Science Friday - FDA Panel Rejects MDMA Therapy For PTSD

Episode Date: July 22, 2024

Last month, the first psychedelic therapy treatment came before the Food and Drug Administration for a vote. It entailed using MDMA, also known as ecstasy or molly, to treat PTSD.MDMA therapy has looked promising as a treatment for PTSD and other mental health conditions in some studies. But the FDA scientific advisory panel that evaluated this treatment voted overwhelmingly against approving it.Many of the arguments against approval had less to do with MDMA itself than with the methodology of the clinical trials done by Lykos Therapeutics, formerly the Multidisciplinary Association for Psychedelic Studies, or MAPS. The FDA panel was presented with allegations of misconduct and incongruous data, including a letter by trial participant Sarah McNamee.McNamee, who joined the trial for treatment of PTSD, is also a licensed psychotherapist and researcher of trauma and psychotherapy at McGill University in Montreal. She joins guest host Rachel Feltman alongside Dr. Eiko Fried, a methodologist and psychologist at Leiden University in the Netherlands, to discuss the decision.If you or someone you know is struggling with PTSD or other mental health conditions, call 988 for the suicide and crisis lifeline.Transcripts for each segment will be available after the show airs on sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

MDMA has been seen as a promising treatment for PTSD in some studies. So why did the FDA reject it? I was in the trial that was supposed to determine efficacy. So how did they know it was efficacious before the trial was even done? It's Monday, July 22nd, and this is Science Friday. I'm SciFRI producer Kathleen Davis. Last month, the first psychedelic therapy treatment came before the Food and Drug Administration for a vote. But the FDA scientific advisory panel that saw this voted overwhelmingly against approving MDMA therapy for PTSD.

A lot of the hesitation against approval had to do with the methodology of the clinical trials, done by Lycos therapeutics and the Multidisciplinary Association for Psychedelic Studies or Maps. Here's guest host Rachel Feldman with more. Joining me today to talk about this are my guests. We have Sarah McNamey, a trial participant researcher at McGill University and a licensed psychotherapist based in Montreal, Quebec, and Ikofried, a methodologist, psychologist, and associate professor at Leiden University in the Netherlands. Welcome, both of you, to Science Friday. I'm so excited to have this conversation.

Thanks for having us on. Yeah, good to be with you. Thank you. Just a heads up. This conversation is about post-traumatic stress disorder. If you or someone you know needs to talk, you can call 988 from any phone for the suicide and crisis lifeline. Sarah, I'd love to start with a question for you because you aren't just coming to this with the perspective of a mental health practitioner. You were also one of the trial participants in this case. I'm curious, what drew you to explore MDMA therapy specifically? You know, was there past evidence on the therapy that interested you? Yeah, so the answer is actually pretty simple.

there wasn't a whole lot of exploration on my end. I was on medical leave because I was experiencing a relapse of PTSD. And one of my friends had heard about it and jumped on the phone and called me and told me about it. And she said, there's a site in Montreal. You got to sign up. And I immediately jumped on it and emailed the study site. But I was already aware that there was research on MDMA for PTSD because I'd been working in trauma research. But it has been kind of bubbling up in, you know,

academic circles and in sort of the mainstream awareness for the last few years. Is that right? Yeah. I think now a lot more people are talking about it. Sarah, I've done some reporting on psychedelics and actually took part in ketamine-assisted therapy for PTSD myself. But for folks who are listening who don't know, could you explain how this process generally is supposed to work? Yeah. So I followed obviously the Maps protocol. I was in a MAPS-sponsored study. Sort of the recipe is They give you three preparation sessions, which are just normal talks therapy, where they kind of like talk you through what the experience might look like and what your expectations are and what to expect. And then over the next three months, there's three full day dosing sessions. So in the clinical trial, you don't know ahead of time whether you're going to get MDMA or just a sugar pill.

And then between each of those full day dosing sessions, there's three regular talk therapy sessions as well. like in total, I got 12 talk therapy sessions and three full day sessions. So that's the recipe. But it really doesn't capture what's going on in the trials because what happens in these therapy sessions and these dosing sessions really doesn't look anything like normal therapy. And so much of what the, you know, so-called therapy part of MDMA therapy actually is, really draws a lot on a whole bunch of pretty controversial stuff that I think myself sort of in retroactively, having spoken to a lot of therapists, raises a lot of red flags from a therapy perspective. Could you tell me more about what your participation was like and, you know, what the red flags

were when you looked back on them? Basically, you know, I was, I was suffering and I just wanted to heal and here this thing got presented to me as something that could potentially be better and more effective and faster than anything we've ever heard of. And I went for it. And I think a lot of people go for it. If I think back to between the point where I heard about the trial and got enrolled in the trial, I researched it intensively. And everything just sounded so rigorous and so research-based and so positive, except for I was in the trial that was supposed to determine efficacy. So how did they know it was efficacious before the trial was even done. So I think that as you come into the trial as a participant, it's pretty

