All right. Good morning, everybody. I'll start to give introductions while people get settled. My name is Dr. Jacqueline Posada. I'm very pleased to be the moderator for this talk. This talk is put together by the Clinical Updates Committee, which you should all check out in the app. And welcome at 8 a.m., first day of APA. Very happy to have you here. So I think for all of you, this is an important topic because all of our patients are asking about psychedelics, and we want to know what to tell them. So we are really lucky to have a very esteemed set of speakers here from a variety of backgrounds. So I'm going to give them all their brief introductions. I'm just going to say something up front about questions. This talk is also being streamed on the virtual meeting, so I'm going to take equal questions between the virtual meeting and questions from the microphone. So I'm not ignoring you if I skip. It's just that we need to definitely incorporate the virtual session as well for all those participating from home. All right. So we have Erin, well, who's going first, Erin or Brian? Okay, Erin. So we have Dr. Erin Wolfgang, who is a psychiatrist at Brooke Army Medical Center in San Antonio, Texas. And he's early on in the training of psychedelic-assisted therapy. He was trained in MDMA-assisted therapy in 2019 and then psilocybin-assisted therapy in 2021 while at Yale School of Medicine. And his primary focus is towards increasing access to psychedelic-assisted therapies for service members and veterans with military-related trauma, and he does a lot of work with emerging therapeutics for the DoD. So an expert in this field. Next up is Dr. Brian Barksdale. He's an MD-PhD psychiatry resident at the University of, at Dell Medical School, University of Texas. We work together. And he is currently on the research track in the Center for Psychedelic Research and Therapy at Dell Medical School. And then last but not least, we have Dr. Nolan Williams, who's an associate professor within the Department of Psychiatry and Behavioral Sciences and the director of the Stanford Brain Stimulation Lab. He has a broad background in clinical neuroscience and, very intimidating to me, triple board certified in general neurology, psychiatry, and neuropsychiatry. And in addition, he has specific training in clinical expertise in the development of brain stimulation methodologies. So with that, we'll get started on this talk. All right. Thank you, Jacqueline, for putting this on, for coordinating this. And thank you all for joining us today on this wonderful Monday morning. And I'm sure folks are still getting coffee in their system, and so, yeah, sorry, I don't know why. It feels like a Monday for some reason. I don't know about you guys. No, for sure. And so, and again, it was really great to see everyone join us this morning. And as you can see, the table we're talking about psychedelics and psychedelic-assisted therapy. Importantly, making a distinction between the two, and how to counsel your patients. And so, if folks haven't already, I can imagine that you will, if not already, be getting questions from your very own patients, as well as other colleagues, in terms of when a patient comes to you and has a question about, hey, I saw this new study come out, or I saw on NBC, or CNN, or whatever, that, hey, there's this new psychedelic or psychedelic-assisted therapy treatment coming out. How do I get access to this, or how can I get involved, and how can I get treated, and that kind of thing. So the hope and the aim, if there's a single primary aim of this talk today, is to hopefully empower you with some, with how to, how to have that conversation with your patient that is most helpful to them, as well as to be able to keep them safe, and if they're going to be using a psychedelic anyway, potentially in a recreational or illicit setting, how can you still advise them to do so in ways that utilize harm-reduction approaches. And so, with that, so these views are my own. So some objectives we're going to hit, hopefully, is to understand the basic neuropharmacology of various psychedelics, to describe the current landscape of the therapeutic use of psychedelics, and to appreciate the evidence base of therapeutic efficacy and potential risks of MDMA, LSD, psilocybin, DMT, and Ibogaine, and lastly, to apply principles of harm-reduction to counseling patients about use of psychedelics and psychedelic-assisted therapy. And here's a brief outline, again, of what we're going to be talking about. We're just going to briefly, kind of have a brief overview of psychedelic and psychedelic therapy in general, and then we're going to take some time, about 10 minutes each, to go into each of these compounds and the associated assisted therapies that utilize these compounds. And at the end, we'll go a little bit deeper into how to counsel your patients about this topic specifically, and how to have a conversation that's based in harm-reduction approaches. So with that, so a brief overview. So here we have the phenethylamines, and you can see the pharmacologic structure of phenethylamines there. And so here you see various compounds and substances that you might already be aware of in terms of norepinephrine, epinephrine, dopamine, various medications that we already use are phenethylamines, to include bupropion, various amphetamines, and we have the tryptamines. Serotonin, tryptophan, melatonin are all tryptamines. Then we have dissociatives, and I definitely want to also preface by saying this isn't the only way to parse out different psychedelics. There are other ways to do it. This is the one way that I found to be personally most helpful, as well as most helpful in terms of helping other folks kind of parse out the differences between these different compounds. So some dissociatives that we're already potentially aware of are ascetamine, dextromethorphan, nitrous oxide, and various others. Then we have the intactogens, or otherwise known as empathogens, primarily, most notably, MDMA and MDA and other compounds. Then we have mescaline, we have LSD, psilocybin, ayahuasca, or DMT, and we have 5-MODMT and ibogaine and several others. And then we have ketamine, PCP, as dissociatives. And then we have what are known as the classical psychedelics. And so these are 5-HTA agonists, and they all have other varying mechanisms of action, but the unifying mechanism of action is the 5-HT2A partial agonism. As well as, in addition to that, they have the subjective effects, various subjective effects in terms of ego dissolution and kind of dissolving of the sense of self and various other subjective effects that come with that, that we're not going to get into too much today. And then we have what are colloquially known as the non-classical psychedelics. And again, this is a very subjective term. Again, there's different opinions on what constitutes a non-classical psychedelic. This is, again, a very subjective way to distinguish different compounds. So these can be referred to as non-classical psychedelics. And then, again, we have the antactogens and pathogens. Antactogen meaning to touch within, and a pathogen meaning to generate empathy. And lastly, so the term psychedelics can be, depending on the context and the person that you're talking to, can involve and not involve different compounds as well. So for example, some folks may or may not consider ketamine as a psychedelic. Other folks may or may not consider the antactogens as a psychedelic. It really depends on the context and the individual you're talking to in terms of what people consider a psychedelic. So this slide in itself could probably be a whole hour and a half in terms of really digging into this. So I'm really just going to leave it at a very brief 10,000 foot view in terms of just hitting each of these. So here we see different compounds on the left. And then we have a different, this is RCT data. There's a lot of uncontrolled observational data that isn't depicted in this slide. But in the second column you see RCT data for PTSD, depression RCT data, suicidality RCT data, pain. And then we have projected FDA approval. Again, this is, it's not that the FDA is saying this is when they're going to be FDA approved, but rather under the assumption, which is a huge assumption that may or may not be true, but under the assumption that they do make it past all phase three trials and do get FDA approved, this is about the timeline that you might expect them to be FDA approved if they were to reach that point. And so you have Ibogaine, which might be past 2030, same with 5-MeO, DMT, as well as DMT might be over past 2030, LSD maybe around 2030 for generalized anxiety disorder, most likely, psilocybin around 2026 for depression, MDMA, they actually just finished their last phase three trial several months ago, and it's currently under submission. And the estimated FDA approval for that, if it were to be FDA approved, is around June of next year for post-traumatic stress disorder, and then S-Ketamine, of course, have already been FDA approved as well as Ketamine. And I'm not going to get into cannabinoids here, but just to kind of leave this here just because folks may have questions about that. Again, not going to get too in-depth here just because, you know, I'll leave it to the rest of the slides to really delve deeper into each of these. So for what we're going to be talking about today are the compounds that you see here. And here you see, hopefully, a decent overview of what the landscape of psychedelic-assisted clinical