Okay, it's 1.30 and we're going to go. So good afternoon everybody, I'm Paul Appelbaum, I'm a professor of psychiatry at Columbia and I'm going to be the chair for this session today on Challenges in the Use of Psychedelic Compounds for Psychiatric Treatment. And what I want to do in terms of just very briefly setting the stage here, although given the number of you who are out there, this seems likely that much of this is going to be familiar to you, but I want to try to answer the question as to why we're here today. What accounts for the growing interest in psychedelic treatment in psychiatry? And the answer is we have seen preliminary research, and I want to underscore preliminary because obviously none of the drugs we're going to be talking about today have yet been approved for clinical use in the United States, that has suggested the potential efficacy of psychedelic medication and more than one psychedelic medication for several treatment purposes. Among them, and among the most prominent of course is depression, psilocybin has been the leading compound tested here and there's now a large literature and just to select One of the more prominent or though by now older studies, Carhart-Harris and colleagues found that two doses of psilocybin were as effective at six weeks as daily escitalogram for patients with depression. Goodwin and colleagues followed up with a report a year later indicating that one dose of psilocybin at a higher but not intermediate or lower dosage significantly reduced symptoms of depression in a fair number of patients with treatment resistant depression at three weeks in a phase two study. So there's lots of optimism about the potential use of psilocybin for depression. But it's not just depression that has galvanized interest in this area. You will see reports in the literature of use of psychedelics for substance use disorders including alcohol use disorder. So this is a study from two years ago by Bogenschutz and colleagues which showed that comparing two doses of psilocybin versus diphenhydramine, essentially a placebo here, plus 12 weeks of psychotherapy resulted in significantly fewer heavy drinking days in the psilocybin groups compared with the control groups. One of the earliest uses of psychedelics to be explored was for cancer associated distress. So this is a 2016 study which demonstrated that one dose of psilocybin compared with niacin and exactly what the comparators should be, what the placebo condition, if you will, should be in these studies is a matter of active debate and contention and it is a conundrum. Plus psychotherapy and a crossover design led to a significant reduction in anxiety, depression, demoralization, and hopelessness among patients who were in some real sense facing death. And then quite recently, just this year, came a report that ibogaine combined with magnesium led to significant decreases in the WHO-DAS which is a functional disability measure and in clinical measures. At one month in a relatively small sample, 30 patients who had experienced traumatic brain injury. So you can see the range of proposed uses for psychedelics in psychiatry is quite broad at this point. You will also immediately discern that many of the samples in these studies have been quite small and that although the data are encouraging, they are by no means yet definitive. The interest, of course, extends beyond classical psychedelics of which lociban is the leading example today that's being explored for therapeutic uses and it clearly extends to MDMA. MDMA, which is a medication that has been used in non-clinical settings as well, has been extensively explored for use in PTSD. This was the first of two studies that have been published suggesting that MDMA combined with psychotherapy compared with placebo plus psychotherapy led to significant decreases in PTSD symptoms. These and the more recent data have been submitted to the FDA and a decision from the FDA is expected by early August. So we will know then whether we will soon see MDMA rolled out in the clinical realm. So as an overview of this session, which will consider a number of aspects of the use of psychedelics in light of the excitement that has built around them, Dr. Koukassian will talk about what you might consider the other side of the coin here, what is an often neglected topic when we talk about psychedelics, which are the potential risks of psychedelic use. I will be coming back to talk about the implications of the very complex effects of psychedelics for the informed consent process, how we talk to patients about these medications and the difficulties that we are likely to encounter in ensuring that their use is appropriate and equitable. And Dr. McGuire will discuss the unregulated and potential off-label use of psychedelics, especially in the context of psychedelic retreats. So before I turn this over to Dr. Koukassian, let me tell you a little bit about her. Natalie Koukassian is an assistant professor of psychiatry at Columbia University Medical Center. She was the inaugural medical director of the Johns Hopkins Center for Psychedelic and Consciousness Research, and her research interests focus on understanding and optimizing the safety and efficacy of psychedelic-assisted therapy and other novel mental health interventions. And so with that, let me turn this over to Natalie. There we go. Thank you. All righty. Good afternoon, everybody. Thank you for turning out. It looks like we have a great, large crowd, hopefully some stimulating discussion, and thanks for the introduction. A