Rachel Yehuda, PhD, discusses "Psychedelic-Assisted Psychotherapy for Post-Traumatic Stress Disorder" (PTSD) during her “FBI Cyber Series” talk at The Friedman Brain Institute. Dr. Yehuda traces her path from skeptic to believer in the value of psychedelic therapy. She presents a deep dive into the history of MDMA, its path from stigmatized street drug to potential therapeutic, its uses in treating PTSD patients, the structure of therapeutic sessions, and new initiatives to train therapists to use psychedelic-assisted psychotherapy.
32:39 – How MDMA Works
42:15 – How I Changed My Mind
56:53 – Q&A
Okay, everyone, let's get started. This is Eric Nesler. I'm director of the Freeman Brain Institute, and it is my pleasure. Thio inaugurate our cyber Siri's lecture for the coming fall semester. As many of you know, from last spring, we had to cancel Ah lot of our outside speakers because of the Cove in 19 Pandemic and instead had some of Mount Sinai. His own speakers talked to us. It was such a successful operation that we wanted to continue with this year and no one better to kick us off for cyber Siris in fall 2020 than our speaker today. Dr. Rachel Yehuda Rachel is director of mental health at the Bronx, Va. The James A. Peters, Va. In the Bronx. She's also director of the Center for Psychedelic Psychotherapy and Trauma. Rachel has had a distinguished career being a longtime researcher on stress. More recently, she has studied epigenetic mechanisms by which stress exposure influences subsequent generations, and she'll be speaking today about a still more recent interest of hers. And that is, uh, psycho. The use of psychedelics, thio assist, psycho therapy and other treatments for PTSD and stress related disorders. Thistle is a very novel area of research, and Rachel has played a leading role nationally in guiding us toward an evidence based approach to this very important subject. Rachel, thank you so much for joining us today. Please take it away. Thank you, Eric, very much. And so I'm just going to get looks. I'm just going to get started when you hear the word psychedelic. It invokes many different kinds of images and associations, whether it is the sixties or the fluorescent colors or anti war protests or counterculture, maybe the music. But almost everybody thinks about psychedelic drugs, the most iconic of which is LSD. And so I'd like to begin by defining a psychedelic drug for you. And this is my own definition. It's a drug that promotes a change in the normal state of consciousness, usually with changes in the acuity of the senses. So if you think about consciousness as a new awareness of of your own existence and state a changing that would be a state in which the awareness of self in the world is experienced differently. That might be brighter colors, more robust sounds, and in some cases there would be something called synesthesia where you here the colors and you see the music, and that is frequently something that happens with psychedelics. You might be wondering why I would need my own definition off of psychedelic drug. And it's because if you look it up in the conventional places that define words, um, you would get definitions that I don't think are adequate. So according to Webster, a psychedelic is a drug capable of producing an abnormal psychic effect such as ah, hallucination and sometimes a psychotic state or a drug that causes severe perceptual distortion and hallucinations and extreme feelings of either euphoria or despair. Um, psychedelic drugs are also called psych Autumn a medic, drugs or hallucinogens, any of the so called mind expanding drugs that are able to induce states of altered perception and thought with heightened awareness of sensory input, but with diminished control over what is being experienced. So I think these definitions are a little bit biased, but more of the point. They're scary. And if they're designed to keep people away from psychedelic drugs, words like abnormal psychic effects and severe perceptual distortion hallucinations, they do a good job. Um, and certainly the idea of giving these kinds of drugs to a psychiatric patient wouldn't be the first thing that comes to your mind with these definitions. Eso Clearly, there's a lot of fear in our society about these drugs on the question is, Is that fair warranted? So let's talk a little bit more about psychedelics. Most are found in nature and are extracted from plants. Psychedelics have been used for that by shamans in indigenous cultures is part of healing rituals and spiritually journeying to some examples of that are mescaline and peyote or die mental trip to mean, and I, Alaska or psilocybin in our magic mushrooms? And what these, um, uh, rituals and spiritually journey ings consist of are really allowing the person to have a no etiquette experience, which means really a sense of revelation or a trans personal state really a transcendent experience. So the idea is that the psychedelic is being taken so that you can commune with your spirit with Mother Nature with your God, maybe an ancestor trying to tell you something. Um, it's not ah, hallucination in the sense that people who are having these experience kind of know that they're having an experience courtesy of the drug, they often say, Sometimes you hear people say I'm tripping. What does that mean? It means they know that there is a certain reality on the ground, but there's kind of a parallel reality going on that is also drug induced. Um, synthetic compounds include trip to means such as LSD, and then ethylene means such as M. D M A. And there are debates about which other drugs are psychedelics, for example, is kind of mean. A psychedelic is cannabis. If you go with the broader, uh, definition off anything that can be my manifesting well, yeah, you consider those compounds. But what I really want to talk to you today about is that there's a renaissance in interest in using psychedelics and therapeutics. Psychedelics were actually used in psychotherapy beginning in the 19 fifties, particularly LSD, until they were classified a Schedule one drugs. So let's talk about what it means to be classified as a schedule one. Drug scheduling means to put a restriction on a drug. Many drugs that we use in psychiatry are classified as Schedule two drugs or schedule three drugs, which means we use them. But we're also really careful about it, for example, amphetamines or opiates. But a schedule one drug means that the government has deemed that there is no clinical benefit to using this compound, and there's a lot to be frightened of. And so this designation made research into the therapeutic potential of psychedelics almost impossible. Now you may be wondering, What disorders did psychotherapists use psychedelics? Four. But in the fifties sixties and seventies, psychiatrists were free from the tyranny of D. S. M. Three people didn't really practice psychiatry that way. I'm for better or worse, we can have some conversations about that. But what I really want to do is describe what psychedelic assisted psychotherapy is on. I want to focus on the fact that it is the non ordinary state of consciousness that is induced by the psychedelic. That leads to a rapid, comprehensive and lasting insight and self acceptance. The insight and self acceptance galvanized healing and symptom reduction, which occur over time as the psychedelic experience is integrated. So the medication itself has only taken a few times during the course of a 3 to 4 months Psychotherapy pro protocol. But the psychedelic allows the patient to penetrate the normal avoidance or guilt or shame that usually distort their understanding of a personal experience that creates sometimes this immutable narrative that perpetuates symptoms. So in other words, the psychedelic is a catalyst of a process, and maybe you need a metaphor to help you understand that. And I have the perfect one, courtesy of Stanislaw Broth. Psychedelics, when used responsibly, will be for psychiatry. What the microscope is for biology or the telescope is for astronomy. And