Thanks for coming, and thank you, AAAP, for having us. It's a lovely group. We love to come to this conference, and getting the chance to actually speak is a very nice thing for all of us, so we appreciate it. We are going to be speaking about integrated trauma treatment with a substance-using population. And first, for our disclosures, Dr. Wilkins and I have no disclosures, and Dr. Ross has a long list of disclosures. We'll take about five minutes to read those, and then we'll keep moving. So many disclosures. In terms of our learning objectives, we have three listed here. We'd like to give you an understanding of the gold standard methodologies for treating PTSD. In this case, we're going to be talking a lot about prolonged exposure and an understanding of an emerging methodology for PTSD treatment, which is MDMA-assisted therapy, which Dr. Ross will be talking about. We want to spend some time thinking through how these approaches impact people and impact change, and then we're going to look at some of the challenges and risks presented by each approach, in particular in this group who struggles with substance use disorders. But I'd like to read the last page of this story before we begin to help frame up this whole discussion, so I can tell you the punchline. The last page says several things. One, we currently have effective treatments for PTSD. Second, we have effective integrated treatments for concurrently treating PTSD and substance use disorder. Despite an accumulation of evidence about the effectiveness of integrated concurrent approaches, they are still in the minority and it's hard to find, in research or clinical settings, this type of integrated treatment. And we hope that this discussion here can be part of a larger move toward recognition of these kind of integrated approaches and greater inclusion of them. So the roadmap for this discussion, Dr. Wilkins and I will spend about 35 minutes describing the nature of co-occurring PTSD and SUD prevalence, impact, what it looks like, a brief touch on some integrated treatment options that are currently available, and then a deeper dive Dr. Wilkins is going to do into the whole idea of exposure, what that is, because it's at the heart of treatment approaches like prolonged exposure. And then we're going to discuss some outcomes using prolonged exposure as part of an integrated residential center. Dr. Ross will give us some background on MDMA-assisted therapy, including pharmacology, as well as a more extensive discussion of how this combined pharmacotherapy and psychotherapy is conducted. We thought we would spend time in both modalities just describing what happens in these therapies. Then some risks and challenges of this approach, and last he'll describe a bit of where we're at in terms of clinical trials, outcomes, approvals, FDA stuff, that kind of thing. And then last, if we have time, we're going to circle back to talk about a proposed study for MDMA-assisted therapy in a residential substance abuse center. And then we'll have questions and answers. So that is why I'm going to stick to my script, because if I wander off, we won't get there. So prevalence. We know the co-occurrence numbers are high. 29% to 79% of those with PTSD have a substance use disorder. 14% to 60% of substance abuse clients have PTSD. And then there's the interaction. Effective substances alleviate PTSD symptoms in the short term, so you have this interaction which is serving in the function of avoidance and blocking natural recovery in the process following any kind of trauma. And we also know that substance use creates conditions, vulnerable conditions for traumatic experiences to keep occurring. So there's a mutually reinforcing aspect to this co-occurrence. And then when both are present, we see a broad array of associated problems, overall worse life functioning, increased rates of health problems, suicide, health care utilization, psychosocial impairments, poorer treatment response in substance abuse programs, higher dropout, faster time to relapse, and a much higher rate of other psychiatric disorders in this co-occurring group. When we look at some data that we have collected over the last six years, in over 1,200 outpatients coming for substance use treatment and 600-plus inpatients, we see prevalence rates of 29% and 40% in those two groups. That's when you look at the PCL-5, which is the self-report measure for PTSD symptoms. Anything 33 or above is considered indicative of probable PTSD. You need to then do a follow-up clinical interview to determine that, but that's an accepted cutoff, and those are incredibly high rates. As you might expect in an inpatient population, you have much more going on, so there's a higher prevalence in that group. When we dive into that 1,200, so this is the outpatient sample, this is a mostly white, mostly working, highly educated group struggling with alcohol predominantly, as well as opiates, cannabis, stimulant use disorders. We wanted to show visually what it means to have co-occurring PTSD and substance use disorder. Bear with me. We took those 1,200 people, and when you use their PCL-5 scores, their self-report of PTSD symptoms, and you know that 33 and above is indicative of PTSD, we divided the group, we stratified them into four groups. The 0-16 on admission PCL-5, 17-32, so that's a group who you think probably don't have PTSD, then 33-49, and 50-80. The largest share of those people are in the 0-16 group, and increasingly smaller decrements of people in each group. If you stratify people that way, and then look at their scores on any number of other measures, this is what you see. This is who is sitting in your office with you. On depression, there's a straight line. Again, on the left, the 0-16 group, next 17-32, next 33-49, next 50-80. BDI for depression, straight line. GAD for anxiety, straight line. And those scores on the right, those are clinically significant scores. Insomnia, straight line. Psychiatric severity on the SCL-10, straight line. Positive affect, straight line the other direction. Negative affect, straight line up. Chances of substance use, using the SIP-AD, straight up. And interestingly, even recovery capital, which is a measure of my environment and how supportive is it or how dangerous is it to changes in my substance use if I were to want to pursue changes in my substance use. Every one of those follows a straight line. When I first looked at those, I thought that was the most horrifying and beautiful pictorial representation of trauma and PTSD and substance use disorder combined. So the bottom line of that is the impact of PTSD in a substance using population is increased distress and dysfunction as a function directly of their trauma symptom severity. So we would probably want to help these folks with both of these problems. And the history here has not been awesome. We have a long history in both mental health and substance use treatment of turfing people to the other side. So in a substance use settings, in a mental health treatment settings, people who are using substances actively are often told to go away and come back when they have figured this part out. Either told to go to self-help groups and come back or told to go to substance abuse treatment centers and then they can come back when that's done, but we're not going to treat you because you're unstable. People showing up in substance use programs don't often get their trauma, PTSD diagnosed. If they do get it diagnosed, they're usually not treated for it because there's a long-standing idea in the substance abuse world that if you treat PTSD, you're going to unhinge people and they're going to be relapsing to their substance use problems. And in the self-help world, there's a lot of ideas about this, mostly around the idea of like don't do anything for a year or just worry about your substance use and your substance use will explain everything if you can get your substance use under control, which is a demonstrably not true idea. And that's Pandora's box. I'm supposed to say that, right? Just in case you didn't know it. The idea of you don't want to open that box up in terms of trauma. The other setting is that in treatment, in research, randomized controlled trials for either disorder usually rule out the participants with the other disorder as the typical exclusion criteria relevant to this discussion today. And that's also included the MAPS trials. For those of you familiar with MAPS and a lot of the psychedelic trials and the MDMA trials for PTSD have excluded people with substance use issues. So we don't know about that treatment for substance users because those people have not been in the trials. So patients with substance use disorder mostly do not receive effective treatment for PTSD. I'm going to turn this over to Carrie. Hi. So like Jeff said, thanks for letting us join you. And I'm going to talk about some of the evidence-based treatments that are available that, again, we're typically not using enough. And the treatments kind of fall into two buckets. The first one is our protocols that are really focused on stabilizing coping skills. These teach clients skills to manage their PTSD symptoms essentially. They're not really going after the traumatic memories or doing any exposure work around that. And then the other column is the more exposure process-focused treatments that are really going after that trauma memory. They're going after the faulty cognitions that come along with PTSD and the psychosomatic experiences. And these are the evidence-based treatments that fall into those categories. So a lot of you know about DBT. So that's a lot of it's not necessarily used as a PTSD treatment, but it stabilizes a lot of the symptoms that people with PTSD often have. Those of you who don't know about EMDR, EMDR has a component to it that is called resourcing, which is really about trying to help clients develop like an internal sense of safety and a safe place, ways to ground themselves. And then you've got the process-focused treatments, which is prolonged exposure, EMDR, and cognitive processing therapy. And I will say that EDNAFOA joined up with the DBT folks and combined DBT with PE to see if they could be more helpful to the people who have suicidal, self-injurious behaviors. And it was helpful for those people. You can combine those things. But the integrated models that we have for PTSD and substance use disorders are Seeking Safety, which is a stabilized coping protocol, and COPE, which I'm going to tell you about. And as I'm talking about exposure work, and just for my own education, how many of you do direct behavioral exposure work? Is that something that you guys are trained in, do a lot of? Anybody? Okay, good. We'll talk about it then. One person back there. Okay. All right. Good. All right. So while I'm talking about exposure work, I'll just be thinking about what Steve will be talking about when we add MDMA, potentially, to exposure. So I skipped over Seeking