lot of my talk and experience is informed by my history back at the Hopkins Center, where I worked mainly with psilocybin. I'm also a clinician at our ketamine clinic here at Columbia now. So without further ado. So generally, before we get into the not-so-nice side of risk, I just want to sort of state that clinical trials of classic psychedelics and MDMA have generally demonstrated that people who are thoroughly screened and well-supported, these drugs are pretty well-tolerated. So most of the side effects and adverse events are pretty mild or moderate, self-limited. But access to psychedelics is increasing through a variety of avenues, some of which we'll talk about in depth in Dr. McGuire's talk, through retreats, changing legal landscapes across the country and internationally. And your patients may probably already have started asking questions about these drugs. So as providers, you should really strive to be informed and prepared to navigate some of these conversations with interested patients. Some background definitions. So classic psychedelics are those that primarily function by serotonin to a receptor agonism or partial agonism. They include psilocybin, LSD, mescaline, DMT, and then there are non-classic psychedelics, so drugs that have overlapping subjective effects but work by different mechanisms. So these include MDMA, which is an amphetamine derivative, ketamine, a dissociative anesthetic drug, salvia, ibogaine that are plant alkaloids. So they have overlapping subjective effects. This is a very useful table that I've stolen from Wolfgang and Hogue that synthesizes a variety of data using the five dimensions altered states of consciousness scale to show you the differences in subjective drug effects. As you can see in red and yellow here are the classic psychedelics, LSD and psilocybin. Ketamine is in light blue and MDMA is in darker blue. So you can see the big differences here being that the classic psychedelics tend to induce more perceptual changes in elementary and complex imagery, whereas ketamine tends to induce more disembodiment relative to the other drugs, and MDMA in dark blue tends to induce more of a blissful state but not as much in the realm of imagery. So there's a lot of overlap in how these drugs feel to patients, and there's also quite a bit of overlap conveniently in the common adverse events that occur. So this is a bit of a table synthesizing the overlap here, mostly with the physiologic adverse events of things like tachycardia, hypertension, nausea, and headache are pretty common with classic psychedelics, MDMA, and ketamine, and again are pretty mild or moderate in severity, tend to be self-limited. People can experience dizziness, difficulties with gait, dry mouth, blurry vision. There's some questionable seizure risk in vulnerable patients, so a little bit of data actually equivocating, showing that some of these drugs can actually potentially have anti-epileptic effects in folks. Very rarely in vulnerable individuals, there's severe cardiovascular events, so MI, things like that, in folks who have a vulnerability to that. In terms of the psychological or psychiatric risk, which I'll get more into here, again, they're sort of shared by the broad, multiple categories of drugs here, with some unique effects and other physiologic effects like bruxism, hyperthermia, and muscle tightness with MDMA, and nystagmus and dissociation being a bit more common with ketamine. Drug interactions, I think, are a pretty important area to know about as clinicians navigating some of these conversations with patients. Probably the most notable drug interaction is that of lithium with classic psychedelics. This is a study in which my colleagues and I, led by Dr. Nayak, did an analysis of online trip reports in which people mentioned the use of a mood stabilizer. We found that of about 60 reports mentioning lithium and classic psychedelic use, there was a stunningly high rate of seizure. In many cases, these patients ended up in the hospital or woke up in the hospital. We're not really sure what the mechanism of this is, but as you can see, this is just not something we saw with lamotrigine, which was the next most commonly mentioned mood stabilizer. And so this is an important one to mention if your patients are saying that they feel like they're interested or they're thinking of trying it or something, that there are significant medication interactions, some of which we might not even know about yet because we haven't really had the opportunity to study them. There may be a risk of, or not really a risk, but a higher likelihood of dampened effects of classic psychedelics and MDMA while patients are on serotonergic antidepressants. The data are a little bit mixed here with some of the more robust laboratory studies showing that co-administration is actually fine and doesn't lead to any dampening, but some survey work showing maybe the opposite in that these dampening effects can last for weeks or months beyond the cessation of the antidepressant. Serotonin syndrome is often asked about, but is actually pretty rare as far as we know, but has possibly been reported with SSRIs mixed with ayahuasca, and that might be because ayahuasca contains a naturally occurring monoamine oxidase inhibiting chemical compound. But generally, the thought is that because classic psychedelics are direct serotonin agonists, they actually don't cause serotonin syndrome, and there have been very few, if any, cases reported that. Here's just an overview of where we'll go with talking