I love this quote because because when a scientist looks in the microscope and see something that was not available before he looked in the microscope, nobody tells him that he's having a hallucination. And similarly, when you haven't experienced with a psychedelic drug that is a a non ordinary experience, it's coming from your subconscious and its material that could be further analyzed and integrated. Another great quote from Alan Watts if you get the message paying up the phone. In other words, the biologist does not sit with the I permanently glued to the microscope. He goes away and works with what he has seen. So this is a very different model of giving somebody, ah, medication. Very unlike the models that we have currently have for psychopharmacology. And now I want to pivot to PTSD for a minute because we're going to talk about psychedelic assisted psychotherapy with PTSD and particularly with M. D M. A. And the reason that we need to explore this and I'm going to say this so unequivocally is that current evidence based treatments are inadequate because even when treatments are well tolerated, the gains are minimal. And the problem here lies in study designs, liberal response criteria and really rushing to ratify solutions because of the pressure to have solutions. And, you know, I didn't always think this when I I've had a long career and 1st 10 years I was told by my colleagues who were doing research in cognitive behavioral approaches that these treatments really work. And I went around talking about how dark treatments for PTSD until we started doing our own research and I realized that, you know, a lot of people drop out of these therapies. Most of the literature has been done comparing an active cognitive behavioral therapy to an inert, weightless control. So if you get a large effect size, you're literally comparing an active treatment to not being treated at all. And the response criteria. Uh huh. What the field of PTSD has decided is that a clinically significant response is a 12 point decrease on a scale called the Caps. The clinician administered PTSD scale. Now you can have PTSD kind of a light version of PTSD with the Caps score of 40. So if you have a 12 point decline, that's about a 12 25% getting better. So that's OK, but most people start out in treatment with much higher scores. I'll show you later. The average is usually about 80 and sometimes higher, so a 12 point decline. Wow, that's not very much. That's like offering a starving man of banana and saying, Okay, hope that takes care of you. It's just not enough. And a few years ago, I actually decided to write about this. Um, it's actually a rant that the JAMA psychiatry graciously called a viewpoint, because if we pretend that we have treatments in a field, then we don't look for things that are better, and this will absolutely predated my interest in psychedelics. But I already knew that we had a problem in a crisis in the field of not having the appropriate therapies, the post traumatic stress disorder. I think by now most people know what it is. It's a condition that can occur after you've been exposed to a trauma. I'll define trauma here to again. A trauma refers to a watershed event. I think that that divides your life into a before and after. That's really how people talk about these events. Before I was in combat before I was raped before 9 11, I was different than after. And what do they mean by different after They mean they're stuck in the past. They have memories, nightmares, distress. They avoid reminders of the trauma. They restrict their lives. They're constantly on alert for danger, on edge. Angry. Ah, lot of times there's a change in your belief system, particularly, ah, belief in yourself, your own view that you you might be to blame or bad because the trauma that happened to you and as such you function differently in relationships on the fact that the event happened begins to dominate and redefine every aspect of life. So the idea that MGM a assisted psychotherapy, maybe a powerful treatment for people suffering from PTSD would certainly be something that we should take a look at. So let's break for at what MGM A is and why it might be useful for PTSD. So the first thing that I'll say about M. D. M. A. Is that it's not a classic psychedelic, but rather it belongs to a class of compounds called intact regions, um, or empathy ins, thes air drugs that enhance feelings of empathy, compassion for self and others. They promote pro social feelings and connectedness. They increase interpersonal trust. MGM reduces fear of emotional injury and makes unpleasant memories less disturbing and increases introspection, Acceptance and insight on this is really the perfect state to be in when processing trauma related material. Notice these references air really kind of recent because there's now a very different kind of approach. Thio studying the Effects of psychedelics Let's take a look at the molecule M. D m. A stance for 34 methylene d oxy methamphetamine, and I've drawn the amphetamine molecule here close right here so that you could see that embedded within the MGM A. There is actually an amphetamine but attached to the aromatic ring, um, is a methylene d oxy group with CH two and two Oxygen's Now. Is this the reason for the psychedelic effects of the drug? Not clear, except that this methylene d Oxy group is also president Masculine. So maybe, um, but this isn't a molecule that looks terribly different from other molecules that are used in treating psychiatric disorders. In terms of the farm, a Coke kinetics M. D M. A. Is very fast acting. It has a 30 minute onset, a peek at 1 to 4 hours, a seven hour half light life and metabolites to which M. D. M A. Is converted are out of the urine and the liver by 38 hours. Well, let's talk about the farm co dynamics of M. D Emma. How does it work to produce its effects? And here, the main thing that has been noted around the effects of MGM may have to do with its actions on the five ht to a receptor so empty, amazing indirect serotonin agonists and it results. Um, it causes mawr serotonin to be in the synapse. It acts on serotonin transporter transporting serotonin to nerve terminals promoting serotonin release, and it interferes with storage of serotonin invested. Cols further increasing releasing the synapse. So it's basically a come out come out wherever you are. Serotonin kind of effect. And it's not only serotonin. Since it's a mono amine oxidase inhibitor, you have a triple re uptake effect. Not only serotonin, norepinephrine and dopamine. And perhaps this is also why you also get a rush of hormones, oxytocin, cortisol, vasopressin and collected. But what's really interesting is that these effects, these acute effects, disappear when the drug is metabolites. And so what needs to be explained in our field is how thes transient effects result in enduring transformational change when used with psychotherapy. And in order to do that, we're gonna have toe apply some new concepts. Um, and the first one is the concept of set and setting, which is discussed a lot when we talk about the actions of psychedelic drugs. Now in psychiatry, we're very concerned about the drug we administer. Is it pure? What is the dose? What is its pharmacology? What is its route of administration, but with psychedelics were concerned about two more things were concerned about the intention of the person taking the drug and their physical, health and emotional characteristics, and We're also concerned with the setting in which that drug is being taken. So here's a good place to begin to introduce the difference between an intention of recreation and therapy. So for recreation, you might have an intention of being pro social and less fear inhibited at a party. That's a different intention than looking in the microscope to glean an insight into yourself. So perhaps the acute effects of the drug are similar in those cases. But it's really interesting to wonder whether the long term biologic changes air similar on that has yet to be studied. So all