Explore the complex landscape of MDMA-assisted therapy for PTSD as the FDA's decision looms. Expert panelists discuss key challenges, regulatory hurdles, and the future of psychedelic medicine in mental health treatment.
In this episode of Psychiatry Tomorrow, Dr. Carlene MacMillan hosts a panel of experts to discuss the FDA's pending decision on MDMA-assisted therapy for PTSD. The conversation explores the current landscape of clinical enthusiasm and regulatory caution, key challenges facing approval, and potential regulatory requirements. Panelists Dr. Owen Muir, Dr. Boris Heifets, and Andrew Penn share their insights on functional unblinding in clinical trials, safety monitoring, and provider qualifications. The episode concludes with a look at the future of psychedelic medicine and the potential impact of the FDA's decision on mental health treatment.
Owen Muir: [00:00:00] If they just, you know, rubber stamp things, and someone dies, or something awful happens Someone's going to come back and make a documentary on Netflix like they did about Purdue Pharma and highlight the FDA official who signed off on the thing after, you know, some dubious, you know, party. Your whole job working at FDA is to ensure you're never looking like that gentleman.
Carlene MacMillan: Welcome to the Psychiatry Tomorrow podcast. I'm Dr. Carleen McMillan, and in each episode, we interview thought leaders in the deep end of psychiatry's next frontier. Dive into the latest research, innovative treatments, technology, and policy developments shaping the future of psychiatry. Join us on this journey to discover what's next in mental health care so you can stay ahead of the curve.
Hello, and
Alison McInnes: welcome to Psychiatry Tomorrow. I'm Dr. Carleen McMillan. And I'm Dr. Allison McInnis. Today, we're diving into a hot topic that's been making waves in [00:01:00] the psychiatric community. The FDA's pending decision on MDMA assisted therapy for PTSD. So this episode grew out of a lively
Carlene MacMillan: discussion on social media with panelists about LICO's application to the FDA for not just a drug, but a drug plus therapy, which seems to be throwing everyone from bureaucrats to Burning Man attendees for a loop.
We all agree that people suffering with PTSD need access to breakthrough, life saving treatments. But the role Lycos and its MDMA assisted therapy will have to play in getting these treatments into the mainstream remains up in the air.
Alison McInnes: With the FDA set to make a ruling in a few days on or around August 11th.
We've gathered an expert panel to dissect the possibilities, challenges, and potential implications.
Carlene MacMillan: Guests, we asked clinicians who are part of our OzMind network to weigh in. The results paint a picture of a medical community both excited and cautious about this potential new treatment.
Alison McInnes: Yeah, that's right, Carlene. Um, at the time we recorded this episode, our survey found that while nearly [00:02:00] 60 percent of clinicians would approve MDMA assisted therapy if they were at the center. the FDA, only 28 percent believe the FDA will actually grant approval in August. It's a stark contrast that highlights the complexity of this issue and that we clinicians are all thinking with our hearts of the great unmet need for PTSD.
And the comments
Carlene MacMillan: we received were equally thought provoking. One respondent called MDMA and other psychedelics, quote, miracle workers in the field of mental health. Well, another cautioned about the need for quote, a more transparent discussion about the obvious financial incentives.
Alison McInnes: Yeah. And I'll point out one more, um, a respondent stated that it is problematic that this study was initially launched by advocates for psychedelics reform.
And much of this discussion is going to center around all the types of bias that may have come to play in this study. In any event, it's clear that there's a wide range of opinions out there. If approved, 42 percent of our respondents said they would offer [00:03:00] MDMA assisted therapy as soon as possible, while others expressed concerns about safety, protocol, and the readiness of our healthcare system to support this new modality.
These diverse perspectives set the stage for our
Carlene MacMillan: discussion today, and we will share out updated results of the survey when the episode airs. To help us navigate these complex waters, we're joined by a truly all star crew of experts. We have Dr. Owen Muir, who's an interventional psychiatrist and author of the popular Frontier Psychiatrist Newsletter.
Dr. Boris Heifetz, an associate professor of anesthesiology at Stanford and leader in ketamine research. And finally, we have Andrew Pem, a psychiatric nurse practitioner and clinical professor at UC San Francisco School of Nursing, who actually participated as a study therapist in the MAPS Phase III trial of MDMA assisted therapy.
Alison McInnes: In this eye opening episode, you'll learn about the complex journey of MDMA from party drug to potential breakthrough therapy, some of the critical safety concerns and regulatory hurdles facing [00:04:00] MDMA assisted therapy, how the FDA's decision might impact future psychedelic research and drug development.
And finally, if the drug is approved, we will talk about post marketing safety monitoring with a risk evaluation and mitigation strategy.
Carlene MacMillan: We'll also, of course, be tackling recent controversy surrounding the MDMA trials, including allegations of underreporting adverse events, diving into the ethical considerations and data integrity issues at play.
Alison McInnes: Okay, so let's dust off our crystal balls and jump right in.
Carlene MacMillan: Hello everybody. Thank you so much guys for being here today and I'm especially looking forward to this conversation with the three of you. Um, so today I really wanted to pick your brains about kind of where you're at. With everything that's been gone going on with the MDMA, um, assisted therapy filing with the FDA, and I think this talk started, this idea hatched because I think, uh, [00:05:00] Boris and I were having a, uh, a little back and forth on X or Twitter and, um.
People were chiming in with all sorts of interesting insights. So, uh, here we are. Um, the first thing wanted to do is just, you don't need to give your whole bio, but if each of you could kind of say why you're here, what's your connection to the space and any major disclosures that would. have any bearing on the discussion today.
Um, Owen, you're first on my screen. So do you want to go first?
Owen Muir: Uh, so I'm Owen Scott Muir, uh, MD. I'm also a distinguished fellow of the American Academy of Child and Adolescent Psychiatry. Uh, I have 900 shares of mind medicine or thereabouts. I have one share of a tie to see how that moves. And, um, I just want, yeah, um, practically my most important disclosure is that I want to see psychedelic medicine succeed in, in the same way that other successful therapeutics succeed, which is by complying with [00:06:00] all appropriate regulations and making sure these things will be safe and effective.