about the psychiatric and psychological risks. They include challenging experiences or psychologically challenging experiences, precipitation of mania, psychosis, HPPD, behavioral emergencies, exacerbation of existing mental health issues, and then boundary transgressions by therapists, which I think is an important area to highlight. Challenging experiences are periods of heightened anxiety, dysphoria, or paranoia, and depending on how we define them, they can occur with quite a high regularity, so something on the order of 20 to 60 plus percent of moderate to high-dose sessions with psilocybin in clinical populations. On the right here is a table of the single-item measure answers on the challenging experience questionnaire in a study of people with major depressive disorder, taking the rate from two sessions from 24 patients, so 48 sessions of individuals who indicated experiencing any of these symptoms. So things like feeling sad, feeling grief, isolation, despair, anxiety, panic, you can see are actually pretty common. Most people experience something like this at some point during their experience. Less common is paranoia, so you can see it's actually the least commonly identified item here, but in other samples, actually, in our forthcoming paper about anorexia nervosa, this was a much higher-rated item. The important thing to say is that good therapeutic outcomes are still likely, in supported settings at least, and it's important to review the potential for those experiences in preparation for individuals who are moving forward with psychedelic-assisted therapy, so tips on how to navigate them and then also following up and getting some closure about those experiences in integration or follow-up care. In the world, in the realm of naturalistic psilocybin use, there's been a survey done by Teresa Carbonaro and colleagues of about 2,000 individuals who had a challenging experience or self-identified as having a challenging experience after consuming mushrooms, and as you can see, there's a small but significant component right out of 2,000, so about 2 to 3% reported behaving in a violent or aggressive manner, about the same amount sought medical help during the acute period of drug effects, and then about 7 to 8% ended up seeking treatment for prolonged, usually psychological difficulties relating to the challenging experience. Things might be a little bit different in the realm of naturalistic use without that high level of support that we've seen and used in clinical trials so far. Precipitation of mania or psychosis was thought to be of higher likelihood in folks with personal or family history of bipolar or schizophrenia spectrum disorders. This is a paper I cite a lot, an interesting study in which these researchers gave the siblings and other relatives of patients with schizophrenia doses of LSD, and they found that 43% of their sample of 44 siblings, so people with first-degree relatives with schizophrenia, actually experienced what they called a pathological manifestation, which was described as essentially things like paranoia or feeling like they were going crazy or other kinds of negative psychological symptoms in the realm of psychotic spectrum symptoms that lasted from two days to six weeks beyond the administration of the drug, so prolonged pathologic manifestation. So it's not an insignificant risk. This kind of study probably would not be done today, and so we don't really have great data on other drugs like psilocybin, but it's just something we make a point of screening for very carefully in a lot of studies. The landscape is changing, though, so there was a recent publication by Scott Aronson and colleagues where they actually had an open-label trial of psilocybin, single-dose psilocybin for folks with bipolar 2 depression, in which no participants out of, I think, 19 developed any hypomanic episodes, and there was no increase in the young mania rating scale scores at all. Several emergencies during sessions, so by this I mean people behaving in an aggressive manner or putting themselves or other people at risk of harm. These are exceedingly rare in folks who are well-prepared and feel like they're with a trusted facilitator or guide, but that's sort of maybe a question that could be tested empirically, right? The reason that this is thought to be so low at places like Hopkins, where we've done hundreds of these drug sessions, is because of the amount of preparation and rapport that is built with participants on the front end before they receive any kind of medication. There's an on-call medical doctor for all sessions. The first line sort of intervention is verbal reassurance, in some cases therapeutic touch if that is agreed upon and discussed in the preparation, meaning a grounding touch like holding a person's hand or putting a hand on the shoulder. Emergency medication is really a last resort. I think, again, in the 700 or 800 drug treatment sessions at Hopkins, this has been used not even a handful of times. These are drugs like benzodiazepines and neuroleptics that are available as needed on an emergency basis. Also, HPPD, a rare and lesser studied kind of risk, but a serious one that can occur after just a single use of a psychedelic drug, is essentially the re-experiencing of perceptual symptoms that were initially experienced during the drug intoxication but beyond the period of acute drug effects. Of course, it has to be associated with significant distress or impairment to fully qualify as HPPD. Halpern and colleagues further divided this into the