this is really about the context in which the drug is taken, which is something that usually we don't worry about, what is actually a very big thing in, um, in psychedelics, and I would like to give you a very brief history of MGM A. It was originally synthesized in 1912 by Merck as an intermediary compound for him. A static drug, it was pounded in 1914 because of discovered psychoactive properties. And during the Cold War, the U. S. Army and CIA became interested in M. D. M. A and other psychedelics and began testing these compounds, but we don't know what they learned, Um, because it isn't available to us. But in the sixties and seventies, we know the therapist started using MGM million therapy under the name Adam because it returned patients to um or innocents state. And they called the drug empathy. And in 1976 a chemistry student introduced a chemist by the name of Alexander or Sasha Sheldon toe M d M A. And he was synthesized the compound and published the methods. And I just want to spend a minute talking about Sasha. Sheldon, who's such a colorful character, is actually known as the godfather of psychedelics. He started his career a doubt pharmaceuticals. A very conservative chemist. He synthesized ZEC drawn, which was a pesticide that made doubt a lot of money. And in return they allowed, um, Sasha to set up a lab it down and study whatever he wanted. In 1960 he took medical in and decided he wants to study that and what the effects are of that. So I was a little bit uncomfortable at the conservative Doubt pharmaceuticals for a few years, and finally Sasha left, and he wanted to set up his own laboratory. He actually went to the D A. And convince them to give him a D A one license, um, in connection with his own lab that he would set up at his home in exchange for them for him, supplying them information about the compounds that he would synthesized when he synthesized maybe close to 200 maybe more psychedelic compounds. And what he would dio is he would invite his friends over to try to test try these compounds and little parties. And he actually documented all of this stuff. All these stories in these two books that he co wrote with his wife, um and Fi call that stands for fun, Ethel A means I have known and loved and tie call trip to means I have known and loved. And there's a lot of science, a lot of stories. And he talks about the shoulder rating scale, which was developed to document the effects of hundreds of compounds that he tested with his friends. But it's his reaction to M d m a that I want to tell you about, and this is from his journal. I found myself able to be to remain completely clear and lucid. I had excellent recall. I found myself able to think, honestly, that's a strange term because you think of honesty as interaction between two people. But to be able to be honest with yourself and think, Why did I do that? I did that because of such and such was fantastic. It was an honest answer in an area where we're so used to denial and disavowing or hiding our feelings, and I felt myself come open. I found it extremely exhilarating because I discovered a completely magical place. And what did he do? He introduced MGM a tow Leo Zeff, a psychologist who was about to retire, who tried it and then came out of retirement and actually distributed M. D M. A. Hundreds of clinicians who administered it to thousands of patients. Now it was on the download wasn't illegal. But, you know, we were at war with drugs. So there are a few anecdotal pieces about this, but not really a tremendous literature on this now. In the late 19 seventies and eighties, within event, inevitably, M. D M. A became a party drug. They changed from the name from empathy, toe ecstasy. Better party name. But the underground Ecstasy compound was almost never pure M. D m A. And was frequently contain methylene dxy, amphetamine, M D a. Methamphetamine, ketamine, caffeine or cocaine. And this actually lead to Mali short for molecule so that there could be a more pure molecule Available. 1984. Senator Lloyd Benson requested scheduling as part of the war on drugs, and The New York Times wrote an article reporting the DEA had signed an emergency measure that were placed M d m a into schedule one because of all the evidence that D. A had received that showed the M. D. M A abuse and become a nationwide problem and it possessed a serious health threat. So I was really interested to look up the evidence and tell you about the evidence that got M D M. A. Scheduled as a schedule one compound. So I put M d M A in the search engine in Pub Med, and this is what I found that M. D M. A. Was first mentioned in the scientific literature in 1974 and they're about six articles through 1985 now. Google Scholar will give you, um, some more. But mostly these are anecdotal. Um, a lot of stuff was written about it, but these are the results of pub met. So the assertion that there was a lot of scientific data to support the ban, um, you know, could be challenged. Um, and indeed, in 1985 clinicians did petition the FDA and the D A to reconsider given therapeutic benefits to thousands of patients. And they cited anecdotal reports, but no randomized clinical trials. So no real data justifying the use. And there was some important people that petitioned, like Dr Morris Lipton, associate editor of the American Journal of Psychiatry. But it was Dr Rick Doblin who filed a lawsuit stating that the d a. D. A. Had failed to make the case that the drug had no therapeutic use. It suggested a Schedule three. Well, he lost, and instead he went on, moved on, dusted himself off and established in 1986 maps, the multidisciplinary association, the psychedelic studies to try to get the data needed to support the therapeutic use of M d. M. A. Um, here is Rick Doblin, giving his Ted talk. If you listen to his Ted talk, which I recommend you'll understand why he's so passionate about M. D M. A. And all the people that he was able to treat and transform their lives. Hey, talks about this. But more to the point, this is Rick Dublin in 1985 on. Well, I'm not really saying anything, but it did take 15 years for him to figure out how to work with the government to get the FDA to approve the first protocol. This is my interpretation. Um, but in 2000 and one, the first phase two protocol was indeed approved, and three years later, the DEA granted approval to proceed. But then things went very quickly. The first participant was enrolled in 2000 and four, and by December 2000 and 16, there were six phase two trials that have been conducted and the FDA granted breakthrough designation. Um, to this treatment and phase three trials are underway, they completed the first one. The second one is going to start an M. D. M. A. Is on track to be approved by the FDA in either 2021 or 2000 and 22 so there have been six published studies on the Phase two trials. I'm not going to show you the results of all of them, but I'll show you the results of the first one and the pooled results. First, I'm going to show you the design of the studies because I don't want you to get the impression that M. D. M A. Assisted psychotherapy is like a quick fix for anything. Because it's not. It takes a long time to go through the procedure. You begin with an assessment and screening. There are 3 90 minute preparation sessions, 18 hour experimental session where the patient receives either M d. M A or placebo, three integration sessions also lasting 90 minutes. Another experimental session. Another 3 90 minute sessions to integrate the experience at this point in wanted. In the first study, there was a primary endpoint. The people randomized placebo had the opportunity to go back and get the M D M A if they wanted it, which almost everyone did. And then everyone got a third session, three more integration sessions and were assessed a two months and in the long term, follow up. This is a lot of psychotherapy um, and a lot of treatment. Um, what do you do to prepare patient for M d. M. A. In all of these studies, they have chosen treatment resistant