And so I am, uh, I'm an interested supporter of the progress and I'm concerned about the safety. Uh, I've also been on the Carlotte podcast about this topic. I have a newsletter which people pay me to read and sometimes I write about it. So that's a disclosure. And I've had, uh, executives from Lycos join me at rapid acting mental health treatment and event.
I run their sponsorship costs 0. Uh, so that's my disclosure there. And that was a little bit of a strategic choice at the time for, for bias reduction purposes. We'll see if it worked.
Carlene MacMillan: Wonderful. Thank you. All right, Boris.
Boris Heifets: All right. Uh, thanks for having me. First of all, and Owen, it's nice to, uh, put a name to a face.
Um, I, my main disclosure is that I'm not a psychiatrist. Uh, I'm an anesthesiologist who, uh, is friends with a lot of psychiatrists that have been working in mental health and have been interested in this area for a long time. Uh, [00:07:00] I'm at Stanford. I'm associate professor of anesthesiology and by courtesy in psychiatry.
Uh, my lab is entirely focused on understanding how rapid acting therapeutics work, non ordinary states of consciousness and their applications to mental health. Then non ordinary is, uh, covers a broad swath of things from anesthesia to psychedelics. Uh, although obviously a lot of our effort has been psychedelics.
Uh, lately, both in animal studies and in human studies, um, in terms of actual real disclosures, I'm on the scientific advisory board of Osmind and journey clinical. Um, I don't know what my shares are worth. I'm very excited to see you guys go public one day. I guess we'll find out then, but, um, really the, the, the honest truth is that I think that this is the way to ensure safety and efficacy in this emerging space is.
Having some sort of closed loop, uh, system monitoring how, um, these, uh, [00:08:00] medicines are deployed and, you know, administered, um, so, and I like the models that you all work with. Um, I've done a little bit of consulting work for Arcadia Medicine and, uh, for Clairvoyant Therapeutics in Canada.
Carlene MacMillan: Wonderful. All right, uh, Andrew.
Andrew Penn: Hi, everyone. I'm Andrew Penn. I'm, uh, I'm trained as a psychiatric nurse practitioner. I'm a clinical professor at UC San Francisco and in that role, uh, part of my time is spent working with the translational, uh, research project in psychedelics, the tripper lab with Josh Woolley. We were a phase three. 3M DMA site for map one, uh, uh, a phase two S-A-M-D-D, uh, study site, and have done an a number of investigator initiated trials, uh, primarily with psilocybin.
And so I've received, uh, research funding support from, from those endeavors, um, and done some, uh, consulting with Otsuka, Alkermes and some, uh, [00:09:00] smaller startup. Uh, psychedelic companies and, um, and on a community advisory board for Tactogen and also the advisory board for, um, for OzMind. So happy to be here.
Carlene MacMillan: Well, and then I should disclose that I am married to Owen. Um, so I guess his disclosures are my disclosures and of course with OzMind, so we definitely want to see psychedelic medicine move forward and, and participate in real world evidence after these things are approved, um, and help clinics get.
started with these things. So I wanted to ask, um, for when the FDA makes a decision in August, and again, we're a couple weeks out from that. Um, what do you think will happen? Do you think that they will vote yes or no? And then you can kind of elaborate on your answer. Um, who would like to go first?
Boris Heifets: All right.
I think, and this is maybe hopeful. I, uh, also, you know, Um, I think that [00:10:00] there's a future here for psychedelic medicine, and this is a shot on, on goal. Um, I think that the FDA is going to vote to approve. I think they're going to vote to approve with a very restrictive REMS and a, it's going to be contingent on a phase four, phase four studies.
So I did a little bit of looking about, you know, other, you know, how they handled this before. There is, there is precedent for all of this stuff that the FDA has. a lot of leeway in how they handle approvals. So just as a quick example, uh, Bevacizumab, it's a, it's a breast cancer drug. It was actually, it was approved, uh, about 15 years ago, contingent on phase four trials being positive.
The phase four, they, I think they, the phase four studies were actually designed like phase three. It wasn't like an observational thing. It was, they had to do a whole nother set of studies while the drug was approved. And then the FDA [00:11:00] withdrew approval a year later, or a couple of years later after the trials came, came back.
So it's, that's, that's an option. And if, you know, they're, they want to be very conservative, they could, you know, they could suggest something Like that. I think that there's a menace, a tremendous public and political pressure to approve. We've seen the FDA do things under similar circumstances with esketamine, uh, and adjuhelm.
Um, so I don't think they're bound by the adcom and I think that. Um, they are probably vote to approve with, with a lot of stipulations.
Carlene MacMillan: All right. And I think we can come back to talking about what those stipulations might look like and what a REMS might look like. Um, but want to hear from the other two panelists, um, who would like to go next?
Andrew Penn: Well, this, this might speak more to my, uh, My defensive structures, but I'm leaning a little, I tend to be sort of defensively pessimistic. Um, and so I, I'm leaning [00:12:00] towards expecting a no or a very, um, some variation of what Boris said, a more restrictive, uh, contingent. Yes. Um, you know, I think it's entirely possible that the FDA could require Lycos to go back and do additional phase three studies, which, you know, would create some.
serious financial problems, I think for that organization. Um, or they could give a contingent approval based on, on, uh, the, the positive phase four data. Um, but I, I think given the complexity of the request in the form of the NDA, especially with the added variable of the therapy component, which I personally as a clinician feel is, is critical, but creates a real It seems to be really stymieing to the FDA, since that is not their, not their bailiwick.
Um, by, by having that be embedded in the NDA, I think it creates some real [00:13:00] problems that, uh, the Adcon kind of gave some idea, you know, obviously the Adcon is not the FDA, uh, not the people that will be making this decision, but just some of the questions that were asked really pointed to some of the complexities of trying to regulate that.
And And that, that makes me less optimistic, uh, at this point, you know, and it's also possible that August 11th could come and go and they don't give an answer, you know, they could just kick it down the road a few months and gather some more data. You know, it wouldn't be the first time a government agency missed a deadline.
Carlene MacMillan: Very interesting. So, okay. So we have one, yes, one, maybe no, maybe kick the can down the road. Um, Owen, you're, you're up last.