overwhelming. There's a lot of hope. There's a lot of hype. There's a lot of desperation. And that's not on the participants. So much of this is in the media and in the sort of like public zeitgeist around it that I don't know that researchers could really mitigate it all that well. So what you have is researchers who already believe that they've got an efficacious treatment. Therapists who are using therapy methods that are quite controversial and participants who are pretty desperate for healing and are hearing nothing but positives. So that was my experience coming in. And I think one of the things I want to draw attention to is that there is a reality

and one that's fascinating from a research perspective that some of the people who are getting better are also getting worse. And I would love to see so much more discussion of that, the complexity of what the experience is from having spoken to other trial participants in my own experience. I would say most people I've spoken to have had these very complicated mixed experiences, which is really confusing. Yeah, thank you for sharing that. I go, I'd love to turn to you to get your input on the study. You know, as someone who has expertise in the field who wasn't involved in these particular trials. Can you walk me through your thoughts on their methodology? Yeah, I wanted to start by thanking Sarah and others who have spoken up about their experiences.

I think that's we need more of that, not only in this area, of course, also in, you know, antidepressant research and other psychotherapy research and sort of more qualitative reports of folks because, yeah, the measures we provide and the numbers we get don't always necessarily reflect people's thoughts or feelings or behaviors. And so that's where folks who work measurement like I do, for example, can learn a lot. So in principle, I think if we ignore the problem of blinding, which I'll get to in a moment, the map study, the two studies, Map 1 and Map 2 were designed in a way, interestingly. You have an idea, you think that MDMA combined with psychotherapy helps people more than

nothing combined with psychotherapy, which is state of the art, right? At least for many mood and anxiety disorders. And so what you do is you do therapy plus MDMA. then you do therapy plus placebo. It's not a bad idea in principle. It is a bad idea if we know that the group that gets MDMA will know they're in the group that gets MDMA. And perhaps even more problematic and that's something we don't talk about too much, folks getting placebo know they're getting placebo.

You heard Sarah's experiences, the hope participants put into the trial, the hype that has been sort of instigated by investigators and media reporting about it and so on. and then you sit there for hours and hours and you know you're in the control condition. That's what we see in these studies. The dropout rate is higher in the control group and so forth. And that makes any inference is really difficult from a study like this.

And that is why I was so surprised that MAPS even went with this study design because, mathematically speaking, it's not a very sound design in a situation where we know that folks will not be blind to their treatment allocation. And that has some implications. First of all, we have the sort of expectation

buy is, you know, that we have the hype and so on in the experimental group and we have the disappointment in the placebo group. And that can lead to a treatment effect where your experimental group, MDMA and psychotherapy, looks like it's performing better than your placebo control group. But what actually happens is that your experimental group, MDMA and psychotherapy, performs as well as you would expect from placebo, and your placebo group performs worse than your normal placebo group, right, because folks are disappointed and so on. Then you have the problem that obviously clinicians aren't blind. You know, if I sit next to Sarah as a clinician for hours and I maybe hold her hand or, you know, I know if Sarah receives MDMA or not. I mean, I shouldn't

be able to tell. I'm not informed, but by the study protocol, obviously, right, that is meant to be double blind. I just checked the MAP's website today before the interview and they still maintain that both trials are double blind. But of course, that's just not the case. Neither clients are blinds are blind nor clinicians are blind. And that's just really, really problematic for a clinical trial. It doesn't really allow for valid inferences, which is why I wasn't surprised FDA advisory committee voted pretty strongly against MAPS having shown efficacy for their treatment suggestion. Yeah.

So does this difficulty with finding a lack of a real control group, does that mean it's just impossible to get good data on MDMA therapy? or is there another way to look at this from a research perspective? So I think there's two problems here when it comes to this blinding component. The first is that the psychotherapy component and the MDMA component are sort of mixed together in a complex way. Sarah described that there was these three sessions and you had psychotherapy in between. And so this is really entangled.

And MAPS has actually never been really clear what the mechanisms are, what the proposed mechanisms are. is MDMA supporting psychotherapy, is psychotherapy supporting MDMA? So you'd need to be able to disentangle this properly in a way. The FDA advisory committee sort of be moaned that as well and said, you know, it would be nice to have an only MDMA group and an MDMA plus psychotherapy group so we can start disentangling these effects. In addition, MAPs allowed basically any type of psychotherapy, right? So from holotraptic breathwork to CBT to, I don't know, shamanic ritual,

and maybe Sarah received CBT or maybe she received holotropic breathwork. It depends on her particular clinician, but there's no standardization. And so if you want to deal with this problem adequately, you need to specify what the psychotherapy component is exactly, which maps didn't do. And you also want to specify what your MDMA component is supposed to do. What is the working mechanism? How is the client supposed to interact with a clinician and vice versa during these sessions? you need much more standardization.