patients. I love that term. Uh, patients that have failed thio get better with the treatments that have been available for them and we know create a minimal response or a less or a temporary one. So the therapists do is create a setting of safety and support trust. They get the patient's story and they orient them toe what is different about this therapy? They explain to them that they're gonna have to trust their inner healing intelligence and that they are going to be taking a non directive approach. They explained the likely effects of M. D. Emma, the procedures of the session and also the fact that sometimes difficult experiences air part of the process of healing and growth. Um, no one uses the word bad trip to describe a difficulty experience because after integration, usually there's a lot of good that comes out of difficulty. M. D m. A. Experiences. If that happens, the therapist elicit fears their concern and concerns and reconfirm commitment to the process and in terms of the eight hour experimental session, the patients received the drug at nine. They're offered a booster 30 to 45 minutes later. Vital signs are monitored throughout the day. Patients get eyeshades and homes during periods of inward attention, and basically, instrumental music is very carefully selected and is a very important part of this experience. The therapist do not present agendas or solutions, but remain curious, open and attentive to the patients developing experience. And they follow the patient's process to create more safety, communicating trust in the patient's innate capacity for healing. The room is comfortable. It's not a sterile medical environment. It's upholstered chairs and beds and lamps and plants and rugs and pictures all to give it, you know, set and setting how you take the drug and the setting is very important. The session over eight hours later, the patient is fully sober and arrangements are made for the patient to stay overnight with a significant other or alone with an attendant, and then the first off integration sessions occur in the morning. Okay, so what happened in the first study? It's very clear that here are the results of the placebo. These air patients, um, that showed almost a 20 point decline in their cap scores. You see here these patients did average and 80 as I said before on the caps on the placebo group. They went down 20 points, which would be considered a clinically meaningful response. But don't forget, by this time they've had many, many sessions at least, um, 12 9, 90 minutes sessions and a few eight hour sessions. So that's a lot of therapy. But the patients that had the M d M A really show a much, much sharper decline. And here I put the line here at 40 to just show you that. And the end is not big here. Andi Czar, crime related PTSD that were tapered from medication in terms of the crossover. When the patients who first received placebo got M D M A. Well, they declined. Aziz Well, And by the third session, two months after the third session, um, these two groups were in the same place. And here is that 40 line mark, but remarkably, when assessed at 17, 17 to 74 months later, the people who received them d m. A, which was basically everyone except for one person, um, maintained their gains. Um, all these months later, this is kind of unheard of in clinical work with PTSD. And if you look at the data from the sixth Pool data from the six Trials, you see a tremendous, um, response here. This would be that 12 point document which you see in the control group, but not in the M d m A group. The side effect profile is very acceptable. During the sessions, people complain about anxiety, fatigue, headache, jaw clenching, lack of appetite and nausea. Um, but they get through it with no seriously at first event. So all in with the face two trials in the placebo group, 23% no longer met PTSD diagnosis at the study, and 56% no longer met PTSD diagnosis. If they had m d m. A. And 12 months later, that number increased to 68% meaning that the gains air constantly accruing and being people are continually integrating their experience. Um, most patients have wonderful things to say about how transformative of this experiences. Here is a quote from a combat veteran. First, I'll read you what he said during the session. It's allowing me to really view this part of my life that we're talking about in a new way than I have before in a more complete way, and I understand it a bit better and at treatment. And he said, maybe one of the things the drug does is toe let your mind relax and get out of the way because the mind is so protective about the injury. I have respect for my emotions now. What's most comforting is knowing now that I can handle difficult feelings without being overwhelmed. And much later, he said, I got a glimpse of more of what I'm capable of growing into. I'm motivated to keep practicing openness until it gets more developed. And there are many, many beautiful quotes from patients who have undergone this experience. So how does this work exactly? And of course, by that I mean, what are the biologic mechanisms that might be operating, uh, to induce this kind of really astonishing change in symptoms that seem to stick? We don't know too much about this, but we have a few oh, a few clues that are worth investigating on what I'm showing you here is kind of an iconic PTSD imaging, uh, cartoon. Really? Thanks. That shows that when you expose people with PTSD to their two scripts of their own traumas, you can measure in the brain increased activity in the amygdala and decreased activity in the prefrontal cortex. And this is a circuit. And the idea here is that it has been suggested that in response to fear, the prefrontal cortex fails to properly inhibit the amygdala, allowing the amygdala to become more to have a more exaggerated response to fear in the form of a traumatic memory. Well, here's what happens to healthy volunteers. After one dose of them DMA they have an increase in the prefrontal cortex activity and a decrease in activity of the amygdala. So this kind of looks very promising. And if this is what happens in PTSD and may indeed explain why people arm or are less reluctant to talk about their traumas and experience less fear in doing so, what are other biologic mechanisms that might permit a state that is conducive to trauma focused work? Okay, maybe endia may promotes fear, extinction and mice and memory consolidation. There is recent evidence from that animal studies. Maybe M D M A. And other psychedelics converge on a pathway important for neural plasticity. I'll give a shout out to Lauren Power, who's writing a beautiful paper just on this topic. Maybe oxytocin. Maybe this is an oxytocin dependent reopening of a social reward learning critical period with M d. M A. These are all very recent papers 2019, 18 4018 published in very good journals, nature cell reports, translational psychiatry and, um, people are actually trying to study this and look into these mechanisms. There's a whole frontier of work that can be done at this point in the talk. However, now that I've showing you the data, I really want to make a confession. Um and that is that my interest in M. D. M. A. Assisted psychotherapy is very, very recent. And even though I have been following this story, I would say that I became aware of it somewhere in 2000 and 11 because people started asking me about it. Um, it wasn't until very recently that I was on board with thinking that this is a good idea for PTSD, and I remember hearing a plenary talk by Michael Mid Hoffer who slides I've just shown you the M d M. A results are Hiss. And he presented those very data that I showed you in a plenary talk at the International Society for Traumatic Stress in November 2000 and 17 just a little bit after the FDA designated, um, MGM assisted psychotherapy, a breakthrough treatment, and I was sitting with some of my colleagues at the VA listening to this talk. And my colleagues are clinical psychologists who are getting very, very excited about possibility of