Owen Muir: So I think it's going to be either no. Or whatever the equivalent of no is that lets the can be kicked down the road. Um, and I don't work at FDA. I have done some FDA consulting. Uh, and, and so one of the things that stands out for me in, in reviewing [00:14:00] the communications back and forth between Lycos and FDA is that when the FDA makes a suggestion, It's less of a, it's a little bit, it's a little bit like your, you know, my, my lovely wife, Carly and McMillan saying, how does this dress look?
There's a limited range of good answers to that question. And none of them are, it's terrible. You look awful. Right? They're not, they're not asking you to only, uh, only answer the question. They're in the question, they're suggesting what your response should be. And some of the responses from, from Lycos seem as if they didn't hear the music, not just the words.
So when FDA says, you know, we think it would be appropriate to have data about safety from EKGs, It doesn't mean, you know, do what you want, and we'll be happy if there's EKG there, it'll be cool if there isn't. There is missing data required [00:15:00] for the approval of a drug, and so the most conservative can down the road would be just the kind of, uh, abstentions abstain adjournment.
Like, Oh, we look forward to deciding when you've submitted the subsequent safety data. So whatever I'm not the best non answer they can give is my guess. Um, and I'm, I'm not. So, a no equivalent or a, or a kick the can equivalent, um, if we look at the history of filbanserin, which was approved for hypoactive sexual desire disorder, we have a good history of, uh, originally Bowringer Engelheim and then Sprout Pharmaceuticals going back and forth with the FDA over many years trying to establish safety, it eventually came to market as Adai with a very restrictive REMS, which was later edited to be less restrictive around alcohol.
Uh. What we see historically is there's a capital intensive process of getting a complex intervention through the FDA and that's [00:16:00] That, that's both like a, a truism of drug development is that these things require much more capital than Lycos has spent thus far generally to get over the line. And if you're capitalizing your drug discovery business to only have enough money to get through one meeting with the FDA, you have undercapitalized your effort.
And so I think, like, for example, there is an investigation that will likely have to happen based on the reports that there were unreported severe adverse events. That's a crime, if that's true. And like DOJ reportable reporting, you know, any false data to FDA. As of 1991, and they have a guidance document about this, is a criminal matter.
And I don't know if it happened or didn't, but they sure as heck have to do an investigation if that's the allegation. And, and so you're in this strange position where everyone would like an approval, and yet we might get an indictment. And I just don't know, but either the SAEs or, I mean, just like [00:17:00] imagine a world where the FDA is like, we approve it.
And also your executive leadership will be indicted for not reporting severe adverse events in a clinical trial, which is an omission, which is a criminal matter that we're referring to the department of justice. I don't see that working. And I see kicking the can down the road of an accelerated, you know, approval process being the most likely outcome.
Carlene MacMillan: That for me is, is also the sticking point. And I wanted to record this podcast as close as possible that we could reasonably do to, to the 11th, because my understanding from the adcom was that there is some kind of investigation going on internally regarding this SAE thing. And for folks that are unfamiliar, there, there was an allegation, um, in the ICE report and then others in the media said that, that.
MAP participants were encouraged to underreport or not report suicidal ideation and even sort of near suicidal attempts. And that is obviously a quite [00:18:00] serious allegation. So for me, that's my sticking point. Because if, if there was, Truth to those, I don't see how they could approve it because then further trials would all be compromised around this SI thing, like we can't have that.
So for me, that's my sticking point, but I'm wondering for you guys, because there's all this talk about functional unblinding, um, and then, you know, a bunch of the people that already tried MDMA, they didn't do the liver tests because the FDA Didn't ask for them. They didn't do the EKGs. Like, are those state, like, what's a major sticking point for you?
I think for Owen, it's clear. It's this issue about SAE, like data integrity, but I guess for Boris and Andrew, like when you look at this, like, like, what do you think in terms of like, what would actually be a roadblock and what is like, okay, this is a We can deal with that.
Andrew Penn: Well, the, the, you know, the, the AE issue is a, and there's the SAE, the, the suicidal ideation is obviously very concerning.
And, and that needs to be [00:19:00] captured in a way that we can translate that into clinical care. 'cause remember, I mean, remember that's the point of this exercise, right? is, is to figure out where are the safety signals that we need to be aware of as we translate this into clinical care. You know, just, just if, if you think back, you know, into, you know, the black box warning around suicidal ideation in young people for SSRIs, for example, that, um, came out, I think around 2003 or so, you know, so most of the antidepressants that we're familiar with were on the market by then.
And then this was post hoc analysis that came out and, and, you know, as, as of arguable, arguable utility, but nevertheless, that, that was an important thing. And it's, and it's now standard of care. If you are prescribing SSRIs to a, especially to a young person to have a conversation around potential for emergent suicidal ideation.
So, so that's the whole point of this exercise, right? Is, is to find out what do we need to know about this going [00:20:00] in to clinical treatment. I think the challenge of coding AEs, you know, I wish the word adverse was taken out. I wish the, I wish the verbiage was changed from baseline, right? Because it, because it makes this assumption, because what it inserts in there is a judgment piece as to on the part of the clinician or the part of the researcher as to what is considered adverse or not.
So, you know, I think we can all agree nobody would enjoy a therapeutic headache. You know, like that, that I think we can all agree headaches are adverse, right? But if you've been depressed for 20 years because you have terrible PTSD and you suddenly feel joy, is that an adverse event? You know, most, most sort of the believers in MDMA would say, absolutely not.
But the FDA looks at that and says, is that a rewarding signal? Is that euphoria? Is that going to make somebody want to go back and do this again and again to try and re experience that joy? And, and so it creates this. this problem where the investigator is having to [00:21:00] determine whether or not this is adverse or not.
You know, and what I would suggest we do in future studies is just report any change from baseline and then aggregate that data later and figure out if there's a signal there. You know, maybe it turns out that feeling joy in an MDMA session actually predicts therapeutic response. Well, that would be, that's great.
You know, we don't know. We don't know. So, so this question of whether or not something is adverse or not has really created some real challenges.
Boris Heifets: I, I guess I take, I take a little bit of an issue with that and that, um, well I don't take an issue with like, yeah, we should, you know, not everything is an adverse event.