trials have looked like over the past about 50 years. And so you see this initial peak of research until about 1970, and the ones that you see after 1970 are, so in 1970, you had the Controlled Substance Act, which developed the scheduling classification system and put LSD, psilocybin, and various other psychedelics to be classified as Schedule I substances, meaning that there's a high potential for abuse and no medical use. And some of the clinical trials that you see that happened that are published after 1970, of course, were not still being conducted at past 1970, but rather just were published afterwards. And then, of course, over the past 20 years or so, you see this resurgence of clinical trials in various psychedelics. And you're not going to really get in and belabor this too much, but this is just, if you look at LSD more specifically, a lot of research in the 1960s, we have this beginning of a resurgence over the past 10 years or so. Psilocybin there is not as much happening in the 1960s, and then you see a greater resurgence over the last decade. And with MDMA, the story behind MDMA is quite different from the other psychedelics in the sense that it really didn't kind of emerge in the zeitgeist until after the 1970 Controlled Substances Act. And it's really in 1970 where we initially see the initial vestiges of recreational use as well as therapeutic use until it was declared a Schedule I substance around 1985. And, of course, you see this resurgence over the last 10 years as well. Not going to get into this, but this is just, hopefully, a brief overview of different clinical trials that are being done for these three different substances. I'm not going to get into this, but suffice to say it's not just generalized anxiety disorder for LSD, and it's not just depression for psilocybin. It's not just PTSD for MDMA, but even though those are the three primary conditions that are being studied now, there are also now this broadening in terms of different indications that are now being studied for each of these compounds now. So one underlying assumption that I often run into is that folks tend to lump different psychedelics into the same black box that is based on the same connotations and preconceptions that we all have in terms of what a psychedelic is, especially in terms of its subjective effects. And so for folks that have never taken a psychedelic, you might have certain assumptions in terms of what you know from the 1960s and 70s in terms of the counterculture and everything that comes with that, and potentially putting holes in your brain, that kind of thing, and telomere shortening, that kind of stuff. And in terms of subjective effects, like you're totally out of it, quote unquote, and dissociating, that kind of thing. The point here is that the subjective effects of different psychedelics is actually quite different. We can't lump them into the same black box of the preconceptions and connotations we have, especially in terms of their subjective effects. We have to start parsing out in our own minds before we even start doing that with our patients in terms of helping them understand this. We as a community of psychiatrists have to start doing that as well, that just like an SSRI is going to be quite different from an MAOI. And the same with this, MDMA is going to be quite different from psilocybin or Ibogaine or DMT or LSD. These are all quite different. So here, what I like to think is a really nice study that was done back in 2020 that compared placebo versus deamphetamine versus MDMA versus LSD in terms of their subjective effects. And I'm not going to get into detail here, but the point being that you do get that ego dissolution, some anxiety, disembodiment, some impairments in cognition and control, complex imagery, elementary imagery, audiovisual synesthesia, and auditory alterations, especially with LSD, but you don't get that with MDMA. MDMA, in terms of its subjective effects, is much closer to LSD, actually, or sorry, to deamphetamine and placebo than it is to LSD and to these other classical psychedelics. And here we see a study that was done in 2007 that looks at the relative physical harm and dependence of these various compounds, and here you see LSD, MDMA, ketamine in terms of their relative dependence of physical harm, and here you see a similar study that shows that in terms of harm to self and to others, you see ecstasy, LSD, ketamine, and mushrooms, or otherwise known as psilocybin, down in the bottom corner and comparing that to other substances that we're more aware of on the top right. And so, because Nolan has to run, actually, and so I'm going to just breeze over this, but long story short, these compounds are neurogenic in the sense that they don't, not neurogenic in the sense of generating new neurons, but rather neurogenic in terms of generating new synapses and branching of neurons. And so, I'm not going to blaze over the point here, but just kind of leave it there. And lastly, this is what a treatment course might look like with psychosis therapy, where you have this, at least with MDMA, psilocybin, you have these six to eight-hour medication sessions, each of which might be about one month apart, and then you have, depending on the study, you might have two or three preparation sessions, each of which are about 90 minutes each, leading up to the first medication session, and after the first medication session, or each medication session, you'll have 90-minute integration sessions, and then, depending on the study, for example, psilocybin might have one or two medication sessions with MDMA, psychosis therapy might have two or three medication sessions, each about one month apart. And then lastly, this is what a, at least a clinical trial setting might look like with one of these compounds, and so this is a study that I was involved in over at Yale, looked at psilocybin and psychosis therapy for depression, and so ultimately, you see here, we simply just repurposed an office space and kind of built out this bed, and you see, you know, we're able to monitor folks' vitals, you have two chairs for the therapist as well, and with that, I'll turn it over to Nolan to, yeah, talk a little bit more about Ibogaine. Thanks Aaron, and thanks for having me, and I hope everybody's having a good morning. So I'll be talking specifically about some open-label data that we just finished up for Ibogaine in veterans with a history of traumatic brain injury, so it's specifically a combinatory drug of Ibogaine plus magnesium, because magnesium is cardiac-stabilizing, and as you all know, Ibogaine has a risk of negative cardiac effects, and so co-administration of magnesium seems to mitigate that. As I think everybody in the room knows, TBI is a signature injury of the Iraq and Afghan conflicts, right? A lot of veterans are coming back with traumatic brain injury and associated neuropsychiatric conditions like post-traumatic stress disorder, depression, suicidal ideation. Suicide is a big problem in veterans, particularly a big problem in special forces veterans, and that's the population that we really studied in this study, and as you all know, conventional treatments aren't 100% effective, that's why you're in this room and talking about psychedelics, because if, you know, other oral antidepressants or whatnot were effective in treating these problems, we would probably not have to be here at this conference, right? We'd be super happy about how things were going. So Ibogaine is a very broad-acting substance. It affects essentially all the neurotransmitter systems, serotonin, dopamine, glutamate, and it has a very particular effect on something called glial-derived neurotrophic factor, which maintains dopamine neurons, and so it's the only substance that we know that's oral bioavailable to do that. It can get into the brain and modify glial-derived neurotrophic factor, which, you know, we think has a big role in the efficacy that I'm going to show you in a second. You know, and so we were brought in actually to do this study in a more unusual way. There were service members going down to Mexico to take Ibogaine, and now about a thousand people have gone down, funded through a non-profit called Vets, to receive Ibogaine, and one of the individuals that goes anonymous on this asked a senior person at Stanford to ask me if we would do a study around this phenomenon, which, as you can imagine, my institutional review board was scratching their head for a little while and spent a little bit of time explaining why I would be doing this, but, you know, as they are, Stanford's IRB is wise and realized that folks were going to do this anyways, and trying to get a handle on why they were doing this. And so I was tasked with three questions. The first one is, why are service members going down to Mexico to take an extract of an African tree that has psychoactive properties and telling us that they feel a whole lot better across basically every domain when they get back? The second one is, you know, so what diagnoses are they coming in with? The second one is, what things are changing after? And the third is, is there some neurobiology to this? This is a first study of kind of neurobiology of Ibogaine effects. We've known for some time that anecdotal reports suggest that Ibogaine is an addiction-interruptive substance, right? And so a lot of the clinics in Mexico and other countries where this is legal, and by the way, it's legal even in Australia and New Zealand, right? So the legal status of this particular substance