this treatment. But as late as November 2000 and 17, um, my reaction to MGM assisted psychotherapy was actually to be quite concerned about it and skeptical. And I want to explain, um, the reason for that because I don't think that, um, I was alone in my skepticism. One of the things that bothered me was that there was an elephant in the room called neuroscience findings, and I showed you this, um, graph before and made the point that there might not have been data to justify scheduling MGM in 1985. But there has been quite an extensive literature since um but that but the literature in general until quite quite recently has not been that reassuring about the effects of M. D. M. A. Um, sure, and I want to show you that now. Someone like me who was very interested in one area, which is PTSD, um, won't spend a lot of time looking at primary data papers in areas that are not related to my work. But I do read a fair amount of review articles to just keep abreast of what's happening in the field. And substance abuse, in particular, is very related to PTSD. We do, full of psychiatric interviews on patients to assess their substance abuse. That's actually something that we are very worried about our PTSD patients. In 1994 this paper came out by her cleaver very well respected name. That kind of justified the scheduling of M. D. M. A and concluded that the rising use is cause for concern because M. D. M. A. Has been convincingly demonstrated to damage brain serotonin neurons in animals. And in 2000 and two, a paper came out with this headline. Severe dopamine, ergic, neuro toxicity and primates. After a common recreational dose regimen of M. D. M. A or Ecstasy. This, um, this paper really got a lot of attention in the late media as well. In, UM, 2000 and one, the night a director, Alan Leshner, testified in front of a Senate subcommittee and showed these scans from a paper that was published in 2000. And what he said was, we know from image ing that cerebral blood flow is affected by M. D. M. A use. We also have evidence from brain images that M D M A. Abusers may have fewer serotonin producing neuronal processes in the brain. The non users, well, without missing a beat. Oprah did a show a few weeks after September 11th on M d M A. And she actually reportedly got one of the subjects from the study, uh, to go on the show. And they showed this picture of her brain, um emphasizing thes of these as holes in the brain. Now any neuroscientists will know that these air not actual holes in the brain, that if you're using a color scheme where increased blood flow is red and decreased is blue. If you make increased blood flow blue then decreased will look black and it's not really a whole. But no one seemed to mind. Um, that overtook thes liberties, because the message that MGM A is harmful waas a message that most people agreed with every 10 years. You know, you get an updated review article, but the message was consistent that there are mid to long term neurotoxic effects as a result of progressive neuro degeneration of serotonin ergic neural transmission system. And even if you look in the night a website day, you'll see this kind of concern, even though at least now they're talking about the fact that I'm DNA is being investigated for its potential about treating PTSD. Now, clearly, I changed my mind somewhere in between 2000 and 17 and giving you this talk today, and I want to spend a few minutes about why I changed my mind, because I think this is such an important topic. I'm actually obsessed with it. A few years ago, I organized plan a recession at the International Society for Traumatic Stress that was entitled what I've changed my mind about and why, and I asked five really luminary distinguished professors to come and join this panel and talk about things that they have really done. A 180 degree shift on based on data. And, you know, it was so hard for people. I mean, people don't mind saying I was wrong about a little incremental thing, But the question of really whether we use data toe actually change our positions and things. It's really been something that I'm very interested in. Um, you know, I did read Michael Pollen's book, but that's not what caused me to change my mind. Read that book I recommended. By the way, Um, well, after I had already decided that psychedelic psychotherapy for PTSD is something that I wanted to invest my time. And I think the way that people change their minds, especially about academic and scientific matters, is that they probably have to go out of academia and yet some input from kind of outside the siloed ivory tower. That's what happened to me, and I think that that is an important part of my story. So I'm going to share it. And if you don't know what you're looking at here, this is an aerial view. Iconic view, um, of a of an event called Burning Man that occurs in the desert each year in Nevada. And I had started going to burning Man a few years ago and really, um, it was a little intimidated by it. It's an amazing thing. But as someone who had never taken us psychedelic drugs and didn't really feel the need to explore my sexuality or anything like that, um, I really didn't understand how I could make the experience meaningful to myself. Um, but it turns out that Maps, who had heard of by then was sponsoring an effort for harm reduction and was looking for volunteers. So I went over to the Maps Camp Zenda camp so that I could offer my services for harm reduction and be trained to do it. And just to give you a closer view of burning man, what happens is that it's a big party atmosphere, and a lot of people really do need somebody to talk to in a nice, quiet place. Um, that maps provides courtesy of those endo effort. So it was in the window tent that I started to talk to people who asked me what I thought about M. D M. A. For the treatment of PTSD, And I told them essentially what I just told you, Um, not the first part of the talk. But the last part of the talk and overhearing these conversations was a man named none other than Rick Dalvin himself. And he pulled me over, introduced himself and said that my information is completely incorrect, and he would really like to be able to give me some more data to consider because this is too important for somebody in the field of PTSD to not really be on board with. And one of the things that he did was introduced me to a veteran who had spent decades really being treated at the V A who had just finished a course of M d m. A assisted psychotherapy. Here's Rick Doblin and you could see a camera here because they're filming a documentary about this patient, which, which is why I have permission to use this picture. Um, and I really talked to him about his experiences, and it was profound Thio here a very, very explicit information about what happened in the session and how it worked. And really, I did kind of begin thio, Listen to people very differently as I heard a whole different set of experiences with psychedelics as transformative. This is the whole world that I had never been exposed. Thio. Um and I guess when I came back to Earth, I'm in New York. I decided to take a look at the literature and see maybe a few review articles isn't enough. And maybe I need to do a little bit more digging. And it turns out that the science paper that I told you about was actually retracted a year later. Um, they didn't really use M d M A. But M d A. And it wasn't a common recreational dose. It was almost a lethal dose. So that paper was retracted. And in terms of this image, well, in the very abstract that change it'll have published. It said that yes, there is depletion in blood flow in two weeks, but that by 2 to 3 months it was increased again, and that low dose recreational M d m. A use does not cause detectable, persistent changes in humans. There might be a regeneration off serotonin ergic nerve terminals on the preliminary data suggest that these effects may actually be transient. So I started to realize that the literature on M. D M. A. Has led to misleading conclusions about the