Safety. Sorry. So Seeking Safety is a pretty straightforward cognitive behavioral strategy that, again, teaches clients skills to manage their PTSD symptoms. And it teaches them about the interrelationship between PTSD and substance use. It really helps them kind of realize, like, oh, when I self-medicate these symptoms, the symptoms actually get worse. I can get re-traumatized. It teaches them a lot of grounding skills, a lot of ways to soothe themselves. But you don't have to necessarily meet criteria for PTSD to participate in this because you'll get value from it. And there is no exposure component to Seeking Safety. So we're not really going after the fear that is part of PTSD. So then we have the most well-researched combined treatment, which is COPE. And I don't know if Dr. Brady is in the room, but she is here at the conference. And she was one of the people that spearheaded this work. And there's a lot of superstars on the cover of that book, people that have been really doing exposure-based work for decades, and decided how can we try to help people with substance use disorders. So COPE includes all of prolonged exposure, and then they added relapse prevention for substance use is what they did here. And I'm going to talk about prolonged exposure in more detail. But, again, they're talking about, like, how PTSD and substance use go together. And just to be aware of those things and techniques, they've added the CBT for substance use. So this slide is in the wrong place, and these slides are set in stone once you give them to AAAP, so I couldn't move it. So I'm going to skip this. And we're going to talk about fear structures. And so it sounds like a lot of people are not trained in exposure-based theories, so I thought I would talk about the emotional processing theory that is behind exposure-based theories like prolonged exposure. It really came around, like, Peter Lang, I think it was in 1979, had this idea that, had this theory that we have memory structures that underline our emotions, underlie our emotions. And these memory structures contain information about the stimulus that activates the emotion. They contain information about the verbal, physiological, and behavioral responses activated by that emotion, and then the meaning that we assign to it. So the meaning that we assign to the stimulus, the meaning that we assign to our reaction. So in this theory, the fear structure is represented as a memory, and it's our memory and our blueprint for escaping danger, right? And we need these to get away from things that are dangerous. And for the most part, they can be really helpful, right? So if I'm walking along a trail and I see a rattlesnake, Dr. Rotnick, if I see a rattlesnake, I'm going to have a physiological response and I'm going to jump away from that rattlesnake because I know it's dangerous, right? So for the most part, those are helpful things to have around. The problem with people who develop PTSD is that they seem to have, these memory structures seem to start to include a lot of erroneous information. And this is where FOA and COSAC, 1986, wrote a great paper, which if you haven't read and want to understand the ideas behind exposure work, it's called Emotional Processing of Fear, Exposure to Corrective Information. It's a great paper. And they started to talk about how these fear structures seem to have excessive responses. So there's an excessive response to the fearful stimuli. There's erroneous meaning assigned to it. And essentially, these people's nervous system is on high alert, even when there's no danger. Their system is vigilant, looking for danger and misassigning where danger is. And how avoidance is the crux of the problem. Avoidance is what maintains this fear structure and makes it rigid and increasingly rigid over time. So I thought I'd walk through how this theory kind of plays out just with all of us in this room because we all have fear structures, but what happens for our fear structures is what kind of determines who's going to get PTSD and who's not. So let's just imagine that through that back door, so we all know lions are really scary, they're frightening, and they're dangerous. They'll eat you, right? So let's pretend a very scary, hungry, angry lion comes charging in that back door. We're all going to have a reaction to that lion. We're going to run, we're going to freeze, we're going to run, fight, we're going to fight. Some of us are going to hide under the chairs, right? We're also all going to have physiological responses to that in our bodies. Every single one of us, our bodies are going to react. Some of us, our hearts are going to pound, we might get trembly, we might faint. And then, after the fact, our very smart minds are going to create a narrative that explains what's happening to us, and we're all going to have different reactions to that. So I might have run out of the room, and I think, thank God I was strong enough to run out of the room and get away from that lion. The person next to me, who also ran, might think, I'm such a coward. People were hurt because I was not brave enough to stay in the room with the lion. So then we're going to assign meaning to that physiological response. So my body, several hours after, might still be shaking and I might have a hard time sleeping, but I go home and I talk to my husband, I'm like, wow, that was really scary, there was a lion. Thank God I got away. And I talk to my friends and I talk at work, and over time, over the course of that week, I'm not having a physiological response anymore. My body's not trembling and I'm back to sleeping normally. But if I were the other person who thought I was a coward, my body might shake, I might not sleep very well, and then I'm thinking I'm a coward. So I don't want to tell anybody about what happened. I shut down and I try not to think about it. And I start avoiding all of you, because you guys all want to talk about it. I don't want to believe I failed, and I want to make sure that's never going to happen again. So I start to avoid conferences, I avoid crowded rooms where I can't protect people. I don't go to the zoo, because now I can't even stand to look at a lion, because my heart starts to race. Lions on TV, I start to feel panicky, I have to get away from it. And my world gets smaller and smaller. And I'm on my way to having PTSD. And so you can see, like, the details encountered in life after trauma, and how you respond to those details sends you down a different pathway. And how one thing, so a lion on TV, can activate my whole nervous system, even though the lion on TV is not scary at all. Not dangerous at all. It might be scary, but it's not dangerous. So not all fear structures are bad. The reference here for driving will make sense when I do the next slide. Sorry, these got a little bit out of order. But if you just stick with the example I just gave you, here on the left, you know, lions charging into a conference room, bad, dangerous, worth getting away from, right? Lions on a TV, behind the cage in a zoo, shouldn't be so dangerous. But if I'm falling into this right-hand column, I think they're dangerous. So this is an example of a person that we actually did work with. She was a young mother who had, she was driving to work with her husband. She had her two small, under five children in the back of the car, and they were rushing, and they were kind of squabbling on their way to work, and they were driving over a bridge. And her tire blew out, and it threw her into oncoming traffic. And one of the children in the back of the car died. So when she came into treatment, all of these things were happening for her. She had stopped driving. She wouldn't, for sure, wouldn't drive over a bridge. She had really pushed away and had numbed out from her partner. Bruce Springsteen had been on the radio when that accident happened. So if she was in a bar, if she was in a restaurant, and Bruce Springsteen came on, she had to leave. She couldn't stay in the room. She couldn't tolerate any smells that she associated with the accident. Her husband had taken a shower and had put on his cologne before the accident. She would literally become physically ill when she smelled it. And the most painful part of this was that she had really shut down from her remaining child because she had become convinced that she was a terrible parent. She had caused the accident. I'm a terrible parent, and I should protect my child by staying away from her. So one of the things that we're, you know, because not everybody gets PTSD, right? Everybody in this room, there's lots of people who have probably had trauma, and I bet you don't all have PTSD. So, you know, FOA and COSAC were like, what's going on with these people who go on to develop PTSD? And so one of the things that we talk about is natural recovery. So if our client, who had been in this accident, had gone on to be like, oof, okay, driving is really scary, but I'm going to get in my car. I'm going to drive. Maybe I have to drive with somebody to start, but I'm eventually going to start driving. Had she heard Bruce Springsteen on the radio, and she thought, I'm going to cry, and she let herself cry, and she had that affect, and she went on. And had she let herself soothe her daughter, who was crying, so that she could realize, like, oh, I can actually take care of my remaining child, she would have been more likely to have gone on to a natural recovery from that traumatic event. So these daily reminders, by engaging with them repeatedly, you start to rejigger that fear structure, and new learning happens, and you're able to discriminate between what is dangerous and what is not. So then what happens with these folks who go on to develop PTSD from the exposure-based idea? We think that they haven't sufficiently processed the emotions that go on with that feared event. So, again, going back to this client, she was avoiding all daily activities. She refused to drive, refused to listen to Bruce, and she started to drink to numb herself. Any reminder of the trauma really activated her. She started to have panic attacks, and so she just started avoiding more and more things, which made her feel more and more incompetent over time. So by the end of it, she really believed that she was this incompetent parent. I will say with this clinical example, just for some of you who might be thinking about it, she also had an enormous amount of unprocessed grief, so we had to deal with the fear that she experienced, and then we also had to deal with the grief that was very unresolved. So what prolonged exposure is trying to do is trying to mimic the natural recovery process, and it does this a couple of different ways. We are going back to that memory, and we are helping them. I'm going to talk to you about how we do that, but we go back and we take that memory, and we're trying to really put them in contact with it, to really emotionally engage with that memory. And over time, what you see it does is it