is pretty varied across countries. So we've known for some time that people will take this as an anti-addiction substance. There are a number of companies that are trying to develop it, again, for that. But this is a different indication, right? And so we recruited 30 of these individuals that were planning on going anyways, special operators, and Navy SEALs, Army Rangers, all of which had some level of traumatic brain injury, and brought them up to Stanford. Did about three days of evaluations, very deep evaluations, so psychiatric, psychological evaluations, neurocognitive testing, traumatic brain injury, disability evaluations, as well as neuroimaging, EEG, blood markers. So I'll show you some of the data that we have from that. They went down to, I almost gave the good news early. They went down to Mexico, they came back about a week later, and then they got evaluated about a month later, and then we ended up following them out, so we're following them out to a year. And so it's interesting in that sense, but all the data was collected by us. And really dramatic findings. I actually wasn't expecting this. I expected there to be something, given what these folks were telling me, but not at this level, so this is single subject data. Again, this is open label, it has all the caveats of an open label trial, in the sense that folks knew they were getting this. But I've shown this to a lot of senior psychopharmacologists, and this level of consistency, with a lot of folks getting out to six months on this, is pretty striking to all of us. And so we were pretty excited about that. This is disability scores, this is a HUDOS disability scale for traumatic brain injury. So looking at pre-post, one month, six months, and so we see that mild, moderate disability coming in from traumatic brain injury. And they were able to maintain down to normal levels and out to six months moral injury. So did you accidentally shoot a civilian when you meant to shoot the enemy? Did you leave your friend on the battlefield? That sort of thing, folks kind of wrestle with those sorts of issues. So a statistically significant reduction in moral injury and suicidal ideation. Excitingly also, an executive function. So these are formal neurocognitive evaluations of executive functions. So folks, cognitive flexibility, cognitive inhibition, processing speed, all improving. And then again, we looked at correlates of effects in neuroimaging, and kind of pre-post neuroimaging effects of this drug. So we observed increases in cortical thickness and key mood regulation areas like the insula and frontal pole, orbitofrontal cortex areas that we think about are normally implicated in emotion regulation. As well as interestingly, increases in white matter volume in the brain, which is something that you don't normally see. I don't know a drug that's capable of doing that. And then we had this very cool AI kind of machine learning algorithm. There's no human input. It's been trained on hundreds of thousands of brains. And so one of my post-docs got very interested in the question of, can you affect the brain age? So if I brought all of you in, scanned your brain, you may not see your exact chronological age. If you've not been taking care of yourself, you may have an older brain than your chronological age. If you've been taking care of yourself, you'll have a younger brain potentially than your chronological age. But if I scan you three times in a month, you're gonna have the same brain age based off of this machine learning algorithm. And so we observed a reversal of age of about 1.37 years. So kind of Benjamin buttoned the brain a little bit. So changes in cerebral blood flow across, again, key emotion regulation regions. And we saw correlations of the disability score with insular cerebral blood flow as a reflection of electrical activity in the brain. And specific subscales of that disability score, as well as connectivity changes across key emotion regulation areas that you would expect, like default mode network, cognitive control network. So we're pretty excited about this. We're trying to find next steps on how to do more trials with this substance. And think that it's appearing that this isn't just an anti-addiction candidate, but maybe also a drug for brain trauma and CNS injuries. So thank you very much, and thanks to the group for inviting me late in the game. Thank you. And I apologize that I have to take off and run to Stanford, so thank you again. And then just to follow up on, just to make one comment, following up on Nolan's piece. And so I just want to clarify that it was all veterans that were in his study, as opposed to any active duty service members, just to make that clear. All right, everyone, I'm gonna go over several psychedelics, mainly just kind of giving some background and really talking about kind of preliminary clinical data on what indications they may be useful in, talk about some limitations there, and I'm also gonna talk about potential adverse effects with the use of these substances, and then particularly medication interactions as we're talking about how to counsel patients. So the first thing I'm gonna talk about is DMT. So DMT, or endimethyltryptamine, is a naturally occurring tryptamine psychedelic that is naturally produced in many plants and animals. There's some evidence that it's endogenously produced in humans. Historically, it's been used by indigenous cultures in the Amazon Basin mainly through a brew, a tisane, that we'd normally call ayahuasca, that contains generally at least plants that contain DMT and then plants that contain MAOIs, and I'll talk why that's necessary. It's also used as snuffs, which are snorted, and generally, you know, these have been used for, there's been evidence that they've been used for thousands of years. They're generally used in kind of spiritual practices, some medicinal uses as well, but generally for healing, divination, and kind of communication with ancestors or gods. And so we should have some cultural humility in that this is very reductionist to stick to call it a medicine, and then also to, you know, really just talk about certain molecules. In terms of background or history, it was first synthesized by Richard Mask in 1931, but at that point, the psychedelic effects were not known. The first appearance in the scientific literature was in the early 1950s, and generally gained wider recognition through the work of Terence McKenna and his brother, and then also scientifically through the work of Rick Strassman. So DMT is kind of unique in terms of the studies that were able to be done after the Controlled Substances Act. So a lot of this work was done in the 1990s, when a lot of research was not being done on psychedelics. In terms of the legality, so it is a Schedule I controlled substance. However, there are exceptions for religious purposes. So for instance, this is a church in Utah, and so there are certain churches that can use ayahuasca for religious purposes, similar to cannabis and other plant medicines. In terms of the pharmacology, so as I said, it belongs to the tryptamine class. It's, again, is a partial agonist at many serotonin receptors, particularly the 5-HT2A receptor, and it also has interactions with other neurotransmitter systems, including dopamine and this unique SIGMO1 receptor, which may relate to kind of regulating BDNF and potentially the immune system as well in terms of maybe anti-inflammatory properties. In terms of ayahuasca, there are other components, particularly harmine, harmaline, and these are potent monoamine oxidase inhibitors that prevent the breakdown of DMT, so it can be orally active. And then also there's another one in there, THH, which also acts as a serotonin reuptake inhibitor. And again, ayahuasca is not something that's singular. It's generally made with lots of different plants, and so there's potentially lots of other molecules that have an effect and may have sort of an entourage effect. In terms of the pharmacokinetics, it really depends on the route of administration. So DMT itself, when it's vaporized or smoked or injected, acts quite quickly. And so generally, peak effects, or the onset is within a minute, and the peak effects are generally within five minutes, and the whole trip itself lasts about 10 to 15 minutes. So that's shown up here. And so it was referred to the businessman's lunch in the 1960s or 70s that you could trip in lunchtime. In terms of ayahuasca, so when it's consumed with an MAOI, it has a much longer effect, and so the onset is a little bit slower within a couple hours, peaking within two to four hours, and then kind of lasting about four to eight hours, generally. It's rapidly absorbed and distributed through the body. It's lipophilic, so it easily crosses the blood-brain barrier. In terms of its metabolism, again, DMT itself is metabolized in the liver by, there's extensive first pass metabolism, so by monoamine oxidase A. So again, orally, it's not active because it's rapidly metabolized. Generally, the metabolites are eliminated primarily through urine. In terms of what evidence we have for clinical efficacy, there's DMT and ayahuasca are kind of one of the least studied in terms of controlled studies. So it's kind of limited, but there's some limited evidence for antidepressant effects, potentially reducing suicidality, and then also some treatment for substance use disorders. So for each of these substances, I'm just gonna show a couple different studies. So if I don't show your favorite one, I apologize. So