch of the Public Benefit Corporation, which is now known as Lykos Therapeutics, has been pursuing this treatment toward FDA approval.

To that end, there's been two phase 3 trials that were published in Nature Medicine. Full disclosure: I worked on one of those trials that was known as MAP1 in around 2020, which was the time that I was working on that study; both of which had very positive results and were submitted as part of a new drug application to the FDA at the end of last year.

The context for our conversation today is that these studies were examined by an advisory board, an ad board that is sometimes referred to as an “advisory committee” to the FDA. This is not the final deciding body for the FDA, but this is essentially a group of clinicians and involved citizens. For example, there's a patient advocate person representative on that board who raised questions about this data. Ultimately, the committee’s advisement will be taken under consideration by the larger FDA as they move towards their decision date, which is scheduled for August 11th, 2024.

[02:30] Thistle, PCN: In your opinion, what is the impact of the FDA committee’s recent decision to reject the first MDMA-assisted treatment for PTSD?

Penn: There's been a lot of trying to kind of ‘read the tea leaves’ in the advisory committee’s decision last week, which was not very positive. For those who don't spend their entire Tuesday watching an FDA hearing, and I can understand why you might have other things to do, there was a presentation by the sponsor of the study. In this case, Lykos presented their phase 3 data, and there was a discussion of that data by the advisory committee. Then there was a period of public testimony that went on for a couple of hours with people raising in support of this treatment, talking about unmet needs for PTSD, and then also some voices raising concern about the studies. Those voices referenced the way the studies were designed and some of the things that happened during the studies.

Then finally, there was the vote that questioned if the committee felt that there was adequate data to support the approval of midomafetamine for PTSD and also some advising on what would eventually be the risk evaluation mitigation strategy (REMS). This is a treatment that would undoubtedly have a REMS, kind of like esketamine or clozaril has that additional layer of regulations that go around prescribing it.

The meeting went on for 9 hours, and as I mentioned, there was the presentation of the study outcomes, which were really very positive. There was a considerable separation between the group that got MDMA plus therapy versus those who got therapy plus a placebo.

The data is quite robust, and I think that is what's been making a lot of the headlines. However, questions were introduced about the data. Some of those get into some of the nuances of conducting research, but one of the challenges of studying a psychedelic is that there's this question of what's known as “functional unblinding.” So, do people who get randomized to one group or the other have some idea of what group they're in, even though they're not told because this is a treatment that couples psychotherapy with the drug?

The therapists are also blinded as to what condition the subject is in. Did the therapists know? And because Lycos did collect this data, at least in the second study, we have some idea that, not surprisingly, people tend to know if they had received MDMA versus a placebo. A lot has been said about this, but it's important to acknowledge that this is not unusual; this is not unique to psychedelics. There was a New Yorker cartoon going around about this, it's risen to that level of a trope. 

When people are in, an antidepressant trial, for example, if that drug has side effects, such as the person who's taking a pill every day and they don't know what condition they're in suddenly gets a dry mouth, they might be tipped off that they're actually in the active drug group and not the placebo. That's not particularly uncommon and doesn't necessarily need to be a deal breaker.

The other issue was the question of how do you code certain types of events? There's this thing in research we refer to as an AE or an adverse event. I think the term adverse is somewhat confusing in this situation because these are people who often have felt really terrible with PTSD for maybe even decades.

This question came up: Well, MDMA can engender, for example, a positive mood. Is that an adverse event, or is that a positive event? Is that a therapeutic outcome? As far as the FDA is concerned, these things would probably be better called “changes from baseline.”
If you came into the study that morning without a headache and you had one at the end of the day, then that's a change from how you came in, and that needs to be recorded. However, there was some question about how these things that the FDA was concerned about might be reinforcing, for example, were captured in the MAPS data.

Then, finally, there was this question that was raised particularly during the public comment section around the sexual misconduct of one particular therapist dyad, in a phase 2 study some years ago.

So, the combination of all of these things really seemed to cast some question about the findings of these studies.

At the end of the day, the vote for whether or not the data was robust enough to support the efficacy was quite negative. It was 2 in favor and 9 opposed.

This sent some shockwaves through the research community and also people who are concerned about finding new treatments for PTSD, which at this point, we only have a handful of evidence-based treatments for—some of which are limited by the patient's ability to tolerate the treatment, such as exposure therapy, prolonged exposure therapy. We only have 2 FDA-approved drugs for PTSD, so paroxetine and sertraline.

So clearly, there's more needed in this area, and this is what's driven this research for all these years. 

[08:42] Thistle, PCN: How can practicing clinicians balance the therapeutic potential and enthusiasm for psychedelics while addressing the pitfalls highlighted by the FDA committee’s recent decision?

Penn: I think for practicing clinicians, this whole question around psychedelic-assisted therapy has gone through a very interesting evolution that I've watched for the last 10 or 15 years. I think most of us were trained probably only very briefly, anything to do with psychedelics—or MDMA is not really a classical psychedelic—but really, this may have consisted of a few pages in a textbook around substance use.

At first, it was this sort of skepticism that I think came out of that narrative of how could a drug that we were taught was a schedule one drug, was a drug of abuse. How could that possibly be therapeutic? And then I'd say somewhere around 2018 when Michael Pollan's book "How to Change Your Mind" was published, that really seemed like a watershed moment. At that point, the conversation really shifted from sort of skepticism to outright enthusiasm.

That sort of fueled a kind of impatience about when we are going to be able to do this. Unlike a lot of other pharmaceuticals, which I would say the vast majority of clinicians are unaware of their existence before they get to late-stage trials or even get out onto the market. This is something that has been in the media and the popular culture. I don't know of many pharmaceutical trials that are the subject of Netflix specials, for example, whereas psychedelics have been.

So, there's been a lot of enthusiasm about this and I think a lot of that is honestly driven by the fact that many of our treatments are not all that powerful. Coupled with the fact that we're seeing this incredible increase in mental health presentations, especially since it was a problem happening before COVID-19, but COVI-19  really sort of broke it wide open that we have this huge unmet need in mental health, particularly around PTSD.

I think the enthusiasm that a lot of clinicians have met this research with is reflective of that, you know, it's that we need better treatments and we needed them yesterday, really. There's been a lot of hope that these treatments would prove to be valuable, and I do think that the data is quite robust on them.

There are some unique challenges about how to study them that we can certainly talk a little more about. But right now, I think we're looking to August at this point. The question is, what will the FDA say in August? I think that will have implications for the field in general.

But there's still a long road ahead.

Andrew Penn, MS, PMHNP, is a plinical Professor in the University of California, San Francisco, School of Nursing where his teaching has received the UCSF Academic Senate Distinction in Teaching Award, among other recognitions. He has practiced as a psychiatric/mental health nurse practitioner, treating veterans and training residents at the San Francisco Veterans Administration Hospital. As a researcher, he collaborates on psychedelics studies of psilocybin and MDMA in the Translational Psychedelics Research (TrPR) lab at UCSF, serving as Co-PI on a phase 2 study of psilocybin for depression and is currently working on a study using psilocybin to treat depression in patients with Parkinson’s disease. A leading voice in nursing, he is a co-founder of the Organization of Psychedelic and Entheogenic Nurses (OPENurses.org), advocating for the perspective of nurses in psychedelic therapy, he has published on psychedelics in the American Journal of Nursing, Frontiers in Psychiatry, and The Journal of Humanistic Psychotherapy.