In fact, joy is not, you know, really an adverse event in the broader context of mental, mental health. But, um, yeah. The idea that this should be a roadblock to approval, which I'm not sure that's what you're saying, Andrew, but it's all right. Well, I guess I'm just curious. It in turn, I mean, so Carly, and you asked me like, what are the sticking points like a criminal [00:22:00] indictment?
Yes, that would be a big sticking point if that's what happens. I think it's going to be very difficult to establish that. I mean, there are allegations. I think, you know, if they, they reported the data they got and like things that don't exist on paper are very difficult to find out about, um, you know, short of interviewing all the participants in the trial.
I don't know how the FDA would go about doing that. Well, if that's for
Owen Muir: a moment, like there is a method for this, which is Uh, you know, request for records, right? They can, they can order this to be suspected. Yeah. Right. So there will be like discovery in any investigation that can ask for text messages.
It can depose individuals involved. And what did they say and when did they say it is going to matter a lot if there's any suspicion that there was criminal misconduct. But it's hard. And I, I have no idea, but I wouldn't want to be in that position. And it's not fast. It's not something that gets resolved between now and August.[00:23:00]
Because I have no insider information. I just worry that that could get in the way.
Andrew Penn: And oh, and remember that all these sessions, you know, I was a study therapist on map one for the last subject at our UCSF site. So I, you know, I have an end of one of running these subjects and we videotaped. You know, all of our sessions for adherence rating purposes and also, you know, for safety.
And so, you know, they're, well, depending on what tool was used to discover, uh, a suicidal ideation, for example. So, you know, when, when I worked on this, we did the, the, the Columbia, uh, the suicide rating scale. Orally. So that's on video somewhere for our subject, you know, asking if, you know, so if, if we, if, if that person said they were suicidal and we wrote down that they were not, you know, that is discoverable.
It would take a tremendous amount of time with a fine tooth comb, um, if that, if that was what they wanted to do, but you know, clearly that's not going to happen in the next two weeks.
Carlene MacMillan: Right. And Morris, did you want to add any other things about this issue? I,
Boris Heifets: yeah, I think I'm, I may, may be [00:24:00] overly naive and trusting and that like, I feel like that would be shocking to find in a phase three trial, like really, honestly, like that, yes.
And if that's true, then like the deal is off. Um, and whether, you know, I, I also have no idea how intensely they're going to investigate, um, you know, you know, what lengths they're, they're, they're going to go to those issues aside. All Um, it just, it seems to me looking at past FDA decisions, and this is a little more, you know, the adcom vote of all of the one is a little more lopsided than before, but it just, and I've never worked with the FDA.
So, oh, and I think actually your insights are pretty valuable here, but. The, the, you know, still massive public health issue that has not been addressed, PTSD, suicidality, like all, you know, foreign wars that, like we've been engaged in, uh, that is a massive public health issue. And, you know, again, when you look at Alzheimer's and, you know, the adjuvalent approval and [00:25:00] esketamine, what was the FDA responding to?
Uh, in approving those drugs and my, this may be a little conspiracy minded, I don't know, but it's a basically a green light to industry like industry has been, you know, all the big pharma companies have been divesting from CNS therapeutics for 20 years, right? Like who wants to make an eighth generation SSRI, you know, that's, it's a tight space to get into.
So that to me, like. What are they doing? They're saying like, all right guys, like we're going to let this one through Uh because we want investment in this space like go, you know run with this and I think that has reinvigorated the alzheimer's fields Dubious ends, honestly, but, and, uh, also, you know, the, the, the psychiatry, uh, pharmaceutical space and you're already starting to see acquisitions of, uh, some of the, you know, psychedelic startups and this, you know, that with, with as a first in class.[00:26:00]
I mean, this, this is, uh, I, I, I think that it's not unreasonable for them to, to approve on, on, on that basis with a lot of like handholding and closed restrictions. We have precedent for very addictive drugs being approved, even in the midst of the opioid crisis, likes fentanyl, you know, intranasal or there, there's, I forget what the formulation was, but for cancer pain, like approved in 2019, like a, you know, with headlines the same day about, you know, Sackler indictments.
So it's not, you know, that's, uh, there's precedent for that. precedent for, you know, Accutane. Every single patient, I think, that gets Accutane in this country has to have their name on a list, you know, it's a requirement for prescription. Um, so I just think they have a lot of latitude and if, unless they want to completely shut, like it, it's a very strong signal to industry if they basically, you know, give a middle finger to, maybe not a middle finger.
It may be like the abstain and [00:27:00] like, we're looking forward to seeing the safety data. Like it might be the best like middle road, but I think there's a strong incentive for them to approve something with a lot of post approval, uh, surveillance.
Carlene MacMillan: Enjoying the Psychiatry Tomorrow podcast and hungry for even more insights into the future of mental health care?
Then you won't want to miss out on the Psychiatry Tomorrow newsletter from AusMind. Join hundreds of forward thinking psychiatrists and mental health professionals staying ahead of the curve with the latest research, technology, and practice strategies delivered straight to your inbox. It's free, it's easy, and it's the best way to keep your finger on the pulse of mental health care.
Just head to ausmind. org slash tomorrow and we'll see you inside. Yeah. I mean, Accutane, I think if, you know, for folks that aren't familiar, um, you know, even if you take it like as an adult grown woman, you still have to like, I believe still answer questions every month. Like if you haven't had your first menstrual period, can you [00:28:00] still get pregnant?
You know, you're asking these quizzes. Every single pill thing has like a picture of a woman with like a pregnant and then a line through, which apparently a lot of people don't I don't really understand what that means, but you know, and then you have to do, like there was this, it was just literally a study where they said like that particular icon, like icon, whatever it's called, icon, people did not understand what it meant.
So like, particularly like teenage girls did not understand what it meant, but they try really hard. You have to get monthly labs. You have to document two forms of birth control. Like it is a production because the risk of fetal birth defects that are fatal is, you It's extremely high, um, and no one wants the, the thalidomide, uh, baby type situation happen again.
So totally agree on that. So when it comes to like breakthrough therapies, which MDMA assisted therapy has that designation, comp 360 from compass has this, other devices have this, like Saint TMS, they all [00:29:00] do get afforded a bit of latitude in terms of the, the speed with which they go through. And then the.