this was actually a randomized controlled trial in moderate to severe MDD. Basically, parallel arm, double-blind, placebo-controlled trial showing significant reductions in HAMD scores at day seven, and in terms of clinician-rated, a decrease in MADRS scores out to day seven. This one is not a controlled study, but it was looking at polysubstance users, particularly alcohol use disorder, and showing decreases in addiction severity index, in craving, and then in some improvement in emotional distress and overall quality of life. In terms of DMT by itself, so there's now becoming more studies with injected DMT. So this is a kind of very preliminary one from last year, just showing in some healthy users and some with, or healthy subjects and some with MDD, showing some decreases in HAMD scores with different doses. Generally, what was used here was between 0.1 and 0.3 mg per kg, which is similar to kind of that ayahuasca study I showed previously. But with ayahuasca use, again, it's not very regulated in terms of the doses, so it's not as well studied as psilocybin, LSD, where it's easier to kind of know what the doses are. In terms of the adverse effects, so physiologically, there are transient increases in heart rate, blood pressure, especially with ayahuasca. There's a lot of nausea, vomiting, diarrhea. This is also seen as a little bit part of the process, so whether that's adverse or not depends on the person. It can cause dizziness, loss of coordination, pupil dilation with smoking, respiratory irritation. Generally, in terms of psychological effects, acutely, it can cause anxiety, panic, paranoia. It can cause temporary psychosis, kind of just difficult emotional experiences, and that's the case with most psychedelics. And again, whether that is adverse really depends on the context and integration. In terms of long-term risks, with most psychedelics, and so a lot of these things will be the same for all of them, is there's a potential for hallucinogen persistent perceptual changes. Again, these are very rare, but we should be aware of them to be able to talk to patients about them. And then also, in people with predispositions like family history of bipolar or a primary psychotic disorder, it can potentially exacerbate or trigger one of those disorders. In terms of medication interactions, again, DMT is serotonergic. It interacts with SSRIs and other antidepressants. Generally, it seems that SSRIs kind of reduce its efficacy, kind of reducing the subjective experiences. There's a theoretical risk with all of these in terms of combining them with serotonergic medicines in terms of the risk of serotonin syndrome. It's rare and theoretical, but it's something that we should be able to counsel patients on. In terms of MAOIs, obviously that interacts with DMT, and that's sometimes the point, which is to increase and prolong the use. But again, depending on which MAOI and doses it potentially could cause serotonin syndrome or a hypertensive crisis. And DMT, again, can increase heart rate, blood pressure, and so you need to be careful with combining with other sympathomimetic agents. Okay, so now I'm gonna move on to LSD. So LSD, or lysergic acid diethylamide, is basically a semi-synthetic psychedelic. It's actually a derivative of ergot alkaloids, ergoline. It was first synthesized in 1938 by Albert Hoffman when he was looking for a circulatory and respiratory stimulant. It didn't have those effects. It kind of put it on the shelf for five years, but later decided maybe to re-look at it again. And when he was synthesizing it in 1943, he somehow was exposed to a very small amount and had subjective experiences of LSD. And then later, on April 19th, he intentionally ingested LSD at what he thought would be the smallest dose that would have an effect, which was 250 micrograms. And so he had a prolonged LSD experience. And that is now often celebrated, as you might know, Bicycle Day, because he rode back to his house on his bicycle while tripping. And so this was quite important, because at that point, little was known about neurotransmitters. This was like the smallest dose of a drug that they thought would, that could have such a profound psychological effect. And so this kind of led a little bit to the discovery of neurotransmitters. And then in terms of the 1950s and 60s, so he was working for a pharmaceutical company, Sandos, and so they produced it as Dlycid, and they distributed it to physicians, psychologists to study it, because initially it was thought to kind of mimic psychosis. And so it was sort of a way to study psychosis and also for psychiatrists to have some empathy for those and to understand the experience of psychosis. But it was quickly found to be very subjectively different and potentially useful in terms of psychotherapy and treatment of particularly things like distress from cancer and alcohol use disorder. Eventually, though, it was adopted by the counterculture movement, where it was very culturally influential in terms of music, art, and social attitudes. That was very subversive to the government. And so eventually it was made illegal and classified as a Schedule I substance, which it remains today. Though I was looking this up, and apparently it is decriminalized in Oregon for possession. So that's the only exception I could find for this. So again, we should know kind of the legality of these substances and where we practice so we can make sure to counsel patients on the legal aspects of use. In terms of the pharmacology, so similarly it is a 5-HTE2A agonist. It also interacts with other serotonin receptors. LSD is a little bit unique in that it has kind of a long residence time in the receptor. And so the subjective effects last a lot longer than the half-life in the plasma. It's also uniquely a D2 receptor agonist. So it's very orally bioavailable. It's absorbed rapidly, basically completely absorbed in the GI tract. Onset generally is within 20 to 60 minutes. Peak effects are usually two to four hours. And then the effects can last basically 12 to 16 hours. And again, it's lipophilic. It easily crosses the blood-brain barrier. In terms of metabolism, it's mainly metabolized by the liver, the cytochrome oxidase system, particularly CYP2D6, 2E1, 3A4 for this metabolite, NOR-LSD, and then these CYP1A2, 2C9, 2E4, 3A4 for this other one, OH-LSD, which is the main urinary metabolite, which can be used as a marker for drug testing. In terms of clinical efficacy, again, a lot of the studies, as Erin had showed, were initially done in the 1960s. And a lot of that was done on alcohol use disorder. And then now more recent studies have been done looking at treatment of anxiety, and specifically anxiety associated with life-threatening diseases, particularly cancer. So this is just a meta-analysis of studies from the 1960s showing some immediate and short-term effects in terms of alcohol use disorder. Didn't seem to last as long as 12 months. There's not any current studies published that I'm aware of in terms of modern studies for LSD, for alcohol use disorder. A lot of that has been with psilocybin. In terms of anxiety, here's some more recent ones. This is from 2014, a small study of 12 patients with some sort of life-threatening illness showing decreases in state anxiety and trait anxiety. So this was initially, if you got the LSD first, you can see the decrease. And then there was, those that got the placebo later got LSD, and you can see the decreases there. This is a more recent one this year showing a similar thing. This was placebo-controlled double-arm crossover. And again, you can see those that initially got the LSD first showed large decreases. And those that were randomized second, after they finally got the LSD, show large decreases. What about adverse effects? So very similarly, in terms of the physiologic effects, elevated body temperature, heart rate, blood pressure, pupil dilation. It can cause also nausea, sweating, things of that nature. Psychological effects, same. It can cause anxiety, paranoia, confusion, agitation, lead to particularly what we colloquially call bad trips or more difficult trips and panic attacks. And then there's documented cases of this hallucinogen persisting perception disorder. Very rare and not well-studied, but it is a possibility. And same thing that it can potentially trigger mental health conditions in those with predispositions such as family history or personal history. And in terms of documented deaths or injuries, oftentimes it's when done recreational in an unsafe environment where it can lead to accidents or injuries. So again, that's one thing that we need to talk about in terms of counseling patients. Set and setting are very important to remain safe. In terms of medication interactions, very similar. So SSRIs, SNRIs seem to diminish effects but have the potential for serotonin syndrome, TCAs. So for TCAs and MEYs, there's very little data. So this is from like, I think the 1980s and 10 patients taking these medications and recreationally using LSD and kind of the effects that they had. So take that with a grain of salt, whether that's true, whether TCAs seem to potentiate the effects and MEYs diminish it. But so I would say it's kind of equivocal. But again, the potential for serotonin. Now, there are some anecdotal evidence that lithium particularly interacts with LSD and may increase the risk for seizures. So that's something that we need to be aware of. Antipsychotics decrease the effects of LSD and other psychedelics and may actually be useful for if there