really helps them have the shift into having a more realistic understanding of that event. We then use in vivo exposures, so those are all those daily reminders of trauma. We're putting them in direct contact with all those things that they're avoiding, so that over time they can start to realize, oh, this is not actually dangerous. Oh, that was dangerous. It's not dangerous. And over time, you'll see these cognitions, so those cognitions at the bottom, almost 201 people with PTSD end up having some version of those cognitions about themselves, and prolonged exposure really starts to shift that. So again, we're looking for full activation of that memory network. We want to activate it so that we can induce new learning through the process of habituation. So this woman thankfully learned that Bruce Springsteen is not dangerous, and she could smell her husband's cologne, and she can drive. And this was her kind of cognition that she ended up with after the end of treatment. She was like, I'm a parent who was in a terrible accident, and I lost my child, but I love my child and can be with my remaining child because they still need me. So who's appropriate? Prolonged exposure is not for PTSD lite. It's for people who are diagnosed with PTSD, and they can meet criteria A for any one of these, and they need to have a memory that we can work with. It can be a fragmented memory, which is not uncommon for people with early childhood trauma, sexual trauma, like horrific car accidents. People don't remember every little piece of it, and that's okay, but they need to be able to have a memory that they can emotionally engage with and have some physical sensations with. Who should not do PE? These are the rule-outs for that, but again, the combination of PE and DBT actually really helped the people with suicidality and self-injurious behavior. So you can sprinkle in a little bit of DBT and possibly include those folks. So what happens when we are doing PE? So the early phase of this is where we're really trying to build a relationship with these people. These are traumatized people. They haven't talked about this. They sometimes have literally never told anybody in their life what has happened to them, and I just had this experience. I had somebody who was in treatment with us, and she'd been to five rehabs, and she had never once talked about this trauma memory. So they can be pretty shut down, and this idea of establishing a relationship and establishing trust, I want you to also think when Steve is talking about the potential impact of MDMA because this is a hard part of establishing, getting going with somebody with PE. It's doable, and it's actually always kind of shocking to me how much patients actually want to do this because when you think about what this treatment does and you think about what they're doing, it can sound incredibly difficult and scary, but they're, like, desperate to not have PTSD, and, like, almost to a one, they'll be like, I know I need this. I know I need to do this work. So it's kind of shocking to me how easy it is to talk people into doing this treatment. So we spend a lot of time, psychoeducation, common symptoms of trauma, and we're really highlighting how avoidance is controlling or has controlled their life. And, again, it's just very validating for people. People have often been living with PTSD their whole lives, and they just didn't even know what it was. It's just normal for them. So when you can kind of really be like, yeah, this is because of that, and it doesn't have to be that way, it's pretty powerful. We give them the rationale for leaning in and exposing themselves to all the things that they're avoiding so that this new learning can take place. And, like I said, people are often like, yeah, yeah, I know I need to do this. And then we identify the index trauma. So unlike some of the other trauma treatments, like EMDR, that can kind of move around and target different things, PE goes right for the most distressing memory you're willing to tolerate. I'll often say to people, like, if you're going with the second most distressing and you haven't told me about the first one, you might want to tell me about it because it's going to come up anyway, and I want to be able to help you with it. We can start with two if that's what you want to do, but it'll come up. So we usually try to talk to them about doing the most intense. Some people have a very clear index trauma. Something has happened at a point in their life, and they had their functioning pre-trauma and their functioning after trauma, and that's a very clear event. Other people have these fragmented chronic early traumas, and that's a little trickier. I am running out of time. Okay. So I'm not going to tell you my story. I'll skip that. The in vivos, we come up with these in-your-life things to go do that previously made you scared. So both for the imaginal and for the in vivo, we are sending them out with the idea of assessing your SUDs, which is subjective units of distress. We rate them from 0 to 100, 50 being this is really scary and makes me really uncomfortable, but I can do it. 100 is I'm having a freaking panic attack and cannot do that, and we're working our way up gradually. You want to start in the 50s so that they can actually have some success because you don't want to reinforce the idea that they can't do it or that they get overwhelmed. So they're going, and they're going out in the world, and they're doing these in vivos, and they're listening to their imaginal. So in their imaginal, we're having them recount their memory in real time as if it's happening to them in the present tense. And as a therapist, it's a pretty non-directive. We're not doing interpretations. We're not making links. I'm typically just saying, tell me what you see. Tell me what you smell. Tell me what you feel. I'm just trying to get them to engage with that memory. And they listen to that recording in between sessions, and they're listening to themselves tell this trauma narrative, and they're rating their anxiety pre, post, and peak, and they're keeping track of it all the way through. And it's pretty, when I talk about prolonged exposure, I often say it feels like magic to me a little bit because it's stunning how much the impact, listening to their own narrative, listening to their own voice tell their story in between these sessions sends them back with more compassion and understanding for themselves. There's something really interesting about that in and of itself. But you want to see them, like, peak up. We want to really engage that. So the first time they do these in vivos and do these in imaginals, they might be at a 90, 95 and think, if I do this, if I listen to this, I'm going to vomit. It's, like, horrible. You want them up at that level, and they drop for, like, 30 minutes, and they drop down. So that might be their first experience. But after they've done it four, five, six times, they're at a 70. Then they get at a 60. It's shorter. It's less impactful. And they start to realize, oh, I can actually do this. This memory is not dangerous. This memory is something I can talk about. This memory is something I can hear. I don't have to be afraid of it. And the same with the in vivos. And so we're looking for making sure they're staying in the exposures long enough that new learning can happen. And we want to see those suds come down. And the late phases are just looking for this consolidation. And the late phase is super fun, actually, because you've established a really nice relationship with this person. They've done really hard, good work. And they just feel so proud of themselves. There's so much competence. There's so much mastery over their anxiety, and it's pretty great to be able to participate in that. You actually start to see them experience more joy. A lot of people with PTSD have very joyless lives. And after they shed some of this anxiety, they're just really able to start to experience that. So this is just a quick slide of the research, which is, you know, it's a gold standard treatment for PTSD. It's been around for a long time. Most people who complete PE have a reduction in symptoms. The problem with PE is there's a high dropout rate. So it is a difficult treatment to get people to do. We do it in our inpatient. The whole system is designed to support them so we can get them through it. Outpatients, it's harder. We have a higher dropout rate, as you would expect. But the average patient in PE fared better than 86% of those in the controlled conditions. And, you know, in the meta-analysis, two-thirds of people who complete no longer meet criteria. So the effects are pretty profound. But, again, it's just a tough treatment. And so that's where the potential benefits of MDMA might come in. All right. I don't think I've ever heard any portion of PE described as kind of fun. But it's kind of difficult. It is difficult treatment. It's really one of the problems. And it's difficult for therapists even. For clinicians who are interested in this kind of approach, it's not for everybody. We've had people get trained in PE, take their first case and say, I don't want to do this anymore because you're just face-to-face with exactly what the client is face-to-face with, which is something I don't want to think about. You said at the end it's fun. At the end you said it was fun. I don't think it's ever that much fun. But rewarding might be a better word. I'm going to skip over ednafoa. Thank God she's not here. She would be mad. And just to describe why this, in our experience now in terms of people we have trained in prolonged exposure, why this is something that they are willing and excited about doing, just to look at in that inpatient sample I talked about before, 665 people with a 40% prevalence rate of PTSD, a sample of 42 of those people entered into PTSD, into prolonged exposure therapy in the context of a residential center, and did an average of 14 sessions. This is a non-combat sample in terms of PTSD, average age of 34 years, and mostly alcohol-related, but again, as with our larger sample, stimulants, opiates, cannabinoid use disorder, so lots of different things, and alcohol is almost always a feature of this, as you can see from this. In this group, there is the criterion A is about 43% I think this is sexual violence, and the rest is divided into threatened death or serious injury. And many people had multiple traumas, so there's a long-standing fight in the field about complex PTSD versus non-complex PTSD, which we're not going to talk about. Again, in terms of criterion A, many of these people had childhood and adult trauma, but when you make somebody choose, because you have to choose one for your criterion A, this group was divided evenly between before age 18 and after age 18. And here's what happens, and this is why the therapists are willing to do this. People come in on the trauma measures, PSSI, which is the clinical interview, diagnostic interview, or the