More significant reliance on that post marketing data in phase four where that's real clinicians Contributing outcomes really kind of seeing things and so let's just say there's no, you know They nothing criminal kind of pans out here with the SAE stuff If that's all the case, what do you guys think in terms of, I think maybe before starting with you, like what would that ideal rems you think look like for mdm, a assisted therapy?
Boris Heifets: Um, in a nutshell, it would be a registry, like a, every, every, they're gonna document, every use. Uh, obviously it would have to be observed that they're gonna mandate the credentialing of the therapist. I'm guessing it's probably not gonna be, is asking for. Um, they're going to the, that would be and then monitoring for a certain length of [00:30:00] time, like with explicit, um, you know, the adverse events of special interest being suicidality, you know, maybe videotape the sessions.
I don't know if that's really like, uh, on, like, I don't see why they wouldn't be able to, um, ask for that. But I think that would be the general, the general shape of things along with a. You know, the just thinking of the other tools the FDA has at its disposal is to require a phase three style post approval, uh, study to basically with long term follow up.
I really liked Owen's, you know, the way you put it with the, uh, The FDA is, you know, asking you a question, it's really, it's a, you know, more than a polite suggestion, uh, is, is encoded in there and, you know, my guess, although I don't know, is that other more experienced companies have, you know, read between the lines and not, you know, politely declined to do a dose ranging study.
So I think that, you know, [00:31:00] that there with the change in leadership, that Lycos is going to be doing a more extensive, you know, phase four. randomized controlled trial with long term follow up after a limited number of doses. That makes
Carlene MacMillan: sense. And then also, I think things like the liver function test, the EKGs, or some of that stuff can be filled in.
Boris Heifets: I mean, a lot of that stuff, honestly, is, like, it's been, there have been, like, we, it's, and we're, you know, for three doses, like, I, I don't think anyone is seriously concerned about cardiac, like, we have people Adderall with, like, CHF, like, it's, it's How is that? How is that an issue now?
Carlene MacMillan: I agree. It shouldn't be the sticking point.
Not to me. Um, resolvable with the REMS. Andrew or
Owen Muir: Owen? For, for just a minute, there's a black box warning on, on stimulant medications for cardiac adverse events. And to get the black box warning or not is not a trivial issue. And it matters whether it has them or not. Now I agree with Boris, you know, we have, we could just EKG everyone coming out of Berghain.
And get a decent proxy, right? There are plenty of people, [00:32:00] remarkably, honestly, who've, who've, who've been exposed to these compounds over decades. And we have a relatively broad sense of in, you know, otherwise young, healthy people, what these drugs are like. What we don't have is what their adverse events are likely to look like in sicker individuals with congestive heart failure, with QT prolongation, with any of those things that are going to be common in people with post traumatic stress disorder.
Forty percent of people coming out of the ICU are going to have PTSD, right? So there's whole populations of people who didn't get into Berghain and would never get into Berghain. This is a dance club in Germany.
Carlene MacMillan: Oh, and pause, pause. Yeah. What's Berghain? People maybe don't know. Maybe it's like Berghain.
Think of Berghain. Berghain is like a infamous club in Germany. Replace that with Burning Man. Somebody's offering at Burning Man could be to do EKGs. That would be amazing.
Owen Muir: Right. So. We have, we have long track records of exposure and, and adverse events, and frankly, it looks like these drugs are [00:33:00] not as dangerous in relatively young, healthy people who are in the position to have friends offer them Molly, which is different from the Thank you.
medical population of status post cardiac ICU admission and subsequent PTSD, you know, heart transplant recipients who may also benefit from an effective treatment for PTSD. So categorizing these adverse effects is not trivial and probably mandatory for doctors to understand what to say at scale.
Andrew Penn: Sorry.
We, we, we could set up a, uh, we could set up a booth on the way in and the way out of Thank you. Because it does, there's often a long wait on both ends, so we could pass the time. Seriously,
Carlene MacMillan: if anyone wants to fund that study to do real world, uh, evidence field testing at Burning Man. Yeah.
Andrew Penn: But to your point, but to your point, Owen, you know, I mean that the, you know, I keep, I'm kind of haunted by, I heard somebody say recently that, you know, you are judged.
On your clinical trial [00:34:00] on decisions that you made seven to ten years ago, but you're going to be judged seven to ten years in the future and you don't know what those criteria are going to be when you make those treatment design decisions at that time. Right? And so, and that's a lot of what's happening now, because I think back, you know, I think it's a It's easy to forget how heady a days it was say in 2017 when the breakthrough SPA, you know, the special protocol assessment was, was granted by the FDA and, and what's, you know, I'm interested in the science of this.
I'm also interested in sort of the culture that surrounds the psychedelic. space, if you will. And, and one of the things that's been fascinating to me is that the ISER report was really, you know, with the exception of maybe symposia was really the first and that was limited to a fairly small kind of audience was really the first time that The, this whole enterprise has been seriously critiqued, you know, it feels like Pollen's book in 2018 is this watershed moment.
You've now finally sloughed off the ghosts of Timothy [00:35:00] Leary. You don't have to talk about that anymore. And now it's full steam ahead, you know, and we're saving veterans and, you know, all these important. Talking points, but nobody had ever really critiqued these things. In fact, if I would say to my psychedelic friends, like, what if we, I know you were on, but like, what if we weren't, what if we don't get it approved?
What if it doesn't get approved? And people look at me like I had three heads, like, how could that even possibly be? And so along comes the ISO report and suddenly there's this critique that has not really existed for the last seven or eight years. of this work. And we're being judged on contemporary standards now.
I mean, this, this is going to be a huge, uh, windfall for anybody who comes next, you know, I mean, this is a risk of being first out the gate, right? You're going to make all the mistakes. A lot of times in these kinds of development processes, it's actually better to be second because you'll benefit from all the mistakes of the first person.
Um, but yeah, this, this question of, of safety data, you know, I mean, I remember there was this talk of, Oh, we'll use the NIDA data. [00:36:00] You know, and it was a sort of perfect, you know, judo move, right? And we'll use this NIDA data that was set out to show how dangerous MDMA is to actually show how safe it is, you know, but the reality is like, you've got to show the FDA, the data from your product, not MDMA writ large, but your Lycos product.