are adverse effects. So psilocybin, it is also a naturally occurring tryptamine psychedelic. It's actually a prodrug because it's metabolized into psilocin. It's naturally produced by mushrooms. There are documented 100, 200 species in every continent except Antarctica. It has the longest evidence of historical use going back at least 7,000 BCE. So there's some cave paintings from Algeria demonstrating what looks like to be psilocybin containing mushrooms. It's been used by the Aztecs and Mayans. They had words for it, which roughly translates to flesh of God. It's been used by indigenous groups across Central and South America, particularly the Mazatec people. Again, it was used for really spiritual and medicinal purposes. There's some evidence for maybe Siberia, Australia, other places, but not as much for Central and South America. It was basically exposed to the Western world through R. Gordon Watson and his wife, Valentina, who basically popularized it through this article in Life magazine. They first were exposed to it by a Mazatec shaman, Maria Sabina. Our friend, Albert Hoffman, was actually the one to isolate the compound in 1958 and actually synthesize it in 1959. It similarly was produced by Sandos as well. It gained popularity similar to LSD in the counterculture and, again, led to a backlash and was made illegal. In terms of the current legality, federally, it's a Schedule I substance, but there are some states and municipalities that have decriminalized or legalized. And so, in terms of states, it's Denver and Oregon, but there are several cities that have decriminalized the possession, such as Oakland. Pharmacology, similarly, it's a 5-HT2A agonist. Again, psilocybin is the pro-drug. It's converted to psilocin mainly in the GI tract through dephosphorylation. It interacts with several other serotonin receptors as well. In terms of pharmacokinetics, so it's generally ingested in dried mushrooms or purified compounds. You can do it as teas as well. Generally, the effects occur within 30 minutes to two hours and the experience generally lasts between four to eight hours, with the peak being about 60 to 90 minutes. And then, in terms of the metabolism, it's a little bit more complicated, but also metabolized in the liver, mainly through the UGT and cytochrome oxidase systems. It's glucuronidated, that's the main way, and eliminated through the urine. In terms of CYPs, CYP2D6, 1A2, and a little bit of 3A4. So, psilocybin, it's the most well-studied psychedelic in terms of modern clinical research. There's a lot of reasons for that, in terms of it doesn't have the political baggage of LSD, but also it's a kind of shorter trip than LSD, and so a little bit easier to do in a clinical setting. But it has the greatest body of evidence for major depressive disorder, or depression, anxiety, associated with life-threatening illness. Treatment for substance use disorder, and there's some preliminary evidence in OCD. So, I'm just gonna show a couple studies. So, this is from the phase two COMPASS trial, showing one dose. Well, so they did a couple different doses, one, 10, and 25, and it was the 25 milligram dose that showed significant effects that lasted out to 12 weeks. There's no difference between the one milligram and 10 milligram dose. This is another study. This one was two doses, but they followed them up to 12 months, showing significant effects in major depressive disorder. This is a more recent study from Bogenschutz, looking at alcohol use disorder, and this, again, had quite good effects in terms of percent heavy drinking days, percent drinking days, and drinks per day, compared to an active placebo. Adverse effects, very similar, nausea, vomiting, increased heart rate, blood pressure. Similar psychological effects, anxiety, paranoia, confusion, agitation, and then, again, the persisting perception disorder. Same thing with potentially triggering mania or psychosis. Again, these things are rare, but there are documented cases of this, and so we should make sure to counsel patients with these disorders or family history so they can make informed decisions. In terms of medication interactions, very similar. So concurrent use may reduce the psychoactive effects with SSRIs, SNRIs, and TCAs, and there's a theoretical risk of serotonin syndrome. There have been some studies where people have been on SSRIs with psilocybin, and they've shown clinical efficacy. So once we get more data, it may be the case that we may have some safety data of what can be used, but MAOIs particularly can intensify and prolong the effects, and may have the risk of serotonin syndrome. Antipsychotics, again, can dampen the effects, and that may be useful. Same thing with benzodiazepines. This is often used to manage anxiety with quote-unquote bad trips. All right, I will hand it over to Erin. Thank you. All right, and thank you again, Brian, for giving a really nice overview of both DMT, LSD, and psilocybin. So at this point, we're gonna move on to MDMA. And so MDMA is what's otherwise known as 3,4-methylenedioxymethamphetamine, also known as Ecstasy or Moly, when it's used in recreational contexts. So it can be both found in this capsule form, typically known as Moly, or in a tablet form or pressed form, more commonly known as Ecstasy. And just to get a little bit into some pharmacology, the primary mechanism is that the MDMA doesn't necessarily act postsynaptically, but primarily presynaptically in terms of reversing the serotonin reuptake transporter, as well as inhibiting the vesicular monoamine transporter as well, which releases, so it goes into, it goes through the serotonin reuptake transporter as well as reversing it. So you actually get an efflux instead of an influx at the presynaptic neuron, in terms of primarily serotonin, but also you get some of those effects in terms of norepinephrine as well as dopamine. And you also see this endogenous release of oxytocin, which also has some implications in terms of, it's not 100% clear yet, but there are some implications with oxytocin in terms of some of the subjective, as well as potentially some of the therapeutic effects of MDMA. Again, there's still a lot more that we need to learn in terms of that, but there is some thinking there, the intersection of oxytocin potentially being rooted in some of the therapeutic efficacy of MDMA. Just to get a little bit more into oxytocin, so with MDMA, we'll start with an intranasal oxytocin you see in the middle, where you do see a little bit bump in terms of serum levels of oxytocin, but what you see with MDMA, interestingly, is a substantial increase of endogenous release of oxytocin. In terms of some of the risks of harm, so with MDMA, particularly when used in recreational context, there's the potential for hyperthermia, hyponatremia, some cardiac complications, as well as effects that are specific to any adulterants that you might find in the substance, or in the XSE or MOLLE. And hyperthermia primarily is thought to be linked to the context in which XSE or MOLLE is typically used. So typically, you might see this at a rave or some kind of recreational context where folks are dancing a lot, they might be under-hydrating, and it might be in a really compact and confined environment where it's really hot and confined and without much ventilation. And so for those reasons, that's why I thought that you do see some more instances of hyperthermia. And so in the recreational context, folks know this. And so often they'll overhydrate in order to compensate for that. And so doing, you do see cases where due to this overhydration, folks get hyponatremia and sometimes have seizures due to that. And then there's also some effects that MDMA has in terms of releasing ADH as well. And so you get this syndrome of inappropriate antidiuretic hormone. And so with that, that also exacerbates the potential for SIADH as well as hyponatremia. There's also a few instances of cardiac complications that happen with this. And again, and people have died with MDMA in their system in recreational context. Not, there hasn't, but when you look at recreational context versus medicalized context, what you see is that there's been over about 1,770 some, now probably 1,800 cases or instances of MDMA being administered in a controlled clinical trial setting with using pharmaceutical grade MDMA. And out of those 1,800 instances, there hasn't been a single instance of mortality due to any of these reasons, primarily because of the highly medicalized context where there is numerous layers of not only medical screening but medical monitoring that come with it. And just to kind of get a little bit more into recreational context. And so of, there's one study out of the UK that looked at across four years they found that of about 81 cases where folks had died with MDMA in their system, the vast majority of cases also had, I think it's about 80 to 90% of cases also had other substances in their system and opioids were the primary substance that were also in folks' system. And so definitely wanna help folks understand the importance of distinguishing, in our own minds again as providers and helping patients understand this as well, making a clear distinction between recreational use and the evidence, a really wide, a large body of evidence looking at MDMA in recreational context versus the evidence of MDMA in clinical trial context. These are very different. And I think the harm that can be done is when we're potentially unintentionally using evidence from recreational context and applying some