CAHPS is often used for PTSD. Those scores go from severe PTSD to just sub-threshold PTSD on average. The PCL, which is the self-report, goes from severe PTSD to below threshold. Depression scores decrease by 60%. Post-traumatic cognitions, which is the PTCI scale, which is concerns about self, concerns about the world, safety, self-hatred, self-blame, those scores drop by 40%, and across the board you have reductions in scores in terms of all kinds of psychiatric measures. Interestingly, the positive affect scale, this is just an interesting thing, and this is part of why we're so interested in MDMA as an approach as well. Does it offer something else in terms of increasing positive affect or increasing an engagement with life as opposed to the removal of trauma symptoms? These are just interesting process questions about different modalities now as we start to enter into new ones. So those are some of the outcomes. As Kerry mentioned, the during treatment part of this is hard for people. They say stuff like, I know I need this, but it makes me sick to do my homework. I'm not sure I can get through it. It's too overwhelming. After treatment, they are really in an incredibly different place, and the removal of significant PTSD symptoms is pretty life-altering for people. Before we hand this to Steve to talk about MDMA-assisted therapy, part of the take-home for us is we have treatments that work. In substance users, we have treatments that work for PTSD, and we should be using them. MDMA may be God's gift to PTSD. It really may be an incredible treatment, and we have treatments that currently work, and we're not using them. With that, I will hand it over to Dr. Ross. It's a real pleasure to be here at AAAP. This is my first meeting in about a decade. I used to come to AAAP for the first 12 years of my career and consider this a real home, and being back here after all this time has been really great, and I'm looking forward to talking about this topic today. You can see from this slide here we have a split screen, and I think addiction psychiatrists are going to be in the middle of this because on the one hand you have MDMA, which is a club drug, which has real addictive liability, which has real harm associated with its use, especially in these subcultures, including death. Then on the other hand, you have this rapidly approaching thing in psychiatry that I think will profoundly change psychiatry, and that is you have MDMA-assisted psychotherapy getting very close to being a prescribable medication. That may happen in the next year or so, and I'm going to get into that. I think addiction psychiatrists and addiction practitioners are going to be in the middle to be able to evaluate the relative risks and benefits of using this drug in this way. I know as an addiction psychiatrist in my training, I viewed MDMA as something that was harmful, and it was only later in my career did I come to see that there had been this other very interesting history to it. The history is fascinating. Merck Pharmaceuticals makes MDMA and patents it in the early 1900s. They actually market it as an appetite suppressant for a period of time, and it doesn't really catch on. The U.S. government tries to use it as part of mind control. This was preceding the MKUltra project that the CIA ran where they used LSD, but before that they tried MDMA as a kind of truth serum. It didn't work out there as well. Then the drug sort of fell into not being used at all until Sasha Shulgin, my pointer here, so Sasha Shulgin is a really interesting guy. He's a chemist trained at Berkeley. He works at Dow Pharmaceuticals. In the late 70s, he becomes interested in synthesizing mescaline, and he sort of leaves Dow and becomes kind of like a pioneering psychopharmacologist in psychedelics and starts making a bunch of different compounds and starts testing them with him and his wife and a bunch of other people. He makes MDMA, resynthesizes it. They use it and they think, oh, this drug doesn't have much utility, but a couple of years later he shares it with one of his psychologist friends, this guy Leo Zeff, and Leo Zeff starts to use it in the Bay Area, and it starts this period of time really from like the early 70s until 1985 that MDMA is used in the Bay Area by psychotherapists. It finds a way. There's a lot of anecdotes that it treats PTSD. It's used in couples therapy. It's used for spiritual purposes, but eventually in the early 80s the club scene develops in Ibiza. It comes to the United States, and MDMA escapes from this therapeutic context and starts being used recreationally. In fact, over this period of time, there was half a million doses of MDMA that were used recreationally, and we started to see the real harms of this drug. An analogy would be what happened in the 60s with psychedelics. If they were used medicinally, they escaped the lab, and you started to see all of these harms associated with it. In 1985, Lloyd Benson was a senator of Texas. He became very alarmed by this, and overnight he got the DEA to make MDMA a Schedule I drug, and it effectively put it into this banned status until this interesting guy came along, Rick Doblin, who really, when MDMA was made illegal, he decided he was going to make it his life's work to study MDMA. So he starts MAPS, the Multidisciplinary Association for Psychedelic Studies, and since then MAPS has been conducting clinical trials in this area, and I'm going to get into some of that data. So we've heard a lot about why to study MDMA, and we heard about the prevalence of MDMA, of PTSD. PTSD occurs in about 6% of the population. It occurs more in men versus women, and there's a lot of morbidity and mortality associated with it, and it's effectively a memory disorder. We heard that the amygdala is sort of like the key central pathophysiologic structure, but there's also hyperactivity of the amygdala in response to neutral stimuli. There's decreased activity in the prefrontal cortex. This is really a big unmet need in medicine. The pharmacotherapies we have, we have Zoloft and Paxil. They work in only about half of people, and we have no other medications that work for PTSD. The gold standard of the psychotherapies, like exposure therapy, like CBT, but they're hard to utilize. It's very hard to get people to engage in prolonged exposure. There's high dropout rates. So there really is a big unmet need to develop novel pharmacotherapeutic and psychotherapeutic interventions, and really what this is, this is MDMA-assisted psychotherapy, and the psychotherapeutic container here is very important. So Sasha Shulgin had this interesting quote, and you can see here the therapists in the Bay Area, they started to notice that people that had PTSD under the influence of the drug, and this was a completely different kind of model. Rather than a 45-minute session, they had eight-hour sessions. They tended to be conducted by a diet therapy team, and what they did is they instructed patients to go into the difficult experience under the influence of MDMA, and they really thought that by confronting the fear head-on that it might lead to changes. MDMA has a very interesting pharmacology to it. It's kind of like a hard drug to classify. It's definitely an amphetamine. It's in the amphetamine class. You know, it's methylandioxy methamphetamine. So it causes presynaptic release of dopamine, just like methamphetamine does. That confers its addictive liability and other toxicity. But in addition, it's a very serotonergic drug. It causes presynaptic release of serotonin. It blocks the reuptake inhibitor, the SIRT. So you get this sort of like big increase of serotonin and dopamine. It, to a degree, activates the serotonin 2A receptor, so it has psychedelic-like effects like psilocybin. But in addition, it has these neurohormonal effects. It affects oxytocin signaling, and that seems to be really important because oxytocin is a chemical of bonding. And what happens during these sessions is people feel so MDMA has anxiolytic properties. It deactivates the amygdala. People are alert during it. They have a sense of being bonded to their therapist. And under the influence of that is really where the therapeutic effects are leveraged. If you look at the animal data, this lines up really well. Animal data shows that MDMA enhances fear memory extinction, and it also modulates fear memory reconsolidation. And it also appears that MDMA opens up the critical period of social learning that's mediated by oxytocin. And there's a sense that what it's doing is allowing for new memory. And if you think of PTSD as a memory disorder, one of the leading hypotheses is that this form of prolonged exposure, if you will, medication-assisted prolonged exposure, potentially changes the architecture of these fearful substrates. So the Mithoffers are a pair in South Carolina. Michael Mithoffer was an ER doctor. Then he became a psychiatrist. And he developed this in conjunction with his wife, Annie Mithoffer, really amazing people. And they drew on Stan Groff a lot. Stan Groff is probably the most famous psychiatrist no one's ever heard of. He was a pioneer in psychedelic research. He pioneered LSD-assisted psychotherapy. But when the Controlled Substance Act, his career was over. So he established a thing called holotropic breathwork. By breathing really fast, you could get into these altered states. And he really thought this was a new model in psychiatry, the psychedelic model. High-dose psychedelic would create a sort of like powerfully transformative quantum experience that led to change. And so the Mithoffers drew on this model. And really what happens is under this unique pharmacology, people's defenses are lowered. They're able to go into things that are fearful. They're in a less anxious state. They're bonded to their therapist. They're sort of neurochemically sort of optimized to go into the difficult trauma. And this is a very different model. So you have two therapists delivering the intervention for one participant. There's a lot of preparation that goes into it psychotherapeutically. So you get to know the person's trauma and index trauma in great detail. You go through all of the PTSD symptoms. You then contextualize that in a life review, how the PTSD has affected their life. You then prepare them for the dosing sessions, which take place. We use our Clinical Translational Science Institute at Bellevue to administer it. We have the participants state their intention. And in a way, this is a directed treatment. Unlike when we give people psilocybin and we don't direct at all, here we say to them that the whole goal is for you to go into the traumatic memory. And either there's an agreement that they will bring it up themselves or we will bring it up with them. So you have eight hours with somebody toggling back and forth. You give them a drug. One default is to have them lie down. You give them preselected music, eye shades. They focus internally. And they go between that state and getting out