type 1 and type 2 classification, type 1 being more intermittent flashbacks that are distressing and type 2 being more chronic and debilitating symptoms on a daily basis that are unremitting in some cases for many years. Again, we're still in the very early days of studying this condition. The risk factors that are thought to be family history of mental health conditions, preexisting psychiatric comorbidities, and tinnitus appears to occur in pretty high rates in people who eventually report HPPD. You can come check out our poster at Poster Session 8 on our anonymous online survey study that we've done in folks who have a history of HPPD, so that is my plug for today. Of course, exacerbation in existing mental health issues is also possible. Some participants might experience more severe or new onset symptoms after taking a psychedelic, and some of the studies out there, there have been cases of suicidal ideation or behavior after a psychedelic, but of course, a causal relationship between the drug and the change in suicidal ideation is not really clear. Hype around psychedelics and the excitement around it culturally might drive heightened expectations and exacerbate demoralization if therapies fail to produce the desired outcome, and so I think it's important during preparation to talk about what a person's expectations are and to talk about what to do or other plans in the event that they don't receive the kind of effect they're hoping for. A really important area just to mention, I think, is the possibility of boundary transgressions by therapists. The power differential that exists between a patient and provider can really be magnified when the vulnerable person is under the influence of a powerful psychotropic drug like a psychedelic. We'll talk about suggestibility a little bit later in this slide set, but that is one of the reasons why, and there have been instances of inappropriate therapist behavior toward vulnerable participants in studies. There's a podcast by Lily K. Ross and David Nichols covers some of that, both in the above ground trials and in the underground, and so this is something I think that's important for people to know about if they're considering doing this in any capacity. Additionally, in the evolving legal landscape here, there's a supported adult use initiatives in places like Oregon where it's not really clearly therapy. And facilitators who work with people seeking psilocybin in those settings do get some training. But in many cases, they actually don't require any formal clinical training to be working with those people. And you can imagine that if these problems exist with transgressions in clinically trained individuals, those without any formal clinical training about the importance of maintaining good, healthy boundaries might put individuals at higher risk. So this is, I think, an area of concern. And finally, in this area, touch, which I briefly mentioned, is pretty routinely used in psychedelic therapy despite lack of empirical support for this practice. And so again, this is so-called grounding touch, or holding a person's hand, or putting a hand on the shoulder. The idea being here that there might be a kind of a slippery slope with respect to touch, and what that might mean, and how that might be perceived by somebody under the influence of one of these substances. So this is, I think, an area for further research. In the last bit of this talk, I want to touch on just some of the other drug effects. So psychedelics can cause a really broad range of experiences for people. And some of them might actually be kind of hard to identify as an adverse event, strictly speaking. So the FDA defines an AE as an undesirable experience associated with the use of a medical product in a patient. But some of those effects that we've talked about earlier in this slide set are a little bit more difficult to say. Like, is this really an undesirable effect? So things like very intensely positive emotions, or euphoria, spiritual experiences, that sort of thing. And a further complication being that we don't quite know whether those experiences are actually necessary for therapeutic outcomes. There's some debate there, and some interesting empirical studies underway. It's possible that they're merely epiphenomena of the actual biological processes, let's say, that are causing therapeutic change. And they're not really necessary to be consciously aware of. There's also significant variability in how adverse events have been reported in some of the early trials in this psychedelic renaissance since the early 2000s. The larger, more recent studies have used tools like the Medical Dictionary for Regulatory Activities, which encompasses things like the common physiologic adverse events we talked about earlier, but not so much the very broad range of experiences people can have, but might be important to know about, which I'll get into now. A variety of scales have been developed, or have been adapted for use, to assess subjective psychedelic drug effects. And here are just a few of them. I have a couple of sample items from the Five Dimensions Altered States of Consciousness scale, just to give you a sense of what those effects might be, that the Medical Dictionary for Regulatory Activities might not capture. So things like feeling extraordinary powers within myself, experiencing a touch of eternity. Medra, I don't think, has a category for any of these things. Conflicts and contradictions seem to dissolve. The world seemed to me beyond good and evil. So again, I don't