of that evidence to make decisions about medical, MDMA use in medical context and vice versa where it's also, there's also danger and potential harm that can come with using evidence from medicalized clinical trial context and inappropriately applying that to recreational context to make it seem that recreational MDMA use is safer than it really is. And so I think it's just, again, really wanna emphasize that point of distinct, again, in our own minds really distinguishing the evidence of recreational versus medical use. Some medication interactions that are really important to understand are when you combine MDMA with MAOIs, there is a potential for serotonin syndrome and of course the morbidity and mortality that can come with that. Versus, and there's this kind of often a misunderstanding that when combining MDMA with SSRIs or any serotonin medication that inhibits serotonin reuptake that there's a synergistic effect but actually you see an attenuation. And the reason for that is because, remember MDMA actually acts at SIRT, the serotonin reuptake transporter. And if you inhibit that, you get a competition at the SIRT, and so that effectively blocks the uptake of MDMA into that presynaptic neuron. And that's why you actually get an attenuation as opposed to a synergistic effect when you combine MDMA with serotonin reuptake inhibitors. So folks might be aware of this, the narrative that MDMA puts holes in your brain. And so that is, that was based off of a study that was published in Science back in 2002 where they found that when they gave primates or injected primates with what they understood to be supratherapeutic doses of MDMA at doses I believe up to 20 milligrams per kilogram, and again a therapeutic dose being about a 1.5 to two milligrams per kilogram, they found that not that there's physical holes in the brain but rather functional holes in the brain on PET and SPECT imaging. But that study the next year was retracted. The reason for that was, as you see here in the report of the retraction was that the drug he used to treat all but one animal in that report came from a bottle that contained methamphetamine instead of the intended drug MDMA. And so there's a whole backstory to that that we're not gonna get into, but suffice to say, the narrative and the myth, frankly, had already gotten out there and that had led to this misconception that MDMA puts holes in your brain. Again, not physical but functional holes. But as you see here, an image from, I believe, the Oprah show that, where they brought someone in and showed this image, this functional image, and you see these functional holes, not physical holes in the brain, but they didn't necessarily explain that in the show. And so they also state that multiple subsequent attempts to reproduce the original findings with systematically administered doses of MDMA were also unsuccessful under a variety of laboratory conditions. So when they tried to reproduce those findings, they couldn't. So they also, with that team, withdrew four other papers. And what we also find is that with healthy controls, using not doses, not injecting doses of 20 to 30 milligrams twice a day, 20 to 30 milligrams per kilogram twice a day, when you look at healthy controls in humans using therapeutic doses of 1.5 up to two-ish milligrams per kilogram versus healthy controls, that it's extremely unlikely that a moderate dose of MDMA leads to neurotoxic damage. Neurocognition is another important question that folks often have. And so this is a secondary analysis based on four of the six phase two trials of MDMA-assisted therapy for post-traumatic stress disorder. And effectively, they found that there's no differences in several different measures of neurocognition when you look at control versus folks that received the active MDMA. And this is in folks that received MDMA-assisted therapy for PTSD. Another question that folks often have is, to what extent does this lead to future substance use after the treatment? And again, we're talking about MDMA-assisted therapy here, not just MDMA use. So across six phase two studies, when you look at about 80 individuals that were administered MDMA-assisted therapy for post-traumatic stress disorder, at 12-month follow-up, eight individuals did end up using MDMA again. Six of those eight had already used MDMA prior, so it was not new use. Two, both of the two individuals that did constitute new use had attempted to use MDMA in a kind of a makeshift therapeutic setting on their own without trained therapists there. What they both found is, I took the MDMA, I try to kind of do this makeshift thing. They both reported back saying, yeah, it just didn't really do much for me. And the reason, because they didn't have the surrounding therapy that is really thought to be the most important part of, not only MDMA-assisted therapy, but also any psychedelic-assisted therapy, and we'll talk about it in a second. And in this same analysis, they found that more folks actually decreased their alcohol use, about 40%, versus not. There was seemingly no impact on marijuana use. And so when you look, so again, the best evidence right now for MDMA-assisted therapy is for post-traumatic stress disorder. And so if you look at our current gold standard treatments for PTSD, we have primarily prolonged exposure therapy, as well as cognitive processing therapy. Again, both really great treatments for post-traumatic stress, but also, I would say, these are the best available treatments right now. And there's a study that came out in 2015 looking at these two treatments for folks and military personnel or veterans with military-related PTSD, and they found that about one-third of folks will no longer be diagnosed with PTSD with these treatments, and about a quarter to half of folks will actually drop out of treatment. You compare that to MDMA-assisted therapy for post-traumatic stress disorder, and what you find is about two-thirds of folks will no longer be diagnosed with PTSD, and less than 10% of folks drop out. And keep in mind that MDMA-assisted therapy, and really all psychedelic therapies, are typically a lot more resource-intensive. So you have two therapists instead of one, and ultimately, it's about 40-plus therapist hours per therapist for an effective dose of 80-plus therapist hours compared to about 12 to 18 with PE or CPT. Yet, you actually get less dropout versus more with greater efficacy instead of less. And so with MDMA-assisted therapy, about after two to three dosing sessions, primarily right now, the thinking is that three dosing sessions might be the optimal dose. Again, two-thirds of folks no longer diagnosed with PTSD. The effects are durable at four years, which I think we'll see in the next slide. FDA granted it breakthrough therapy designation back in 2017. The last phase three trial was recently submitted, completed several months ago, and hopefully will be published by the end of the year. There's at least a 90% chance of FDA approval next year, and that's just looking at, if you look at all psychiatric medications that get to this point, finishing phase three studies, about, actually, 92% of those will be FDA-approved at this point. But that doesn't account for the fact that the organization that has been doing these studies to establish an agreement with the FDA that if they meet certain criteria, that it in fact will be FDA-approved. And so this 90% is potentially a conservative estimate. So, again, FDA approval projected to be in mid-2024. And if you look at all the phase two trials of MDMA psychotherapy for post-traumatic stress disorder. After about two treatments, you get about half of folks no longer be diagnosable versus about a quarter of folks in the placebo group. At one year out, you get two-thirds of folks no longer being diagnosable. And then at the longest published follow-up right now is looking at, I believe, two of those phase, or sorry, one of those phase two studies. And they followed folks up to about almost four years out, and they found that three-fourths of individuals were no longer diagnosable with PTSD. And then when you bring in the first of two phase three trials that was published, the first one being in 2021, published in Nature Medicine, and they found that after three doses of MDMA, that's the therapy, that two-thirds were no longer diagnosable. So this is some preliminary findings that are yet unpublished from an IPD meta-analysis that we're conducting with a team at Yale, looking at MDMA therapy using not aggregated data, drawn from the published data, but rather using raw data and reconstructing a meta-analysis from the raw data, and basically found that there's, confirming what we already know, essentially, that MDMA has a high, has a strong effect size in terms of reducing symptoms of PTSD, as well as for depression, comorbid depression in folks with PTSD, as well as for comorbid sleep disturbance in folks with PTSD. So just gonna take a little time to speak about legal settings, as well as harm reduction concepts and approaches to be able to discuss this topic with your patients. And so, one way to look at it, this isn't the way, but just a way to look at it, is there being a spectrum of non-medical to medicalized settings. And so, of course, it goes without saying that recreational use is illegal. And whereas there are some pathways for religious use, and it is technically legal with various caveats that are, I would say, outside of the scope of this talk. And, of course, there's the organ model that was alluded to