of it and wanting to talk. It becomes a very long psychotherapy session. Sometimes people talk for eight hours straight, which is really quite something. But it's really interesting to see what happens during these sessions. So definitely there's some prolonged exposure here. I don't think MAPS would say this is prolonged exposure, but that's really, in my mind, what it is. You're asking the person to go back into the index trauma. There is a fair amount of restructuring that you want to do afterwards because there's integration psychotherapy afterwards. There can be intense psychodynamic insights. You have two therapists and one patient, so you have really interesting transfers and countertransference. In this model, they introduce touch as part of it. In this holotropic breath work, touch is used to help with catharsis. But you have to be very careful here. There was actually a case in Canada. It's amazing that this can happen. Two Canadian MAPS therapists who were doing this research treated a woman that had sexual trauma and PTSD. And the male therapist ended up having an affair with the participant and re-traumatized her. Really sort of horrible. So you have people that are in very, very vulnerable states during this. So you have to be very careful with touch and boundaries. So in terms of toxicity, MDMA definitely has real toxicity. It has addictive liability associated with it. It has medical toxicity. Although the main toxicity here is really methamphetamine. Methamphetamine, then cocaine, causes the majority of sort of the medical toxicity that you see with stimulants in terms of cardiovascular stuff and neurologic stuff and death. But with MDMA, the rates of it are much less. But they definitely happen. And psychologically, dopaminergic stimulants can worsen mania, can worsen psychosis. Chronic use of it, you can get withdrawal phenomena and depression. So there definitely is a significant adverse effect profile associated with MDMA, especially when used over long periods of time. And there's this whole thing that they're neurotoxic. This was a sort of big deal early in MDMA research. But this looks to be that it's probably real. If you look at animal studies, this is chronic heavy MDMA administration. There's reductions in serotonin, the serotonin metabolite, the reuptake blockade, and cortex hippocampus and striatum. And the interpretations have been different. Either this is neurotoxicity or that these are just neuroadaptations to chronic use. But when people, humans, take MDMA over a long period of time, they're real. From a neuroimaging perspective, there appears to be alterations to the serotonergic system. And there seems to be cognitive impairment in heavy long-term users. But the studies really cannot point to MDMA having done that. There's polydrug use. There may be other factors. But long-term heavy use of MDMA is certainly concerning from a cognitive impairment perspective. And it's a drug that is addictive. But it's pretty rare to have MDMA use disorder dependence. Only 3% of people ever do develop it. And it's probably the serotonergic effects dampen the dopaminergic rate of rise. And so these can be used in a compulsive, ongoing way. But it is relatively rare. Now let's get into the research here. The research really has exploded in the last couple years that in 2016, MAPS published some phase II data and then went on to phase III. And the phase II data was about six studies. In the end, they were able to combine it into 105 people who were in treated and the intention to treat analysis. And this is the model here. There's a lot of preparation with the diet team. There's a dose of MDMA. You have integration. Three sessions afterwards, you have another dose. These are a month apart. In this study, it was two dosing of MDMA versus placebo. And there was a crossover here. The group that got placebo ended up getting open-label MDMA. And the data was really interesting. This is CAHPS. And you can see, like, the mean here is in the 80s. This is really severe PTSD. And you can see in the MDMA group, there's this reduction after two doses. There's a big difference between these two groups that's statistically significant with the large Cohen's. And you can see the open-label group, when they get a single dose MDMA, their CAHPS score comes down and isometrically approaches the other group. And if you ask one of the CAHPS questions, you can, the CAHPS both gives you a severity score, the CAHPS-5, and a diagnosis. And all those that were treated in 90 with MDMA, two out of three no longer met criteria for PTSD. So this data was really interesting and promising. And in terms of adverse events, really safe when used in the setting, two to three doses, really no significant SAEs attributable to the MDMA, which is really important to optimize safety with this drug. So phase two established safety, large effect size in terms of the primary outcome. The FDA granted MAPS breakthrough status in 2017. And MAPS has now done two phase three studies. The first one is completed. The second one was just completed. We were one of the sites at NYU. And it continued to be severe PTSD. The CAHPS was greater than or equal to 35, not 50. And the model here was three doses of MDMA versus a saline control, all in conjunction with psychotherapy. The primary outcome was at 18 weeks post-baseline. And there were varying doses of MDMA depending. You start low and go slow is sort of like the model here. And what they were able to find, they treated 90 individuals. The safety data was very good. There were no SAEs attributable to MDMA. There was nothing around suicidality or cognitive impairment or addiction. And what was really interesting here is this was very significant. The between group primary outcome is here. The Cohen's D was about .9. So pretty large separation. You can see the separation gets bigger between one dose, second, and third. That there's really this additive effect of MDMA plus the psychotherapy. But you can also see, this is interesting, that there's significant reductions in the control group as well. And we can think about why that may have been. And we can look at it here. So this looks at response rate. Response rate means you had greater than or equal to 10% drop in CAHPS. This bar here means that you no longer meet criteria for it on the CAHPS score. And this means you're in sustained remission. So you can see about 80% of the people respond to this intervention experimental group. And there's about 50 here. So that's like pretty substantial. But there is a difference here that's significant. You can see here about 33% of people are in full remission at the primary endpoint here versus about like 5%. So I think what's happening here is these individuals got three sessions of prolonged exposure. So they really had like a robust psychotherapeutic intervention. But the MDMA on top of that has significantly improved the outcomes. And this has sort of set the stage for the next phase three study that has just been completed. The data is being analyzed. And if that study shows what this study showed, then we're at an interesting historic moment where the FDA may consider rescheduling MDMA to be a prescribable medication for PTSD. And, you know, there's probably going to be a REMS program associated with that where they're going to mandate that there's certain psychotherapy. Because this is not something where you want people in the lay public to think they can go do it by themselves and they're going to get better. This is really much different. It's a really targeted psychotherapeutic intervention. Lastly, there was a study looking at the use of MDMA-assisted psychotherapy to treat AUD by itself. This was open label, 14 individuals, two MDMA sessions. They took people who were post-detox. And what they found here is that there were sort of sustained reductions in drinking compared to this. So there's, I mean, this is a very small pilot study. But it's interesting to think that this model could be applied to primary substance use disorders. And I've been a therapist as part of this research for a couple of years. It's very interesting taking people who are very sick, who have severe trauma. I can't even talk about it in screening. And under the influence of the drug are able to go directly into the trauma. And it's been pretty interesting to see the transformations that happen pretty quickly and then over time with people. And, you know, you always feel, it always feels good as a clinician to be able to treat somebody that gets better so rapidly. And so this has set the stage for this really interesting discussion that we had. And I've known Jeff and Carrie forever. And the idea of, CMC has a wonderful inpatient residential program in the Berkshires. I think many of you have sent patients there. So we started having this conversation. What would it be like to put this intervention into a residential dual diagnosis program? And at first it just seemed crazy. You're going to take people who are newly sober that have PTSD and you're going to give them MDMA. You're going to expose them to a drug of abuse. That just seems. But we were all beyond that kind of thinking. And the idea started to gel a little bit more. Could you use this in a very targeted way to get at the underlying PTSD after you've established abstinence? And could that change the trajectory of their substance abuse? So with that, I'm going to hand it back over to you now. So we spent about a year then trying to set up this trial. We put it on hold at the moment pending FDA approval. And hopefully when that happens, we will get to begin this trial, which would be just an open label trial with 15 people. And again, it's going to be such a small sample that what we won't get to do is ask really interesting questions like, does MDMA target substance use disorder independently of PTSD? The Ben Sessa study that Steve was looking at was showing you guys with 14 people in it, ended up with these wild reductions in alcohol use. And it was not a study of PTSD. And for some reason, their conclusion at the end was that the mechanism of action was that they were treating trauma because all people with alcohol use disorder must have trauma, which I thought was wholly unsupported by their data. But an interesting idea. But these are where these things start to get blurry and mechanisms of action are really hard to pull apart. So when we do this study with 15 people, we won't have any answers. So if we tell you we do, don't believe us. But we will be able to see whether it has an impact independently on substance use disorder and independently on their PTSD and do a follow up a year out. And this would be the trial, the 11 week residential stay. There's all kinds of other issues to talk about here about how do you have people stay inpatient for 11 weeks and all that kind of stuff. But that's the design. And we would screen people to make sure they qualified as having PTSD and substance use disorder prior to admission. They might need a medication washout because there's all kinds of, which I can let Steve comment on, all kinds of medication washout issues related to MDMA administration in all of the MAPS trials. And then upon entry, there would be a three week window in which we would be doing treatment as usual. So this is a version of an integrated trauma SUD treatment, which was the whole purpose of this whole discussion. Do we have integrated treatments? And this would be another variant of that. MDMA assisted psychotherapy for PTSD and treatment as usual for substance use disorder. Again, putting aside the question of does MDMA treatment have a direct impact on substance use disorder independent of PTSD is another question. But in this case, it would be an integration of two treatments, one for substance use, one for PTSD. And part of the hope would be that the PTSD treatment would be less gruesome and less challenging for people than prolonged exposure is. And again, when I was pointing out the prevalence rate in this inpatient setting, 40% of 660 patients is 260 people. 