And yeah, it's, it may be roughly identical, but. The FDA doesn't care about that. They want to see data from your product.
Boris Heifets: I just, I think it's, you know, I may, maybe I've been, I'm in, I'm in a bubble. There's actually no question that I'm in a bubble, but you know, the, the, the idea that directly monitored therapy in a clinical setting Um, even, you know, with clinician, you know, clinician judgment, like knowing what this drug is, knowing what it's at, you know, that it's a stimulant, that it would require, um, and like another, like, uh, another round of, um, you know, formal safety testing for cardiac events.
It's just, it's, [00:37:00] it seems like. I mean, really, oh, like a overkill in a way, I mean, you know, that you should, if you're giving, you know, if I, I don't actually, I don't know if anyone, how well you know this bravado Rams, but are they like required to have a, What are they required to have in terms of safety and training?
Owen Muir: So I did it yesterday morning, so I can tell you, uh, yeah, and so we're getting, you're getting pulse, you're getting blood pressure, you're getting, was there dissociation? Was there sedation? When did it resolve? After how many minutes? What were the vitals at baseline? What were they 40 minutes later? What were they before discharge?
Did the, any hypertension that was emergent resolve prior to discharge of the patient? What's the plan to discharge them home? It's an extensive REMS program. And, you know, the first of these REMS, the clozapine REMS, may be the best guide to this because that was another drug for a treatment resistant condition which had extraordinary requirements from the FDA and was acknowledged to be very [00:38:00] dangerous and came to market with the mandatory monitoring.
Like, If you're going to have something that has risks associated, there's going to be appropriate monitoring. And we don't know the appropriate monitoring now. Zyprexa relprev is another good example that has post injection delirium sedation syndrome and an associated REMS of three hours of monitoring after the dose and EKG on site should you need it.
Uh, and you know, that's not something that killed you or sexually assaulted you. Uh, it is a risk, uh, and it gets monitored, and that was slapped on after the approval of, of, or at least in the course of the clinical trials of the drug, it was identified that this post injection delirium sedation syndrome was a risk.
You know, the FDA, their incentives are not to let something out in the wild that's going to kill people and they're going to get egg on their face. Right, if they, if they just, you know, rubber stamp things and someone dies or something awful happens, someone's going to come back and make a documentary on Netflix like they did [00:39:00] about Purdue Pharma and highlight the FDA official who signed off on the thing after, you know, some dubious, you know, party and then was invited to work for Purdue several years later.
Don't be that guy. Right? Your whole job working at FDA is to ensure you're never looking like that gentleman who made those decisions and then ended up working for Purdue Pharma. There is embarrassment that they have to manage or prospective risk mitigation around being personally shamed.
Carlene MacMillan: And they're in a real bind because they will be personally shamed if they do not approve this also at this time, right?
And we're already seeing that, um, in, in the marketing about PTSD and suicide. So one of the things about Spravato REMS is it, you know, it's very strict about the two hours. That's a very important element is how long people need to be monitored. Many of us keep doing Spravato. Most patients are, do not need the full two hours, but that's, that's a hard requirement.
And if you let them go early, or if you make a mistake in your documentation, you will get a call within [00:40:00] 24 hours from the REMS people saying, you know, what, what did you do? So that for the MDMA thing, I, what I saw in the sort of suggested REMS, it wasn't quite specific at that level for me. It seems like they need to do some hammering out.
But I think with the MDMA assisted therapy, the AT part, that's where I have some questions. And I think Boris, you said that they would approve something, but you think it might not be what it is. Like Lycos is hoping. Can you, can you say a little bit more about what you mean there?
Boris Heifets: Really, I guess it's in terms of the, like, I think what, you know, Lycos is aiming for is to have, uh, you know, a very loose, um, requirement on who's, uh, on credentialing really, on like, who's, you know, who's allowed to get therapy.
This ties into the concerns about you have people who are in a heightened state of suggestibility that may be vulnerable to, uh, you know, therapeutic malpractice. Uh, so how do you protect against that? Um, [00:41:00] it, you know, who, who's trained to give, who, who's the best psychotherapist? It's often just not people with MDs.
Uh, so it's, you know, you have to, you have to open the, uh, the gates a little bit to let other people in. Um, other practitioners in with experience and, you know, the people coming through CIS, like, is that count as a, um, as, as, as an appropriate credential, is there a practice board that they answer to? Um, those things, you know, are hard to build the airplane as you're flying it.
Um, I don't know that those things really exist, uh, yet, but there are practice boards for nursing doctors, for psychotherapists, um, psychologists, social workers, you know, that, um, could, you know, adjudicate these kinds of things. I don't think they're going to be that specific about, you know, what type of therapy is going to be delivered, but they almost certainly will be specific about who's, you know, qualified to administer it.
Carlene MacMillan: Yeah. And I've been thinking too, not only [00:42:00] about the licensing boards, which we are seeing, you know, some actions against, uh, at home ketamine use and things toward certain clinicians when there's bad outcomes. I actually think that malpractice carriers have a significant role to play here too, because There can be REMS, but a malpractice carrier can say, Hey, if you cut, we're covering you for this, we're going to expect, you know, the video monitoring, or we're going to expect another person, like they can put some layers on that I don't think are really within the FDA's purview.
So I'm kind of anticipating that. And I know there's some companies in the space sort of specifically interested in covering these types of therapies and already thinking about that. So that, that makes me feel a bit, a bit better. Um, but it's very unusual. Like, do you guys know of any other situation where the FDA has had any sort of therapy, like we have Suboxone that's like, they approve Suboxone, but it just says you need like some support, like anything like this where it's actually like, They didn't just put MDMA, it's MDMA AT.
Andrew Penn: I think Suboxone and Naltrexone are the two meds that have [00:43:00] some, some verbiage in the, in the prescribing. Uh, Veren Yeah. Verenity. But not
Carlene MacMillan: like, it's not the label. But you know, It's not like,
Andrew Penn: you know. No. Well, those two on the label, it says that it's suggested that this be part of, but it's not required.
And, and, you know, this question, you know, we sort of talk about psychedelic therapies and broad strokes and, and, and I would say that MDMA has particular, particular differences to it. You know, subjectively, obviously it's a very different drug than psilocybin, but arguably it is also, it's a, if we're talking about trauma.