earlier, where, for example, the state of Oregon is the first to pass this model whereby there's facilitators that would be licensed by the state of Oregon to be trained in psilocybin, particularly psilocybin, not psilocybin as a therapy, because legally it's not a therapy, but rather facilitated use. And so you have these facilitators, not therapists, that are licensed by the state to facilitate the delivery of psilocybin, not in a therapeutic, but a facilitated, rather a facilitated setting. So that's one model that you'll see that may be getting traction across other states as well. Again, that's a non-medical setting and paradigm. And again, also just to speak a little bit more about that, I think that's gonna be one, I'm not gonna say challenge, but I think one issue that is gonna be a really tricky thing, I think, for our field to really contend with and how to talk with patients about this, because again, this is not medical use in terms of this Oregon model that might be spreading to other states. This is non-medical, it's a non-medical paradigm. And so how do you talk about that with patients? Because you have this evidence of psilocybin-assisted therapy. Again, psilocybin-assisted therapy for depression is showing efficacy, but that's not what we're talking about here with the Oregon model. We're talking about non-medical use that technically is not therapy, it's facilitated use. And so it's gonna be a tricky thing to navigate that. And I think the evidence-based approach to having that discussion is that there is no evidence in terms of the therapeutic efficacy of facilitated non-medical use in this Oregon model. And I think that's just the fact of the matter. And so there's also pathways for medicalized use for countries in the Caribbean, Mexico, and elsewhere that is technically medicalized, but it's unregulated. And so it's not a legal prescription, actually, where it is medicalized, where you have physicians who are frankly willing to take on certain personal risks to deliver these treatments in a medicalized setting, but technically not necessarily legal, because it's unregulated. And so, again, that's just another piece of the puzzle that you'll have to have in navigating that discussion with your patients. And so it's medicalized, but it's not technically legal. And in clinical trials, of course, it hopefully goes without saying that that is a legal setting. Expanded access or compassionate use has now been approved across the country for MDMA-assisted therapy, which is an FDA-approved legal setting and pathway. And, of course, if these treatments become FDA-approved, then that, of course, would be a legal setting. And so, at least at this point, especially before these are FDA-approved, how do you have that conversation with patients? Because I think the big picture, I don't have a slide on this, but I think the big picture, in my mind, the big picture takeaway is actually the idea that this is getting national attention, and this is a national conversation, and this is even before FDA approval of the first psychedelic. And so how do you, so there's this gonna be already a demand now, and this is before FDA approval, I'm just imagining what the demand is gonna be like once these are FDA-approved. Yet the access to these treatments are gonna be so limited, frankly, because these are highly resource-intensive treatments, like I mentioned earlier. And in the same vein as surgery being a highly resource-intensive treatment. And they require highly specialized training that can take weeks and months long to get trained in these modalities. So how do you navigate that conversation with a patient who's coming to you asking, I'm hearing about this, but essentially I can't access it anywhere. At this point, at least, the only real legal access is through clinical trials, pretty much, and expanded access, coming on board. And it's pretty much inaccessible. For example, at least at one expanded access site for ME assist therapy, just for a small handful of five to 10 slots, you have a wait list of over 1,400 folks on a wait list just for five to 10 slots. It's effectively inaccessible. How do you have that conversation? So folks can go to clinicaltrials.gov, and you can recommend that folks go to clinicaltrials.gov to access legal routes. And it's kind of diverting folks from illicit and recreational use to these legal pathways. Because again, recreational use, so the issue is that because access is gonna be so limited in legal settings that folks are gonna realize there's very little access, and they're gonna self redirect to illicit use. And I think that is the huge disaster that, and crisis, I think, that we're gonna be coming upon, where because there's so little access in legal settings, that folks are gonna self redirect to illicit use and recreational use. And a small portion of those, like I mentioned earlier, that people die. Not often, but people do die when they use these substances in recreational settings, particularly when they're combined with other substances, and particularly when they don't realize it's being combined with other substances. And so people do die, and I think people are gonna die because there is not enough access in legal settings. And so the responsibility for every single person in this room when a patient comes to you is to help them understand that, to help redirect them to legal settings so that we're reducing harm and maximizing or minimizing risk. So again, harm reduction techniques. Of course, the first line, the first response when a patient comes to you is please don't do this in recreational settings for all these reasons that we already talked about. Here are some legal avenues. But if you're gonna use it in a recreational setting anyway, I hope, you know, thank you for telling me, thank you for letting me know. Here's all the information that you need to understand how and why that's potentially a harmful idea. But if you're gonna do it anyway, well, there's testing kits out there to be able to test the compounds that you're using because a lot of times they are adulterated with things that could kill you. And if you're gonna use it anyway in a non-medical setting, to use sitters, use this by yourself. And again, with ecstasy, not pharmaceutical-grade MDMA, but with ecstasy and MOLLY, the most common substance that's also on board are opioids. And so be sure to get Narcan, or I can't say Narcan, naloxone, and be sure to have that. And have your sitter, you know, make sure the sitter that you're using understands how to use the naloxone. So another, I think, really important concept to hopefully take away is this paradigm shift that's happening, again, this is just my personal opinion, but this paradigm shift happening from the model of chronic medications shifting to now this concept, or paradigm of medication-assisted therapy, or the classic paradigm, as we're all well aware, is with chronic medications that the cause of psychiatric conditions are rooted in disordered neurobiology. And that the role of the, if that's the case, the role of the medication is to, in order to offset this disordered neurobiology, the role of the medication is to offset that disordered neurobiology, in order to do that, you have to have medication in your system perpetually, effectively, to continuously offset that disordered neurobiology. That's the paradigm we're effectively working in right now, with our medications, versus the emerging paradigm of medication-assisted therapy, whereby the cause of psychiatric conditions is rooted in disordered cognitions, emotions, and behaviors, and this is nothing new. But if that's the fundamental paradigm that's driving treatment, and how to treat, then it's the therapy, not the medication, that's the most important aspect of treatment. And then the role of the medication, whether it's psychedelic or stellar ganglion block, that's another topic, is to enhance the therapy. And that's the role of the medication. And the medication, if that's the paradigm, then medication is, the medication is really only gonna be taken infrequently, whether it be one to three times total, and only in a supervised medical setting, analogous to surgical anesthesia. No one is taking surgical anesthesia home, or taking it every day, unless you're Michael Jackson, and you have, which is really unfortunate, right? But I think the point being that you can literally, I think Michael Jackson's a perfect example of a situation where if you take a substance, in this case a literal surgical anesthesia, and you use it in a totally inappropriate setting, administered by, in his case, a cardiologist, who wasn't, was totally inappropriate in delivering that treatment, in an inappropriate setting, you can die. Whereas with this paradigm, the idea is that you're using the substance only in a highly medicalized setting, only delivered by highly trained individuals who are trained and credentialed, eventually, to do this. So, we have five minutes left, and this is the last takeaway that I would offer you. And helping, not only helping you understand how to conceptualize psychedelic psychotherapy, but also how to communicate this to your patients. So, there's the analogy of psychedelic therapy to surgery. So, psychedelic therapy is psychedelic, is analogous to anesthesia, in the same way that therapy is analogous to the surgery. Where anesthesia without surgery is just temporary analgesia, without addressing the underlying issue. And that will make you feel good, temporarily, while you're under the anesthetic. But