50 people go into treatment for PTSD. And it's time consuming, it's costly, and it's hard treatment. So if we start to have an alternative treatment for PTSD that is more attractive for people, that might really shift that balance. And the way it rolls out is like the MAPS trials that Steve was showing you. Weeks one through three, preparatory sessions for the MDMA sessions as well as treatment as usual for the substance issues. Week four, you have the first full day MDMA session. Then in weeks four through six, integration sessions plus continuing with the treatment as usual substance sessions. Week seven, second MDMA session. Week seven through nine, integration and treatment as usual. And week 10, the final MDMA full day eight-hour session followed by two more weeks of integration and treatment as usual sessions. And that's the design. The interesting psychological questions would be, these are some of the impacts of MDMA assisted therapy. Reducing defenses and fear of emotional injury, enhancing communication and introspection, increasing empathy and compassion, creating an openness to considering new information, ability to engage in a trusting manner. These are critical issues in PTSD therapies. These are the things that don't go so well often for people in PTSD therapies. They can't actually allow the relationship to develop. They can't actually trust what's going on. There isn't a development of self-compassion and it's just too painful to remain in there in the trauma process. But if you can start to have those perspective shifts and if MDMA could be part of that, you might be able to engage people in a much deeper way and for a much longer period of time. So that's our take home hypothesis idea. It's hypothesized that the use of MDMA assisted therapy as part of this kind of combined protocol will facilitate deeper and more persistent engagement in both the therapy process as well as the ongoing change process post-intervention, including the integration of new perspectives. So we'll see. But that's the idea. And we would love to open this up for questions and thoughts and comments. And there's a mic right there and have at it. So Ken Rosenberg from New York City. And this is really quite amazing. Could you be more explicit about how you would combine exposure work with MDMA? Like how would it work? Because if I understand correctly, that's not been the model so far. Is that correct? MAPS would say that's not. I'm just curious how an exposure and MDA experience would work. There we go. So MAPS would say that the psychotherapeutic platform is nonspecific. But in my mind, this very much is exposure therapy because you ask them ahead of time to identify the index trauma and you rehearse before that they're going to bring it up during the influence of the drug. And you query them. Has it come up? And if it doesn't come up, you direct them to go into it. So it's very much directed therapy exposure, imaginal exposure during the sessions. And again, the company doesn't say that. But to me, that's what's going on. And what we are going to do, because we don't actually want to be reinventing anything or inventing anything. So in this initial trial that we hope to do, we would be using the MAPS protocol and adhering pretty closely to it, which despite what Steve says, is meant to be relatively non-directive. So we're not considering ourselves to be doing prolonged exposure therapy sort of morphed into MDMA-assisted therapy. We're going to be doing MDMA-assisted therapy kind of as defined in the context of substance use treatment programming as well. Rich Francis. I heard about them using things like this in Israel with PTSD and finding good success with agents like this. My concern is, and I'm going to share it pretty directly, is having seen the commercialization that happened with OxyContin and now what's going on with marijuana, which we heard about at the meetings. And having seen how, whether it's pharmaceutical companies or rehab for-profit programs or outpatient rehab for-profit programs, and how many people who will not do it in the way that Steve is describing. And even when people read the stuff that's coming out of NYU on psilocybin for treatment of alcoholism, which has to be read critically and has potential but also has issues, that the people on the street are going to take this very, very differently, especially if it's FDA approved. That our membership will be divided. Some people will be very, very careful. I'd like to poll our membership on how they feel about commercialization of this. But some people will be very careful and will do it properly. And some people will do this in ways that will make a mockery of what psychiatry is, which may have happened to us already with OxyContin. I think, and I feel guilty about whatever happened during that era. I mean, and I was pretty good. That's a comment. I'm just wondering your reaction. I wonder what other people's reactions are about commercialization that could happen. Yeah, those are all really important points. And I think we have to educate the public that this is not like do it yourself. That there are real harms associated with this and this should only be done under careful supervision. Now, when you add commercialization in there and you add a for-profit motive and a company wants to get their drug out there, you can get into trouble, especially a company like Purdue Pharmaceuticals that, you know, that dupe people. Here, the company that's doing this, they're very much cloaking this as MDMA-assisted psychotherapy. And they use skilled psychotherapists and there's a lot of training. And I think if you do that, it's going to be on better footing. But then, you know, there was this example I told you about of this very unethical behavior. So yeah, I think people will not use it in the intended way. There'll be bad outcomes. There'll be sensational outcomes. And we'll have to continue to educate people about the harms and benefits and how to use it safely. But I share a lot of your concerns. And from the therapy side, I share your concerns as well. I attended the MAPS training and there's a lot of psychotherapists being trained in these psychedelic-assisted treatments. And I try not to be a judgmental therapist, but I definitely have the reaction of like, ugh, your boundaries are not quite solid enough to be doing this work. So I do think the cart is out of the barn, whatever the phrase is, a little bit. So some of this is going to be coming out. And I do think, I worry that some negative things will happen with therapists that are going to cause harm, for sure. And the benefits and the amount of people suffering from untreated PTSD is massive. So again, I think finding ways to use these novel treatments carefully and thoughtfully. I had a second part of the question. I used that prerogative to do that. I went too far. Anyway, my second part is you showed that the oxytocin may have been one of the mediating mechanisms. Rocky Murata has been using oxytocin for dual diagnosis of severe patients at Silver Hill and finding tremendous success with sublingual oxytocin. It's a very small study. I think you presented it at this meeting once. I wonder, could we try that and would it be less harmful? Yeah, you always want to try something that's going to work that has less harm. Number one, we don't know that this works yet, and that's why these efficacy studies have to be done. And if it does work, you have to design trials in a way to look at mechanisms. Nobody has done that either. Oxytocin is an interesting compound. It actually is a good compound when it's within your group. It increases in-group bonding, but it can also be a chemical that causes aggression when applied to the out-group. So oxytocin by itself is not always good. Depends how you use it. And yeah, intranasal oxytocin works as well, but I think what's happening here, I think the oxytocin allows the bonding and the fear to come down that they can then go very deep into an eight-hour exposure therapy. So I think that there's several mechanisms going on, but I think that's interesting to consider. Hi, I'm Peter. I'm a Sinai fellow. One of my questions I have about the MDMA data, which I'm quite excited about, is how can we make it scalable? Because it seems so resource intensive and I'd be curious to hear your thoughts on that. It's hard to scale an intervention that takes two therapists and takes an eight-hour session three times over a three-month period. I don't know how you pay for that. Now MAPS has started to think about the commercialization and payers are going to have to be ultimately the ones that pay for this. I think there's going to be a cost-effective argument that PTSD, the societal cost is enormous. An intervention, if two out of three people no longer have symptoms at 12 months and that goes longer, what are the benefits to society of that intervention? I think equity is key here. These treatments need to be available for everybody, not just the wealthy. I think MAPS is an example. They're an unusual commercial company. They really started as a non-profit and their hearts are in the right place wanting to do this correctly, but I don't know what will happen at the next stage. One final comment that I have actually for you, sir, is that I actually just did the MAPS training also in October and I was really impressed to hear that they had hired a patent attorney to make sure that none of these novel pathways or novel therapeutics could be patented and then commercialized, at least on a big pharma level. Who knows how it might still be commercialized, but hopefully not as bad as some others. Thanks. Hello, thank you for this talk. I'm Zola. I'm a fifth year resident in family medicine psychiatry at UC Davis in Sacramento. And an exposure trained person. Yes, I am. We were very lucky to have a psychologist who gave us a very extensive CBT curriculum for a number