safety of M. D M. A, particularly when used in the context of MGM assisted psychotherapy. And I'm giving this talk here to my colleagues at Mount Sinai because I actually think that we have really been influenced by the studies that have come out about drug addiction in a way that sometimes makes it difficult for us to think about psychedelics in a different way. But it can't Effects of serotonin depletion, while their present are not necessarily harmful or related to long term neuro toxicity. On the conflation of data from recreational use and therapeutic work, maybe may be very harmful to advancing Therapeutics. Most people will say that studying M. D M A recreational users does not even guarantee that you're studying the effects of M. D. M. A. So we need to create a new science, I think, to investigate the issues relevant to MGM assisted psychotherapy, and I showed you evidence that this is starting to happen. But so much more needs to be done, and I realized for myself personally that in order to be part of creating a new signs. To investigate these issues, I would need to learn more about M. D. M. A assisted psychotherapy. And fortunately, Rick Doblin had invited me to the next maps training, which took place in Israel a few months after I met him in January 2000 and 19. And this training was at a place called the They um Shalom, which is one of very few Arab Israeli villages on. The training was with 70 therapist, Israeli and Palestinians was led by Michael and Anne Mithoff for and the minister of health was there and made an announcement that Israel would be the first country that would approve MGM made for compassionate use. And it was a very, very exciting moment. The training for M. D. M. A. Uses very rigorous. It's usually about seven or eight days long. Uh, this this particular one was six days, but 12 and 14 hour days, and there is a manual for this treatment. But the training consists of really watching videos of the sessions and really discussing the process and what has been done. And one of the things I learned and I learned two things in the training that I'm really grateful for. In addition, of course, Thio learning how to do MGM assisted psychotherapy. The first thing I learned that as part of the risk evaluation and mitigation strategy that Maps has promised to the FDA, I m d m a. Once it is approved by the FDA, will can only be prescribed and will only be provided to certify therapists who are trained by the sponsor maps. So it was actually really glad that I have been trained because once this is approved, this is gonna be a hard get and it's only gonna be administered and certified clinics and the D. A will have to get involved in that as well. The other thing I learned when I was at the therapist training was that maths had actually sponsored an FDA approved protocol for clinicians to understand therapeutic approaches, uh, and effects of M d. M. A. So you, the therapist student can be here while Michael and Anne give you one day M d. M A and one day placebo. And I are got to have that experience and if talking to someone who's done M d m a is powerful. Having the experience yourself is even more so, and I really learned a lot. I learned, for example, that therapists really do not need to direct the patient to think about trauma, and they can ask the patient to rely on the inner healer. The therapists are there to hold and encourage the process, but that the but that the patient will find the trauma. And many times Theo events that are very, very important and pivotal to understanding why you're stuck are not the ones you think they're going to be when you go in. The other thing I learned is that the eight hour sessions are really necessary to find the material, but that a lot of work gets done. You kind of feel like you've had 10 years of psycho analysis in those eight hours, but it's a very, very, um, rich process to me. I thought about labor and when I was in labor to give birth to my Children, it started out with contractions that were far apart and people trying to coach me through ah process that was going to get progressively more difficulty, but that at the end I would have a baby, but not one of those people would ever think to tell me at the end of the third of four contraction. That's all we have time for. For today. There's something about just continue, yes, and the unit of work that I think is very here healing. And I think one of the really magical components about this treatment and the other thing that I've learned is that the effects of an experimental session last for months and years. You're constantly reviewing what you saw in that microscope and making you associations. And it was after this experience for me in March 2000 and 19 that I really wanted not to do a study or two, but really set up the Center for Psychedelic Psychotherapy and Trauma at Mount Sinai in partnership with the Bronx via and I started talking about this to a lot of people trying to get them excited, and we've made some progress. Um, the center is going to really have four components. One is clinical trials with psychedelics and the first M D. M. A proposal has been approved by the FDA, and hopefully we'll be able to do that trial at the V A. We're planning psilocybin Studies from Mount Sinai were planning studies of scientific mechanisms and couple of IR beef submissions have been made molecular and epigenetic work, and we're planning a very comprehensive training and education. Well, I'll tell you in a moment about the therapist training that we just have. But in order to really, um, pivot the next generation for receiving these treatments, we have to be able to train residents and psychology entrance on, have to work with psychedelic assistant psychotherapy. We have to create postdoctoral fellowships and lecture Siri's. You'll be hearing about mindset, which is electric Siri's, that we're going to be starting, and we have to establish a pipeline for corrective information to the public and the scientific community. So the training we just had this July we were able to train due to a philanthropic gift. 30 clinicians from the Bronx, Va. Michael and Anne Mithoff for did the training. We trained psychiatrists, psychologists, nurses, social workers, psychology trainees, residents and postdoctoral fellows who are all on their way to the next steps towards certification. This is unheard of. We're going to try to start a train the trainers program so that we could be an official maps certified site to train, perhaps people from other vous, perhaps people from other academic centers. So that's a really important part of what we're doing. And this part about information before Cove it I was really having the tremendous opportunity to be speaking around the world with Rick Doblin about psychedelics in very important forums. This one it happened to be in Davos, the World Economic Forum. People around the world are very open to unenthusiastic about the potential for MGM and psychedelics, and this is possibly why Maps was able to raise $30 million in two months for their face three trials because people are understanding that psychiatry needs to have new treatments for them. And I think that this is just such an important um, horizon. And when you go out of academic circles, the feeling about these medications are often very different than what we hear in the mainstream. So that's been just very interesting for me. So this is my last slide, and I'd like Thio give you some conclusions and thoughts. Obviously, the integration of psychedelics and psychotherapy represents, um, exciting, uh, frontier in psychiatry. Um, is more than a frontier. I think that it's potentially a revolution in how we do things. And I think also that it is a moral imperative and the opportunities for scientific innovation in trying to understand the effects of these compounds are many. And this is an invitation to my colleagues who are listening, because if you have some ideas about what you might like to dio, please contact me and we'll see if we can make them