Decoding the FDA Committee's Decision to Reject MDMA-Assisted Therapy: Part 2

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 delves 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.

Missed Part 1, where Penn explores the research behind this controversial treatment, the committee's concerns, and the potential implications for future PTSD therapies? Watch it now here.

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

Read the transcript:

Meagan Thistle, Psych Congress Network: What strategies or innovations do you think could help mitigate issues in clinical trials, specifically in the context of psychedelic-assisted therapy, to ensure robust and credible study outcomes?

Andrew Penn, MS, PMHNP: One of the big challenges with psychedelic-assisted therapy is the question of functional unblinding: people tend to know if they were given the drug or placebo.

One way to mitigate this is with a dose stratification strategy. A company called Compass Pathways, which is looking at psilocybin for treatment-resistant depression, did this. They gave people either a full dose of psilocybin, a small to medium dose, or a very tiny dose, which was thought to be essentially a placebo.

When you have that kind of data, then you can start to see if there's a dose response curve. It also introduces more uncertainty into the question of blinding, so you can tell people in the study, “you're going to get a dose of psilocybin. We can't tell you which dose you're going to get, but you will get a dose of psilocybin.” So, there isn't this question that often hangs out in the room when you do these dosing sessions, which I've done many times as part of my lab work, where the subject is wondering, “did I get drug or placebo?” The clinician is probably wondering, “did they get the drug or placebo?”

We know that everyone's going to get some amount of drug. Now, it might be a very tiny amount, but that little bit of information would be behind the blind.

MAPS decided not to do that because of a concern that they had from their phase 2 trials that small doses of MDMA actually generated more anxiety for subjects with PTSD. There was this question of whether or not it was ethical to subject subjects potentially to something that might make them feel worse. There's other data that would kind of call that angiogenic effect into question, but nevertheless, they made a decision not to introduce this intermediary dose. This makes the data more vulnerable to this question of functional unblinding.

In the study that I worked on with major depression and psilocybin, we used a niacin placebo. We had what's known as an ‘active placebo’—niacin is going to make you feel kind of weird and flushed, but it certainly doesn't have any psychedelic or antidepressant properties. So, you can use something like that to introduce a little more uncertainty into the mix, but the FDA doesn't want that for phase 3 trials; they want things tested against an inactive placebo. Similarly, they don't want head-to-head trials.

Many clinicians think that a drug under investigation and being examined by the FDA needs to be tested against an existing drug, such as fluoxetine for depression. And they don't. They absolutely don't require that, and so those tests often don't get done.

The other question is the role of therapy. Where this gets tricky is that the FDA does not regulate psychotherapy. Some of the questions that were asked during the committee meeting made it pretty clear that that's unfamiliar territory for them. This is not just a drug treatment; it's really a psychotherapy treatment that is catalyzed by the use of midomafetamine just a handful of times. But that introduces some real challenges from a regulation standpoint because the FDA does not regulate psychotherapy.

The specificity of the psychotherapy protocol was called into question, and while there was a psychotherapy protocol for the MAPS study, there were questions around the adherence to that model; even though the data was collected, there really wasn't the opportunity to discuss that with the FDA in this hearing.

So, another question is, if this drug were to be approved, what would be the protocol around it? And what would be required of therapists to do? What kind of training would they have to do? Would they be required to have fidelity to a particular therapy model?

These are questions that the FDA is not particularly skilled at examining because their primary role is looking at the efficacy and safety of drugs. The psychedelic-assisted therapy model does introduce some novel and challenging elements to this whole process, which I think we saw last week, this advisory committee really struggling to try and understand.

Thistle, PCN: What are the most critical steps for integrating psychedelic treatments into “mainstream” health care, ensuring accessibility and equity, while maintaining patient safety and treatment efficacy?

Penn: One of the things that's unique about psychedelic-assisted therapy that is different than a novel compound coming from a pharmaceutical company that is a drug-alone treatment is that these compounds have been out in the underground market for a long time for many decades. In some cases, with [treatments] like psilocybin, there's indigenous use that goes back millennia.

These are things that people come up to me after I give a talk on this and say, “well, my patients are already doing this.” And they're right. I don't think it's widespread, but it's certainly out there and is more prevalent in some areas of the country than others.

So, this question of where this fits into our existing model is a really important one because one of the values of having an FDA-approved treatment is that we have some capacity to at least have oversight over the safety and appropriate use of these treatments in that medical setting. The other argument for having this available in this kind of setting is that it improves equity. Because even if you live in a state where there's access to some of these treatments, such as Colorado or Oregon, they're still quite expensive, and there's no insurance coverage for them.