of different indications and then also supervision for our CBT for PTSD cases. And so I was very fortunate to have that resource in my educational environment. I'm also close to San Francisco. I also have done the MAPS MDMA for PTSD training. And this is definitely an area of interest. And so a couple of comments and then a question. The first comment is if anybody wants to read more about an adverse event that wasn't actually included in the study data because it was outside of the kind of study time. If they look at the Cover Story podcast through New York Magazine, it goes into this case with a husband and wife. Husband who actually didn't have any certification active at the time. And so there wasn't really a board to report him to, which was another thing. And then conflict of interest. There being a co-therapist and a couple, then it's, you know, this person doesn't want to report their own husband, which was, which are two things that were horrifying to me, especially since this is somebody that these are people that are very vulnerable. And, you know, we talk about bonding with the therapist. There are definitely people that can take advantage of that. And I wonder how outside of a REMS process, outside of going to this, you know, this training, which was great. But as I noticed as well, there were some comments from people that I would be very scared to put in a room with some very vulnerable people. And so I am so, I just don't want us to fumble the ball in like the last ten yards with this, if there is just, if it's maybe done just a little bit too quickly. Or at least there's not a very clear certification and supervision plan for this. I don't know necessarily if that is the case. Unfortunately, MDMA is a Schedule I substance, or having no medical benefit and not being able to be used safely by a practitioner. I know that the dual practitioner model, one being licensed and one not necessarily needing to have a license, has been more egalitarian. And it's allowing more people to be brought into this space. Not necessarily you have to have like an MD in order to do this, but someone has to be able to prescribe things and respond to abnormal vitals, etc. But, yeah, that was another comment. And the last bit, which was approached by my colleague who asked first, is the cost of this and the access to that. Because it's about 26 hours of therapy, not including the telephone check-ins that are happening in between a lot of these sessions. And, yeah, I'm wondering how we could possibly allow folks to access this and then what, if any, conversation you've seen around insurance and payment for an intervention like this, if you have been privy to any conversations like that. Just to be clear, that was like ten questions. No, no, no, it was like two comments and then the last one was a question. So those are all great comments and I think things could go off the rails and people can behave very unethically. I mean, I never understand how a therapist can have sex with their patients. But it happens. 6% of therapists involved in sexual activity with patients. I remember during my residency we heard the stories about certain psychoanalysts. So it happens in our field and it should never happen. When it happens here, when you're under the influence of a drug, it's particularly creepy. And problematic. In terms of equity, MAPS is really interested in that. They want to make this available in an equitable way. You know, going back to the justice principle from the Belmont Report. How do you make sure that a treatment is equitable? Our healthcare system is not very good at doing that, period, for all kinds of problems. So how do we do it here? MAPS has thought about it. They've hired... A lot of commercial development is somebody they just took from Pfizer. So they're thinking about how to do it correctly. They've engaged with insurance companies. They're thinking of having some scholarship program. They want to reach underserved people. They're making a big effort to do that. But we'll have to see. Because it's going to be very expensive, like you said. Yeah. Just on an hourly basis. Thank you. Thank you. Thank you. Hi. Karen Drexler. Medical director for AAAP. But also attending psychiatrist at the Emory Healthcare Veterans Program. Funded by the Wounded Warrior Project. Where we do prolonged exposure therapy for PTSD. And I help treat the co-occurring high-risk substance use and substance use disorders. And I just wanted to say thank you for the work that you do in that space. And my experience is we see a lot of joy. And we have a lot of joy in our work. For the reasons that you all articulated. That people get a lot better. So my questions, though, are more about the MDMA therapy. Could you speak to the blinding of the patients in the clinical trials that you talked about? Because I attended a NIDA workshop in February. Where I learned that at least for the substance use disorder space, that's a real challenge. So did you assess whether the patients knew which group they were assigned to? And how was the blinding? Yeah, so the blinding is pretty poor. In fact, they didn't really try to blind. The FDA was okay with the saline control. And there's huge expectancy effects that come with drugs like MDMA and psilocybin. And having an active placebo that can obscure the effects and not have therapeutic effects. Ketamine would be a great control. But if you're having an MDD trial, you may really mess up your primary outcome. The main thing that the FDA concerned about, as long as the primary outcome, and in this case it's clinician-administered caps, is done independently by a central rater. And as long as that is extremely blinded, FDA is okay with whatever your control is. From a scientific perspective, I don't like that. We've tried to blind with psilocybin. Niacin failed, diphenhydramine failed, low-dose psilocybin failed. I mean, they were all poor. So we need to come up with something that has better blinding integrity. Here, I mean, I guess you could give them an amphetamine. You know, just like Adderall is a control. I mean, there'd be much better controls than saline. And to improve, and they do, they look at blinding integrity. They ask both the participant and the investigators to rate it. But it's essentially functionally unblinded from that perspective. Right, and so, and my understanding too about this manualized therapy is there's a lot of preparation that sets expectations. So that folks who are on the active medicine, kind of their expectation is it's going to be like the best experience ever. And then if you don't have that, so it sort of, I think, exaggerates the difference between the groups. Because the people who are on the active medicine know they're on the active medicine and they have an enhanced expectation of benefit. And the people who aren't on the active medicine know they're not on the active medicine and they have an enhanced disappointment with their assignment. It's very hard doing placebo sessions here, but what we found is even with placebo sessions, I mean, you can see the data that people get. People are getting better. Spending eight hours with two caring people going into your trauma three times I think has a therapeutic valence to it when done in that way. Okay, and then, if I could, a second question is this issue about sexual abuse of patients is not trivial. And this one case that I really appreciate you pointing out is not isolated. So can you speak a little more to what risk mitigation you will do, at least in your facility and in your plans going forward, to both inform prospective patients and to mitigate this risk? Because it happened in the 80s, it happened in the 60s and 70s, and it was part of why MDMA ended up on Schedule 1. And I just fear, like Dr. Francis, that we could just be seeing this happen again. And we, you know, fool us once, shame on us. But the second time around, we really should be doing better to protect patients. Yep. I think you're preaching to this particular choir, who all live in fear of that exact thing. Especially in the context of the data seeming quite good about this being a very effective pharmacotherapy and psychotherapy combination for PTSD. So the idea that that would get shattered to smithereens by unethical behaviors, which, in I think all of our opinions, are more likely to happen in the context of this kind of therapy than other therapies, is terrifying. I'll speak to the very specific things that are usually part of the MAPS protocols and would certainly be part of ours. And by the way, we're waiting for FDA approval. We'll still then run this as a trial, not as, okay, we're just going to do this now. Mostly from our perspective under the heading of, we actually want this to be completely above board with an IRB review and everything else associated with it, to try to maintain some sense of, this is still work that's underway and still being investigated. Not like we've got the green light and we're all set to go and it's a free-for-all, which is some of the fear out in the world. The very specific things, I mean, that's part of the reason that there's two people in the room at all times. That's part of the reason there's a gender split. I think MAPS may have recently changed the gender requirement, but there still are two people in the room. Again, you're having all these difficult problems both directions, and then it's not cost-effective to have two therapists sitting for eight hours, all that kind of stuff. All these sessions are also videotaped and are theoretically reviewed. I don't know the details specifically of the Vancouver case, except for I had some reading on that, which said that those tapes were submitted to MAPS and they were never reviewed. Can I have a follow-up on that? Part of the challenge is that this vulnerability isn't just confined to the long eight-hour session. Right. So you have this bonding with the therapist. You create this relationship. Yeah, and so the abuse can happen the next day or the next week. Yeah. So what do you say specifically around... Cover story. Check it out. All of it. Yeah. So specifically, how do you talk with patients about informed consent about this? Yeah, I mean, the way we do this safely is we do it at an academic medical centre with all of the safeguards in place for good clinical trial research. So there's extensive risk mitigation strategies in the inclusion-exclusion criteria. And we only pick very skilled psychotherapists for this, that you have to be licensed. Our criteria are more stringent than what FDA requires. We feel that you need very skilled psychotherapists that have been treating PTSD a long time. You want to make sure they're stable, sort of screen for personality disorders, if you will, because in this field, you can have the wrong kind of people that are interested that have narcissistic pathology or other kinds of pathology. So you have to be very careful who your treatment providers are. We have to have extensive