The second and maybe more important one is that, no, we're not doomed because placebo control trials will be very difficult in this area. There's two ways this is commonly tackled in other literatures in medicine and psychiatry. The first is, if maps were to carry out a study and say they combine MDMA and psychotherapy in one arm, as they did, and in the other arm, they do the best available treatment for PTSD. Let's say you get psychotherapy, maybe you get some anxiolytics adjacent to help with some of the anxiety, and then you have to take care for what we call threats to internal validity. So you want to make sure that both treatment arms have the same amount of psychotherapy

or have the same amount of contact with the clinician. And so if this is given, if there's a second arm, the control arm, that gives the best state-of-the-art therapy. And MAPS shows me that MDMN psychotherapy outperforms the state-of-the-art therapy, I would find that pretty convincing. So that's the first thing you can do. You can have a better control group. And the second is you do a dose response relationship studies. And that means you have, for example, four or five arms.

There was a catamint study on this pretty recently. You have a control group that doesn't get any drug. And then you have four groups that get, let's say, MDMA in psychotherapy. And you increase the dosage of MDMA in each group. All of these folks will probably know they get MDMA, right? even minor doses will trigger experiences that are unblinding. But now you can see if the highest group with the highest dose works the best. And that would support a sort of MDMA mechanism underlying this whole thing. Sarah, I'd love to go back to your experience, you know, especially given that

you work in the mental health field. Did this trial change how you feel about MDMA therapy more broadly or the validity of continuing to study it? I wouldn't say change. because I don't think I had strong feelings or thoughts about MDMA therapy before I was in the trial. And then for the period that I was getting screened and then enrolled in the trial and maybe for a year afterwards, I was absolutely convinced beyond reason that like MDMA was it. It was the cure. Everybody needed to have this. And this despite the fact that like every single day I was trying not to kill myself. And then as I kind of started working through some of these experiences, I'd say I'd say, I do still think that MDMA has potential, and I used MDMA illegally after the trial ended, and it helped me recover from some of the trauma from the trial itself.

What has been really shaken for me as my trust in the research on psychedelic and in the researchers, you know, there's often this talk about anyone who criticizes MDMA just doesn't understand it. Whereas I think perhaps people on the outside of this field who are criticizing it might have a different understanding that could be helpful. And same for participants who have been harmed. I think, you know, I know of many participants who have really, really tried to make researchers aware of the problems their experiences and really been budding up against walls. Well, and I go, you know, it's very possible that this FDA decision was disappointing to people who, you know, had been hearing a lot of hype about. about MDMA therapy and really thought it could help them. I know there's a community of veterans in particular who have been really excited about the prospect of psychedelic-involved therapy moving forward.

So what do you think are the next steps for these populations? What should the research community be doing for them? Yeah, so the first thing is I'd love to talk to more folks and I'd love to hear more voices on this, why they're excited. Are they excited because folks have been promising the big revolution for 30 years without delivering much evidence? Or are they excited because they have own experiences, for example, which I would trust much more, you know, than the word of some hyped up researchers about this. And if folks have their own experiences and think this is really promising, my hope moving forward would be that this is like any other treatment. because if we've learned one thing from 40, 50, 60 years of literature on psychotherapy and

other pharmacological drugs for mental health problems, there is no one thing that is a miracle cure that works for everybody. This is something we all can come together on. Everybody agrees in this field that certain things work better for certain folks, and we actually don't know it always why and how. And so my hope for, for example, MDMA assisted psychotherapy would be that if we study this properly, we can identify the folks for whom this is more promising than for other people and then sort of deliver the appropriate treatments for the people in need. But that's

not happening right now because, for example, many studies which are concerned with psychedelic assisted psychotherapy, be it MDMA, Cylacin, and so on, are largely recruiting folks with prior recreational experiences. But that's perhaps good in a way, right, because these folks know what's coming for them. Maybe they're most excited. They have positive experiences. But, of course, in principle, this isn't the target population for an FDA approval, right? And so I think we need to understand, we need to recruit broader sets of participants. We need to record who they are, you know, how many previous PTSD episodes have you had or how long has your trauma been lasting, but also, you know, personality trades and recreational

drug use and more information so that the statisticians among us can then sort of like, look, what of these features that people bring into a study are those that make them particularly promising to be cured from a given treatment, sort of this whole precision medicine, precision psychiatry angle that we have all been talking about for the last decade. Well, thank you both so much for joining us. That's all the time we have for now. I'd like to thank my guest, Sarah McNamee, a trial participant researcher at McGill University, and a licensed psychotherapist based in Montreal, Quebec, and Iko-fried, a methodologist, psychologist, and associate professor at Leiden University in the Netherlands.

Thank you both so much for joining us. Thank you so much. Thanks for having me. If you or someone you know needs to talk, you can call 988 from any phone for the suicide and crisis lifeline. And that's all the time that we have for now. A lot of folks helped make the show happen this week, including Annie Nero, Emma Gomez, Charles Bergquist, Danielle Johnson, and many more.

Tomorrow, we'll talk about why a marine biologist went rogue and her mission to make shark science more diverse and inclusive. But for now, I'm SciFRI producer Kathleen Davis. Have a great start to your week.