happen. I absolutely looking towards my very brilliant colleagues that have access to the greatest ideas and technology to really help with this. But I've also made some meta points that I want to be sure that I underscore. Are we comfortable with the processes that yield are evidence based treatments? What is the role of science, the science guide policy, or vice versa? I think the story of how M. D. M A was scheduled is a cautionary tale. But the story of how science and scientists perpetuated it is also something to look at. And I am looking at myself, and part of my passion for wanting to make it right has to do with the fact that maybe some of these attitudes have inadvertently caused treatment that could have helped millions of people not be available. But hopefully we will do the due diligence to see if they should be available. Now. How do we ensure we are revisiting our ideas and our fundamental assumptions? And are we taking enough risks to yield rewards? How do we change our minds and the ability to look? Think that things in a new way is exactly what we need to understand? Because that is the secret ingredient off what makes PTSD patients better. It's their ability to get unstuck and think about what happened to them and how to go forward in a different way. So if we can understand and do it ourselves, we can bring this to our patients, hopefully towards a better future. So that's all I've got and thank you very very much for listening to me. Fantastic, Rachel. A virtual applause from all of us. Thank you very much. Um, we do have time for questions. I see a question from Karen Terran. Karen, do you want on mute yourself and ask directly? If not, I could read the question. Um, sure. Thank you. Amazing talk. thanks so much for sharing. Um, I was wondering how one would think about blinding in clinical trials like this where wait assumed that the patient would know whether they've been given a placebo or psychoactive compound. Um, it's a problem, but you won't believe that a t end of each session day the patient is asked. Do they think they have gotten M d M A or placebo? They usually get it right. But there have been occasions where somebody thought they got MGM when they got placebo. The whole music eyeshades, a psychedelic music relaxation, um, and setting is sometimes very true. Then you saw that there was a very strong response to just the psychotherapy alone. Um, and so, yeah, it's a problem. But I think that I don't think patients will lie about their just because they know they have had m d m a. But it is one of the challenges of working in this area. There's no question about that. Thank you. And Rachel, I need to go to my next zoom call. But Scott Russo has agreed Thio preside over some additional questions, so please keep the discussion going. Everyone thinks is my life on Zoom. Thank you, Rachel, for a great talk. Thank you. Yeah, that was a great talk rates. So there's still there's some questions lining up. I think the next one was from Daniela Schiller Going on yourself and ask, or we can just read it. Um, Daniella wants to know whether treatment will be available to non clinical diagnosis. Um, you know, I think that there's such a thing called off label use, but this is gonna be regulated very carefully, at least in the beginning. But there are many clinical trials underway, Um, in eating disorders and depression, um, Children and autism with M d m A. So I think that it's going to be a matter of time once PTSD breaks the ice. I think people will understand that any time the problem is unenviable mental event that is getting in the way, this might be a good solution for it. And, of course, there are political movements afoot to decriminalize the use of psychedelics. So, you know, we don't know what the future holds. One of the fascinating things about psychedelic psychotherapy is that it actually seems to be a bipartisan issue, something that Republicans and Democrats can both agree on both supporting, um, maps and both seem to support this kind of work. So I think that I think that we'll see what the future holds. So Sarah Hamid actually had another question about the placebo controls. Rich, I know you. You were answering that question with Karen when I came on, so the placebo is a pill, But in one of the phase two trials, they actually used a very low dose of M d m a 40 mg, which, of course, is not ah, low dose of a psychedelic. You know, we tend to say, go low, go slow or whatever. We're very conservative in terms of our dozing of medicine, but for psychedelics, you don't wanna have a low dose if you've got If you're in your seat belt ready to take off, you wanna fly, you don't want to just have a little right to the end of the runway. So it turns out that having a low dose of the psychedelic is, um, not necessarily conducive to a good experience. And that's just another difference between using psychedelics. And it's challenging because when we were designing these trials, conservative people say, Well, I don't wanna I don't want to use such a high dose, but you want to get that experience. And so you want to manage the fear of too high a dose with too low of an impact. And then Aaron Hazlett Aaron, do you wanna, um, you yourself and ask directly or sure. Can you hear me? Yeah. Perfect. That was a great talk, Rachel. So my question is, I loved your slide that showed that there's a frontal amygdala abnormality, potentially, that this might target. And I'm wondering because borderline PD individuals have this kind of abnormality is because this has been shown in several imaging studies. So I'm wondering if the co morbidity of having bpd, which a lot of people with PTSD have, is something that you're going to be looking at because I think it could be potentially interesting. Yeah. I mean, I am not sure in our study if if having bpd is or isn't an exclusion criteria, but I know that many people that trials have had personality issues. I don't think that this treatment is contra indicated. For that. I think that it will be important to try to do this work in personality disorder. That's ah group that is notoriously difficult to treat and may very well have issues and events from their past that that might help Thio access in this way. So I think that that could be very interesting. Awesome. So, Colin Spencer, you wanna come online and ask your interesting question about epi genetics? Yeah. Hey, I'm Collins. So there was actually ah, really good, like nature review paper that came out last week looking at LSD. It's psychedelics and Germans all post that and the chat afterwards. But a lot of the findings were primarily from neuroimaging studies and sort of looking at functional pathways through that. And I think that's great. But I feel like one of the most promising things about psychedelics is understanding the biological mechanisms of how they work and then sort of moving towards, ah, personalized medicine approach to these drugs and how they would work best for patients. And so what do you think are some of, like the most promising avenues to explore in terms of biological mechanisms, whether that be through neural plasticity like epigenetic marking, remodeling or some similar approaches? Yeah, I totally love the question and appreciate it. We actually are working with maps, um, to collect cell, very samples. Um, in conjunction with their face three trials toe Look at epi genetics and maybe tell um, chili hammers. Um, I think that this is a really interesting question, and we're going to be adding this kind of component to our work. The critical question for me is not the changes that occur immediately, after or acutely, which is where the field is focused a lot. But what happens later? This is a process where people are continuing to process what has happened to them. Eso um I would say that we would wanna be ableto really look at several phases to see what develops. And I like your personalized approach because one of I didn't have a chance to go into all the fears I had about this treatment. But one of them was that I