supervision and oversight by the PI. Our sessions happen at Bellevue Hospital, safest place on the planet to have any emergency. It's in our Clinical Translational Science Institute. There's all these safeguards that we have to deal with medical or psychiatric AEs. How you take that and put it into the community is concerning. And I think a really concerning example is what's happening with psilocybin medicinal legalization. This happened recently in Colorado. It happened in Oregon. And here, any lay provider can administer this intervention medicinally to whomever. And that really worries me. If you had something like this with that, you can imagine horrible things would happen. So I think we have to be careful. And I'll just say that that's – so I agree MAPS is a really interesting organization and have done a lot of things right. I'm worried they're training so many people that this idea of being able to supervise people when they actually start, they're not going to be able to do the amount of supervision for the people that they've trained. So I think that's a big gigantic hole in the bucket that is concerning. Thank you. And thank you for bearing with my questions and thank you for my fellow questionnaires – questioners. But I want to commend you and thank you for mentioning this issue of sexual abuse because I've been to other presentations where they don't talk about it. And so my question specifically – and this is sort of maybe for you all to think going forward – is when you talk about informed consent before you start with the patient, what do you tell them about this risk? What do you tell them? You're asking about the informed – the risk of if they get really bonded to a therapist and the therapist actually abuses them? Yes. Do you talk with patients about that? You know, MAPS should update their ICF to include that. I mean, it's like unthinkable to us at NYU to think of something like that. And so, yeah, it probably should be in the informed consent so that people know about it. It's an excellent point. Thank you. Yeah. All right, thank you. Real quickly, I was wondering if you could comment on the impact of psychedelic treatment on different criteria of PTSD symptoms. I'm convinced that it's helping the PTSD symptoms, but does it tend to help more of a re-experience or hyperarousal or avoidance symptoms? And does it depend on the different kinds of psychedelics? I'm asking this question because I have a patient who has complex PTSD from childhood, as well as a combat PTSD. And for him, his only symptom of PTSD, as far as he can tell, is inability to bond with people and inability to feel happiness. He feels always empty. He doesn't have a problem talking about his traumas. He doesn't have a problem accessing his memories. But it's only becoming a problem for him because he doesn't feel like he can bond with his daughters. So I was wondering if you can comment on that. Thank you. Sure. So the literature with PTSD and psychedelics is really just MDMA. Some people are trying psilocybin and unclear what will happen there. The person you just mentioned I don't think would be a good candidate. They don't have an index trauma where they're getting triggered and having re-experiencing it. And so this wouldn't be somebody that I think this intervention would be helpful for. Anna Scandos, New York City. Thank you so much for giving this presentation and for going over the psychotherapy in detail. I can tell you it was something that's not usually part of RCMEs as a psychiatrist. So thank you for that. I have two questions. One, is there any kind of predictors of a dropout rate? And that could apply to either whether you're doing it with or without MDMA. And if there is, how can that be utilized in treatment? So if they have one treatment, are they then leaving in a more vulnerable state? Or do they have some improvement, right? Because to some extent. So are they coming away with some benefit? And the second is the therapist's traumatization by hearing it and what the prevalence is there? Or is there some feedback loop? Because you're doing prolonged exposure with a therapist. So is it hearing it in some sort of beneficial, not beneficial, but a way that would not expose a therapist to being traumatized? And if they are, what kind of support do they get around that? So the first question about dropouts is the retention rates here are like 98%. And the reason is that they've designed an open label component to it in the phase two data. In the phase three, at the end of the parallel design, they have the options. So something like 98% of people complete. They don't have enough dropout people to even be able to analyze that data. But that will be, and these, I mean, phase three trials are typically thousands of people. These are both like about 100. And it's only because the effect size is so large that the FDA is probably going to allow this. But we need a lot more people to be treated, to have a better sense of predictors of response. We're not there yet at all. My question is, if I understood it, what if the therapist has their own trauma? And what if that comes up? Vicarious trauma. We make sure to take care of our therapists. We have ongoing supervision. I mean, you know, when you're doing a study and people are dying, you want to ask people how they responded. And when you treat people with severe PTSD and you hear really horrific things, you want to make sure that your treatment providers are having a chance to process and be tuned up, et cetera. Or just in general, encouraging good self-care. So we're on top of that because, you know, as treatment providers, I mean, in addiction, we hear all kinds of difficult things. And how you take care of yourself is really important, especially in a study like this. And just with exposure treatments in general, with the prolonged exposure, we also take really good care of our therapists. They get specific supervision on their trauma cases. And, you know, we're constantly talking about how they're reacting to what they're hearing and making sure they're taking good care of themselves. It's interesting, just as a trauma therapist, I think you also habituate a fair amount to just hearing things. Like, I might be supervising a younger clinician who is hearing something and it is really rattling their system. My system doesn't react as much as it used to. Thankfully, I don't feel dead. And I don't think I under-respond. But you do habituate to just knowing, like, this stuff does get worked through. And I think that's the value of having senior therapists, is to have that confidence of, like, yeah, I've seen this be really tough and I know things can get better, so let's hang on here. I was going to say something else about... No. Oh. Yeah. Wicked eye. I was just going to say what Jeff said earlier about, like, there's some therapists who just don't like to do this work, who don't like to do exposure work. I mean, therapists who do exposure response prevention with OCD, they're doing everything that they're suggesting their client do. So I might be licking a toilet seat. You know, like, that's not something I'm ever going to do. So I'm not going to do that exposure therapy. But I will do. So I think there's also therapists Hi. I'm Audrey Freshman, New York City. I've always been fascinated by and I've done work on the intergenerational transmission of PTSD as a risk factor for substance use disorder. So in some ways, when you say that the approach is going to reduce PTSD and reduce SUD, it wouldn't be a surprise to me because I think that the initiation starts from the risk, which brought me to the work of Rachel Yehuda on Holocaust survivors and I became interested in the intergenerational transmission and the epigenetics involved in PTSD. I was wondering what if any studies are done on the MDMA in regard to epigenetics, if there are animal studies done. And my second question would be, I know you said you didn't want to talk about chronic PTSD, so yes. But I want to know because in the Holocaust population, 60 years after the Holocaust, PTSD remained a durable factor and so it's hard to understand for me, well, I'm curious about what you think about that impacting let's say chronic PTSD. I understand it more in a singular event as I could over time. Yeah, so Rachel Yehuda is a colleague of mine and she's done amazing pioneering work on epigenetics in trauma in particular with Holocaust survivors. A lot of this work has just been looking at efficacy. No one has been designing studies to look at mechanisms, including epigenetics. So I think we have to start, especially with these bigger studies, both on the neurobiologic side of things and on the psychological side to have a causal model and to be able to do neuroimaging and collect biomarkers and epigenetics and exosomes, everything to really interrogate mechanisms of action. So in this trial, they can have chronic PTSD. There has to be an index trauma that you're working with, but a lot of these participants have had multiple traumas and chronic trauma and I would think that if you're one of these lucky people, two out of three, that you're in sustained remission, your chronic PTSD may be remitted for a year or longer. So I think it has the potential to treat chronic forms of PTSD. Jeff wasn't saying we don't talk about, he was talking about the squabble in the field around complex PTSD. We use the prolonged exposure for people with chronic PTSD all the time. They've got ongoing, long-term child sexual abuse, physical abuse, so we do use it. I think he was just not wanting to pick up that part of the discussion. Because we were limited in time. One other question, though. Is she measuring or are you looking at cortisol levels then in relation to the MAPS studies? Well, people like Rachel Yehuda are starting to do that in her studies, but MAPS hasn't done any biological measures at all. Pharma companies and in a way they're like a pharma company, they just want to establish efficacy and get their drugs approved. They don't really care how it works. But in the scientific community, we're very interested. And it really lines up with the underlying pathophysiology of PTSD. People have started to think, let's do some neuroimaging. Let's take a look at the amygdala, the prefrontal cortex, the functional connectivity, and let's see if the mechanism there lines up with the efficacy so you can back into how it might be working. I don't know if we're getting in trouble because we're going way over. We're happy to answer questions if you all want to stay. I think one more. We should have a few minutes for the presentation. It's a good question. We might actually need that. Thank you so much. Thanks for coming, guys.

integrated trauma treatment

prolonged exposure therapy

MDMA-assisted therapy

PTSD

substance use disorders

co-occurring disorders

effectiveness

therapeutic container

psychotherapeutic approach

MAPS research

FDA approval

alcohol use disorder

harm prevention