Trauma. And in most of the study subjects, it was interpersonal trauma, you know, it wasn't that you were in a hurricane, it was that somebody harmed you, you know, who maybe was even supposed to take care of you, so developmental interpersonal trauma, you know, that, that doesn't heal in a vacuum. Right. That heals in some kind of therapeutic container in which trust can be [00:44:00] reestablished.
And, you know, the whole hypothesis of MDMA is that that trust is enhanced with the drug and that, you know, obviously that has to be held with the greatest discernment and, and, and ethics, um, because it's very abusable as well. Um, and, and that's different than psilocybin. You know, something like psilocybin, uh, you know, I've sat with many people under psilocybin and you know, it's funny, there's a lot of people who want to be psychedelic therapists.
I'm not sure what they imagine my day looks like, but it's a little bit like watching paint dry. Sometimes, you know, you literally have somebody on a couch with eye shades and headphones on occasionally taking deep, meaningful size. But otherwise is entirely having an inner experience and that's fine.
And, you know, maybe there's something about that, that is, you know, there appears to be something about that, that, that is, is salutary and that's great. But the, the point that I'm getting at, um, in a very long winded way is that that, you know, the, the skill sets that are going to be needed for these [00:45:00] different compounds may vary somewhat, you know, an MDMA may require a tremendous amount of discernment, especially when people are vulnerable, especially maybe if somebody, uh, starts having sexualized feelings towards the therapist to be able to navigate, you know, that that's a real, you know, sort of cilia and sharpness kind of path to, to navigate carefully.
Psilocybin may not need as much of that. You know, maybe that may be something where it's a much more internal process. You know, I'm co founder of Open Nurses, which is intended to advocate for the role of nursing in this because, you know, nurses sit with people in altered states of consciousness. All the time going to pack you go in the ICU, you know, 12 hours of somebody who thinks they're in a hotel and it's 1955 that's just a shift in the ICU.
You know, like that's cool. We can do that. Um, you know, you soil yourself in the middle of that. No worries. We'll get you cleaned up, you know, and when was the last time you heard about a sex scandal involving nurses? You know, it's, it's just, we deal with, we deal with people's bodies all the [00:46:00] time. The public trusts us.
It's not a big deal. We can do this. Right. So, you know, but that, that may be a slightly different skill set than it takes to work with somebody with MDMA. And that's not to say nurses can't do that either. I absolutely think they can. And so, you know, and by the way, we're cheaper than a lot of other, uh, professions as well.
So there's an economic argument as well. And there's, there's 5 million of us in the U S. So you could siphon off 1 percent and have a ready made workforce of 50, 000 people, which we're going to need in order to do this. So, so, you know, I think we have to think creatively about who's going to do this and what sort of professions are, are well suited to what kinds of patients.
Carlene MacMillan: Absolutely. And I think Andrew, you did some great advocacy during the, I guess, the open comment period about the FDA guidelines for psychedelic trials to really kind of center the role of nurses, which I think is totally aligned with. And then you also brought up this kind of first mover advantage. So as we're wrapping up and thinking MDMA is going first, so that's hard.
We saw with paratherapeutics and digital therapeutic [00:47:00] space, they went, you You know, file for bankruptcy and shuttered and now several years later, we have CMS saying they're going to cover digital therapeutics and we have many that are in the pipeline or approved. Right? So that was we all like, you know, raise a glass for pair.
But, um, with MDMA, not only do you have first mover, but you have probably the most complex problematic substance in terms of boundary violations and just the way all the things you mentioned. So it's, it's not an easy road. And I think Lycos is in a really tough position. And I guess as we think ahead, if we like what we know now, like if we could go back in time and kind of design the perfect kind of psychedelic trial, you know, things around blinding and not any kind of final thoughts from each of you, just, you know, at a high level, like what would be kind of key things you think such a trial would, would need, like must have that maybe wasn't centered in these early trials?
And we want to go first,
Boris Heifets: long term follow up,
Carlene MacMillan: long
Boris Heifets: term follow up would have answered [00:48:00] so many questions, uh, in terms of efficacy, it is very different. I don't, no matter what is happening in that therapy room, if you have good long term outcomes without continued use of the drug, um, without, you know, telling people what group they're in and actually having good retention.
Um, that, you know, I feel like that, that could have addressed a lot of things. Obviously, like the dotting the i's, crossing the t's, collecting the safety data would be confusing. Easy thing. I think this will be at best a pyrrhic victory for Lycos and in 10 years we're not, no one is going to be using MDMA, they're going to be using the derivatives that all jumped in as soon as MDMA was available.
Carlene MacMillan: Yep. And I know Compass has long term follow up built in their COM 360 trial and I think that makes a ton of sense. owner Andrew must have.
Andrew Penn: Well, there's been, there's been a lot of talk about this functional and blinding question. And, you know, it, it, it [00:49:00] assumes that there's this sort of perfect situation in which, um, which that doesn't happen.
Right. And, and the reality is in a lot of psychoactive. Drug trials, you know, take, take just psychostimulants for ADHD. Do you know you're on a psychostimulant? Hell yeah, you know, you know, compared to a placebo. Right. And so, so do functional and blinding is not unique to psychedelics. I mean, it makes for good New Yorker comics.
Right. Um, but it, but it's not, it's not a unique problem to that. And the interesting thing, if you look at the MDMA. You know, the phase two aggregated data and then, uh, the, all the way up to map two, the last phase three. What's interesting is that the effect size, if you measure, say, no longer with PTSD diagnosis for the MDMA group has been pretty consistent somewhere between about 82 to 70 percent of that group.
But what's fascinating is that the, uh, the placebo or the just therapy alone group has grown in effect all the way up now to like [00:50:00] almost 50%. of people who only get the therapy without, without MDMA, no longer have a PTSD diagnosis. So the thing I'm really interested in is what the heck's going on in that therapy that's so effective, right, that we can amplify another, you can add another 20 percent of effect on if you add the drug.