In order for this to be available, not just to people who can pay for it out of pocket—and we're often talking about several, if not many, thousands of dollars for one of these treatments—we really have to have a treatment that's available through commercial insurance, Medicare, or the VA, which is where many people who don't have those kind of resources get their health care. That is an important step for equity and access.

Also, having FDA oversight over these kinds of treatments allows for, in that context, a certain degree of expectation for safety and appropriate training. I imagine that these things will probably continue to exist in underground settings in parallel with state-regulated systems. It remains to be seen how that's going to work out.

Even if you are not particularly interested in providing this for your patients, it's important for clinicians to have an understanding of it. It's similar to our understanding of cannabis—you may not think much of cannabis, you might not be very enthusiastic about it, but nevertheless, you need to be able to converse with your patients about it. Just like we need to know about any new treatment, even if we're not necessarily prescribing it, in order to be able to discuss it with our patients.

This is another area where it's going to be helpful for the clinician to be able to at least have conversations with patients, take a harm reduction approach, and be able to have conversations about safety. For example, to be able to think about what medications a patient might be taking that might be incompatible with taking a psychedelic. Also asking: “where are you doing this? With whom are you doing this? Where are you getting your compound from? Are you sure that it's safe and unadulterated?” That [last question] is one of the challenges of drug prohibition is that it creates a robust black market, but that black market being unregulated can often come with its own perils, such as questionable providence of the drug or contamination of the drug.

These are all things that it would behoove clinicians to be able to talk about with patients.

Thistle, PCN: How might the FDA committee’s decision impact the direction of future PTSD treatment options?

Penn: You know, with regards to this or future of PTSD treatment in general, I'm glad to see that this is an area that is really starting to get more attention. One of the reasons why this the midomafetamine research has been so important is that it's really been 20 years since we've had any kind of pharmaceutical innovation in this area. And the working clinicians who are watching this know that mostly we're kind of not trying to knock out symptoms of PTSD, we're really not doing anything that treats the underlying disorder.

You know, we're addressing things like sleep, anxiety, and mood with individual medications. But I think psychotherapy tends to do a better job of kind of addressing the bigger picture of PTSD, but access to psychotherapy, especially evidence -based psychotherapy for PTSD is really quite challenging. And so I think in general, it's a it's a good thing for patients with PTSD to have this kind of greater attention focused on that condition.

And my hope is that this will be part of a host of novel treatments for this condition, which really causes so much suffering and disability to many people and many of our patients as we well know it as clinicians.

Thistle, PCN: Any final thoughts on this topic?

Penn: You know, I think this moment for a lot of people in the psychedelic space was quite surprising because we've had a long stretch where the cultural baggage that came with psychedelics from 50, 60 years ago/their use in the 1960s has sort of dropped into the background. There was a lot of mischaracterization of these compounds as a result of the drug war and prohibition. But in the last 25-plus years, we have really moved into this space of more thoughtful, meticulous research in this area.

As with any new research area, there are a lot of challenges to be worked out. I think that this event [on June 4th, 2024] while disappointing for some, is also really important for reflection. How do we move into this space in an even more deliberate way? What sort of challenges can we anticipate for future studies?

MDMA is just one compound under investigation and the other one that has received a lot of attention is psilocybin. Increasingly now, we're also looking at LSD. There have been some very interesting findings, looking at LSD treatment for generalized anxiety disorder and, of course, psilocybin primarily for major depression, but also for substance use disorders.

So, I think there was a lot of hype around this meeting, and I think there was a sense that if this didn't work out, it would be the end of the “psychedelic renaissance,” and I think that's probably prematurely writing its obituary.

This will most certainly be informative for any future research as to what kind of challenges we're likely to face and what kind of questions we're likely to look at from the FDA. I think what this may call for is that we really just need to do more of this research in order to answer these questions. But at the same time, because of the complexity of psychedelics and the culture, the train is not waiting at the station for the FDA to get on board.

There's been a lot of different ways that people are accessing these compounds on their own, one of which is through these state-regulated programs, such as in Oregon and Colorado, another being through religious freedom. There are some groups that use psychedelics, usually plant or fungal-based compounds, as part of a religious practice, and that is protected under the First Amendment.

There's also always been an underground network of people who offer these treatments, and that isn't going away either. So, you know, it's a very complex ecosystem in which there are different ways to access them.

I think there are a lot of areas of inquiry that are still very much underway and probably will continue to be for some time to come. Whether or not that will sort of dampen the popular enthusiasm for these compounds, that remains to be seen.

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.