it's not addressing any underlying issue, unless you have the surgery there to cut deep into the core issue, to actually, to cut deeper at a level that is impossible without the anesthetic, or technically possible, but really would be aversive to the individual being cut into. But with the anesthesia, in this case, the psychedelic, you're able to cut deeper into the wound to actually address the underlying issue. And that's why we see such a great efficacy and a low dropout. And another additional perspective I would offer is the idea between a knife versus a scalpel. Where a knife in the wrong hands, in the wrong context, there's a higher risk of harm. I could probably kill you, if I really wanted to, with a knife. And with the wrong intentions. Versus a scalpel, in the right hand, and in the right context, delivered by a highly trained professional with high standards of personal morals and ethics in a highly medicalized setting, there's great potential for dramatic clinical benefit, even when everything else has failed. And the last kind of perspective, a third perspective I would offer under this analogy, is the idea how you have orthopedic surgery, for example, for a musculoskeletal injury, being analogous to psychedelic psychotherapy for a psychiatric condition. Where with a musculoskeletal injury, you have an NSAID, which helps symptomatically. Where you have physical therapy to attempt to address an underlying issue at a certain level, but there's a certain threshold that just can't be addressed with physical therapy. And if that fails, after six to eight weeks, typically, then you have orthopedic surgery there, which is a more highly resource-intensive treatment, but you have a smaller sliver of folks who've reached that point, because hopefully, a certain amount of folks are helped with first-line treatments. But again, at least we have that safety net of something that really works, that actually addresses the underlying issue, if the first-line treatments don't work. The same idea, in my mind, we're seeing with psychedelic psychotherapy, where antidepressants, that can help with symptoms. We understand that, we have a great body of evidence for 50 years that establishes that as a fact. Psychotherapy attempts to address the underlying issue, but again, when that fails, when you can't cut deep enough with the psychotherapy, with the medication, then that's where we need a last-line treatment that actually works, and is durable as well. So with that, with the little time we have left, I'm sorry, Jacqueline, for running a little over without much time for questions. We have, well, that was a great talk. Thank you so much. Thank you. I'll give Dr. Winchell the first question. Thank you very quickly for a great talk, since we have no time. But in the current journal of the American Journal of Psychiatry, there is a fairly convincing case report of a patient in a study in psilocybin who did not reveal that he was taking trazodone. And nonetheless, there appears to have been a rather robust therapeutic impact on his treatment-resistant depression. I have been wondering, to what extent are we aware, and have we separated the therapy from the pharmacologic effects? Or is it a model that appeals to us, and it's basically dominated the research, and we don't really know how dependent the pharmacologic or long-term benefit is on the psychotherapeutic component, and is it for psychedelics in general, or any of these medications? I would say generally we haven't been able to separate that. There haven't been studies that look at psychedelics themselves without therapy, in terms of if there's a therapeutic effect. So I would say generally we don't know, and I think people are resistant to maybe test that. But I think that will be done, to try to separate if you aren't doing the preparation and integration afterwards. But obviously, there's a lot of evidence that that's, especially again when we're counseling patients, that that's done in the studies, and these things are important to have in terms of safety, psychological safety, is the integration afterwards. Thank you. I'm going to bring up a question from the chat. So for either one of you, does the use of one psychedelic impact or inform the potential use or efficacy of other psychedelics? For example, if a patient with PTSD and depression is treated with ketamine, would that impact the efficacy of MDMA in the future? Yeah, thank you for that great question. We just don't know yet at this point. And more research is needed. We hate when we have to say that, but just more research is needed, because we just don't have enough to know. I wanted to ask, I think it was a similar question. There's no indication of what kind of treatment would be helpful within the use of any of these medications, any of these psychedelics. And it's very clear that certain treatments would be better than others, and I think it behooves us to figure out what treatment to use. I personally think mentalization-based treatment would be the best, because it deals with compassion and vulnerability and clarification, and it's a gentle treatment. My other question is, your last statement kind of bothered me. I work with borderline personality disorder, and I also am aware of all the studies on psilocybin, like substance abuse, alcohols, et cetera, et cetera, have very, very high incidence of comorbidity with borderline personality disorder. These people go through years and years and years of trying this and trying that and trying this to no avail. So I think that psychedelics should not be used as after trying everything else. It might be better to start thinking about it in the beginning, so that people have a chance of a life, not after 10, 15, 20 years of failed attempts, which often lead to suicide. So I wonder if you had any thoughts about that. Yeah, thank you for that really important question. So when I say, at least when I remark that psychedelics probably has to be a last-line treatment or a second-line treatment, I'm more thinking in terms of its resource-intensiveness, in the same way that surgery is a highly resource-intensive treatment, but highly efficacious, yet resource-intensive where it would be nice to be able to offer everyone surgery who could benefit and to widen the aperture of folks who would be eligible for surgery, in the same way that it would be, I think, I totally agree that if we could widen the aperture of folks that have access to this highly resource-intensive psychedelic assist therapy, that there could be great benefit in that across a population. Again, I think the fundamental issue, though, is going to be because it's so resource-intensive that access is going to be so limited that you do, as a system, from a system-wide perspective, the reality is that the aperture of folks who are going to be eligible for psychedelic assist therapy probably is going to be smaller than we would hope. I think that you're making an error because I think people are using it on their own, and that is the most dangerous of all. I'm going to segue to one of the online questions, and then we're going to take one more in-person question because we need to clear the room for the 10.30 talk. On that topic of people using it recreationally, would you ever recommend a small dose of Risperidone or a benzodiazepine for people who are openly saying, I'm going to take this recreationally, can you help me as my psychiatrist? I think, similar to what Erin was saying in terms of providing Narcan, I think in certain situations it does make sense to provide a PRN medication to be used, especially if someone has predispositions or already have a diagnosis of, say, bipolar illness or some past history of psychosis. I think that is reasonable to do that, and that's, again, a harm reduction principle. You're not encouraging use. This is often done when patients don't want to be on medications. I often will say, here's a prescription to have on hand. If things worsen, you can use this. So I think in a similar way, what you're doing is you're preventing harm by potentially providing something like a small amount of Risperidone, Olanzapine, or maybe even benzodiazepine. All right. Last question. Yeah. So my question is, so for patients who are taking antidepressants like SSRIs, they say, hey, I want to use Molly, I want to use Ecstasy at this rave, and taking a harm reduction approach and knowing the theoretical risk for serotonin syndrome, would you counsel people to hold their SSRI for a day or two, or how would you counsel them about that? And then the other question is, like, people with bipolar disorder who are also wanting to do this, the risk for mania, how would you counsel them about it? Yeah. That's a really tricky situation, because if you're—I mean, of course, there's evidence that came out the last year or two showing that when folks come off their antidepressant, they are more likely to have a recurrence in their depression. So, yeah, in my mind, it would be more about just helping them understand the risks that they're undertaking by coming off of an antidepressant versus if they were to stay on it, and helping them come to their own evidence-based conclusion on what to do with that information. But it's a tricky situation. Yeah. All right. Well, thank you, guys, for a great talk. Thank you all for your attention. Thank you.

psychedelics

psychedelic-assisted therapy

harm reduction

DMT

LSD

psilocybin

depression

anxiety

PTSD

substance use

Ibogaine

psychiatric disorders

pharmacological insights