But the therapy, I mean, that's a 50 percent reduction. response rate or remission rate. That's, that's pretty damn impressive. Um, so this, I, this sort of fantasy that we can totally blind therapy, you know, and the reality is once this gets out in the world, all clinical work is open label. Right? Everything we do in our offices with patients is open label.
I know what you're getting, you know what you're getting. Does that have, does that create expectancy biases? Absolutely. A smart clinician, an artful clinician knows how to amplify those. You know, the first thing I teach in my psychopharmacology course is about the placebo effect. Because it's your biggest ally, right?
And so in clinical trials, it's your enemy in clinical practice. It's your ally, you know? So, so I [00:51:00] wish that, that, I mean, this is a real big fantasy here, but I really wish that the clinical trial model was more, Yeah,
Carlene MacMillan: and just a shout out to a trial I learned about, I think is going to be enrolling soon out of Yale.
Um, I learned it at Horizons, a transdiagnostic psilocybin study that has criteria, much more reflective of real world, much more open, um, much more realistic. I'm very curious to see how that works. Um, more trials like that, um, obviously they have to be sort of more academic and not the pharma ones, but it, it was, it was great to see.
All right. Owen, you have the last word here. What's your dream wishlist or top item for a psychedelic trial?
Owen Muir: Not everything on earth is ethical to compare to placebo. Uh, my joke for this is parachutes, right? We couldn't ethically run. a randomized control trial for parachutes and sham parachutes, that trial would be stopped early because the sham parachute group would [00:52:00] immediately die and maybe someone would land in a bush.
You can't run that study ethically. So there are individuals who looked at this in the past. So if you look at the trial design on lamotrigine for bipolar depression, that was a withdrawal trial. We had to, for safety, titrate everyone up on a dose and only after there were at a dose and stable on that dose where they either continued on the drug or given a withdrawal design in which placebo was, was inserted.
And we did time to relapse to bipolar depression, uh, the long acting injectable of arapiprazole. Uh, the, the first version of that was also a withdrawal design. Everyone was induced on oral medicine, given a shot of the drug and then switched at some time point to the subsequent drug. Right? We have mirror image designs in the long acting injectables, which John Cain has long supported.
Uh, if you look at the clinical trial design on clozapine that was used, right, there was eight weeks of active treatment, uh, to make [00:53:00] sure everyone enrolled was a non responder because only non responders in eight weeks of open label Haldol. Can you imagine being on a unit with? Patients with schizophrenia who hadn't responded to any other drugs then being given eight weeks of a drug to make sure they still didn't get better and only then randomizing them to Clozapine versus Thorazine, another active agent.
That's a remarkable and heroic piece of science, which I would argue is similar to what was going on in this MAP study population. These are heroic efforts in science. And that also means there's a requirement to think as skeptically as possible about how these trials will be interpreted. And again, with the benefit of, of seven years of hindsight, we can have much different thoughts with different data in our minds than they had the inception.
So, I would love to see more, more, uh, you know, the ability to demonstrate a blind being preserved. Can we create a, a sham that doesn't create the intended effect while at the [00:54:00] same time preserving the blind? And I don't know if that's possible. And it may be using lower doses, either possible or it's not.
And then you have to know something about the study population. And one thing we know about treatment resistant post traumatic stress disorder is they don't tend to respond to sham. Or placebo. Like that's not a responsive cohort. So a good example of this would be Dr. Williams trial, uh, on Ibogaine, right?
There was no, in that study, and that's not an FDA approval trial, everyone was open label and we know the response to sham in that population of traumatic brain injured veterans with, you know, co occurring suicidality, trauma, et cetera, is not spontaneous remission on average. Similar, like the SAINT trial enrolled very carefully people who had 13 years of, you Sorry, 13 failed medication trials on average and 20 years of depression on average.
So the enrollment in these trials of highly treatment resistant populations may give us a better ability to distinguish signal even in unblinded [00:55:00] studies. It may be we need crossover trials or we need, you know, if blinding is not possible or we need to use something, you psychedelic ish compound. that didn't treat PTSD, like having a negative that we could compare to would be a remarkable tool in the investigation of subsequent compounds.
This is hard science to do. We don't have the answers yet. And so I think, you know, the, the green light for more research and frankly, more government funding of, of, you know, investigation into essentially. blind, blindable compounds. We'd love to have a psychedelic compound that did nothing other than make you trip.
And, and I don't know that we have that.
Carlene MacMillan: Yes. Yes. Someone make that drug, please. Yes.
Andrew Penn: It's like Gabba, like the Gabba Penton of psychedelics. It has everything you need except for benefit. I could not disagree more.
Carlene MacMillan: Maybe that'll be a part two. We can all, I [00:56:00] think we, you know, speaking of blinding truly opened my eyes today to a number of different thoughts.
Hopefully it did for our listeners as well. I want to thank all of you. And then I'm hoping after August 11th, we can all take as Anders is a deep, meaningful sigh. and figure out a path forward here because I think we all want to see patients get helped and see these breakthrough treatments get safely and reasonably accessibly deployed.
Owen Muir: And I can't wait for Boris and I to talk further about this because I can't wait. Yeah,
Carlene MacMillan: you guys can just stay on and you know, we can all battle but no, we should maybe we should I'd love to have you guys back anytime. This is great.
Owen Muir: I love being wrong. And I hope I really honestly hope I'm wrong. Like I hope this gets approved.
Boris Heifets: I think actually you probably have the most realistic take on is the, like, we look forward to seeing this reapplication, like revise and resubmit, which is revised and [00:57:00] resubmit.
Carlene MacMillan: Yeah, I really think now we're going to have to have you guys back to, uh, to do a little armchair analysis of the decision. So, yes.
All right. Well, thank you so much, guys. And, uh, Yeah. Good rest of your day.
Boris Heifets: Thank you. Nice seeing you all.
Carlene MacMillan: That's it for today's episode of the Psychiatry Tomorrow podcast. We hope you found our discussion informative and inspiring. If you enjoyed the show, why not share it with one mental health clinician in your network?
Your support means the world to us and helps us reach a wider audience. And if you're enjoying the podcast, we'd really appreciate it if you could leave us a rating and review on your favorite podcast platform. It only takes a moment, and your feedback helps us to improve the show and reach even more listeners who are passionate about mental health.
Thanks for listening, and we'll see you in the future.