wasn't sure that the people studied were representative of the entire universe. I mean, to take m d m A. When the culture was scared us so much about psychedelics, I thought they're not going to be representative. Um, that's to be seen, But I do think that it's possible that there is a profile of somebody who might not get that who might not benefit. Maybe it's something that we may learn. And if we can have a biologic signature to tell us that in advance, that would be very good. But meanwhile, we don't really have not responded to this treatment. Um, in the Phase two and Phase three trials, not very many. Its's really it's really kind of remarkable. That seems to be an experience that is mostly very beneficial. I can't even keep up with the questions. Rachel, so much interesting. Let's talk. I think Vanessa had a question after. See, Vanessa? Do you wanna meet yourself? Hi there. Can you see me? Okay. Hi, Rachel. Just wondering if that's with substance abuse will be excluded. Or if in the data has there been any cross over to other reinforcing substances that would later be problematic. Um, I see that Carly has responded in the chat about borderline personality disorder. I'm pretty sure that that if somebody has ah current addiction problem right now, that is problem. They're not good candidates for this for for our trials. But I do think that many people anecdotally have reported that they did try to use substances for healing and that once they took M d m A and did the m. D. M a assisted psychotherapy, they no longer felt the need to do that. So I think in the future there is a very big role for psychedelic psychotherapy for substance abuse. And in particular, people are talking about a compound called Ibogaine directly for substance abuse. So I think there's, Ah, horizon out there. Um and we shouldn't be afraid to treat substance abuse with a psychedelic, just as we're not afraid, apparently, to treat opiate addiction with cannabis. I mean, maybe there are rash announced here. Um, that way we shouldn't be afraid to explore. Thank you, I think. Randy, do you want to come out and ask your question about the placebo effect? It's an interesting question. Sure. So one of the really high impact studies that sort of got you know, this new rebirth of psychedelic research started came out from Hopkins in 2000 and six with Roland Griffiths Group, and they they gave suicide in the Healthy Volunteers and in the paper, and I think it's figure three, It shows that less than 10% of the placebo group they actually rated their experience. Oh, and the placebo group got methylphenidate in this case. But I'm less than 10% of the placebo group actually rated their experience among the top five or 10 most significance of their entire lives. So and this Wondering, uh, you know what this might say about the power of the placebo effect in the power of the human mind to generate experience more generally, Yeah. Again, I could have never answered this question without my own experience, but I had never in my life had the experience where I am, someone's ward for one full week, and their full job is to take care of me. And, um, I think that when you're enrolled in things kind of research and you're getting to therapists, I didn't really mean you didn't mention that part. Two therapists are really all about you. Um, even before you take the drug and maybe even after there, I don't think that that's a common experience, Andi. I think that there's a lot of healing there and that we need to really learn from that. I believe that That's probably how Cultures, um in the past may have really helped trump survivors by just giving that on completely focused directed attention to them. So there's really something to learn from there. Most people who have a psychedelic experience that has guided, like this do report that it is one of their top 10 experiences, and I think that I think we need to stay really curious about that. Um, and in general, in psychiatry, when a patient comes to us and says they're taking any drugs, we're not curious. We want we want to stop it. And in the in the skid that we used to diagnose psychiatric disorders, would they just lay out all the drugs? They don't say. Well, don't worry so much about LSD, because that was probably different. But it's LSD, cocaine, heroin, you know, just sort of all laid out there. And to somebody that doesn't know, the idea is that if there is a yes, that's not good, we should do motivational interviewing. We should try to talk them out of it. We should try to find out why and make them not want it. But staying curious about, well, what is this doing for you? What are you getting out of this? Um, instead of pathologize ing, it is our next step. Now, maybe in some cases, there is a problem. But we could listen first and then decide I'll read the next one because Tristan's mike doesn't seem to be working. Um, he said you spoke a little about the need for changing public and policy outlook to move psychedelic therapeutic use forward. What do you see? Is the next step for science, communication and policy moving forward? Well, yeah, I think that after, you know, this is this'll is very important question. Thank you for it. You know, the hurdle of FDA approving a treatment is one hurdle, But then academia will have a lot to say about what we think of the treatment. There have been treatments that have come out for PTSD. I'm thinking about MDR that just didn't get the blessing of academia entered the V. A is the way other treatments are. So academia has a very important role in vetting these treatments and creating a narrative that is more nuanced. So that so that we could give it at least a fair shake eso. I think that what academics have to say can be very defining. But we don't want to be a relevant. And what's outside of academia is certainly a growing movement to try to embrace a treatment that will work because psychiatry hasn't really been able to produce thes in a way of that benefits enough people. Um, with enough benefit, I guess it's how to say it. I don't I don't want to say that psychotherapy in PTSD never works at all. It does, and often it prevents people from getting worse. But there's a difference in reducing symptoms a little, or even reducing symptoms a lot and then giving someone the tools with which to really see themselves in profoundly different way. Alright, so Lydia, are you still online with us? You wanna come on the piano? Yes, thank you. Thank you very much for your talk. I was just curious. I've read about studies at John Hopkins, um, dealing with early onset Alzheimer's and depression, and I was curious if it's been considered for this new center at Mount Sinai. Alzheimer's we haven't thought about Alzheimer's is the center is for trauma related conditions. Um, but we are very interested in looking at geriatric PTSD because I think that as people get older, much older Ah, lot of these, uh, they don't avail themselves of these other kinds of treatments, and they kind of get used to or the trauma related symptoms become kind of lodged in their identity. And there have been excellent studies using psychedelics for end of life and fear of dying kinds of indications. And so, being able to give somebody who has been suffering with PTSD for decades and opportunity to kind of do every cataloging of their life, it's really seems to be a very important thing to do. I think we've come to the last question. Carly, You wanna come on? You want to jump on? Wow, I can read it. Carly wants to know about alcohol or substance use disorder other than caffeine or nicotine judged to be a safety concern or exclusionary for your studies. Yeah, eso Carly is my research coordinator, and she's informing people, uh, including exclusion e I won't know them by heart. E is actually doing all the work e Well, I think Oh, my God. You kept almost 100 people on for an extra 15 minutes. So I think you set the bar really high for our new season. Thanks, Rachel. I was spectacular. Very much for inviting me. Appreciate it. Bye, everyone.