know that Medra is really equipped to capture those kinds of effects in people. These are things that they might want to know, they might experience going into the experience. Meaningful, personally meaningful or very spiritual experiences can happen. This is from the seminal Roland Griffiths paper from 2006, where people identified quite commonly some of these experiences as being in the top five most meaningful in their entire lives. So something on par with the birth of their child or getting married or the death of a parent. Again, not captured by the standard AE scales or anything like that, and important to cover in the consent process, which Dr. Applebaum will get more into. Personality change has been sort of associated with some psychedelic use. So this is from a paper by McLean and colleagues, secondary analysis of the tobacco use study with psilocybin that found that people who experienced a more mystical kind of experience, as rated by the mystical experience questionnaire, had a significant correlation with longer term changes in trait openness. And that was especially true of people who experienced a so-called complete mystical experience, which is achieving a certain threshold of a rating on each subscale of the mystical experiences questionnaire. So you can see that those who had a complete mystical experience had a significant increase in basically every facet of trait openness, but those who did not tended to stay the same pre and post. And this is not, I would say, this is not unique. So some mental health treatments can produce change in trait openness, things like prolonged psychotherapy. But this is possible within just a couple of treatment sessions, as opposed to years of psychotherapy. Suggestibility, I think, is an important area to touch on here. This is just from one study by Carhartt-Harris and colleagues in 2015, where they gave patients healthy people, LSD, and rated their creative imagination scale rating. So on a scale of 0 to 4, people sort of read different kinds of scenes. And the higher score indicates that they had a greater vividness or realism of the suggested scenarios under the drug effects of LSD. So for example, they read a description of water running over their hand or being in a certain kind of scene. And it was more easily rated as real or vivid with LSD. Neche, Devino, and colleagues also had an interesting paper. They analyzed written reports of participant experiences in the tobacco use study with psilocybin. They found that reports from patients after their drug experiences commonly used language that was similar to what was found in the therapy manual for this study. So in some cases, verbatim language about the kinds of changes they might experience in their identity as a smoker or a nonsmoker appeared in their trip reports the next day. And accounts from the first wave of research also referenced things like this, that psychotherapeutic concepts appeared unexpectedly during psychedelic experiences, even though they seemed, perhaps, to people in the preparation as being foreign or not really something they vibed with. And so they cover a little bit more of that in Neche Devino's article here. Two minutes. Two minutes, all right. So we're coming up on the end here. In terms of other belief changes that can occur under psychedelics, so this is just a little bit of a busy table from a paper looking at effects of psilocybin with support in healthy people with an interest in spirituality, showing that those who received a high dose with either standard support or a high support scenario ended up reporting changes in things like the death transcendence scale, the daily spiritual experience scale, faith maturity, general mysticism. So all of these things, which include pretty important beliefs, can change after psychedelics. And the final thing I'll just put here, so this is from Sandeep Nayak and colleagues where they did a retrospective survey of people who had at least one psychedelic experience. And they asked them to rate their belief in things like mind-body dualism, belief in the paranormal or some spiritual belief, attribution of consciousness to mammals or non-mammalian things like plants and nature and things like that, and found that there was actually a significant change in some of these beliefs before compared to after, and that these effects have kind of stuck around. The exception was that superstition, superstitious beliefs did not really change. So take-home points here. The most common risks are minor and self-limited. And the risks of use outside of the clinical research settings might be more significant, so we're still doing some research about that. Anxiety, challenging experiences are common, but not usually associated with poor outcomes in supported settings. And the wide range of effects that psychedelics can produce are important for people to understand, but it might be difficult to capture or convey with existing frameworks used elsewhere in psychiatry and medicine. And finally, that suggestibility induced by psychedelics can heighten patient vulnerability. And this is something important to convey to anyone who comes to ask you about psychedelics, I think. This is, I think, an excellent resource put out by APA, and it has a pretty good guide on how to discuss these questions with your patients who ask about them about the current state of the research. It's a couple of years old at this point, but I think still has really good guidelines, so something to check out. And finally, just some acknowledgments here. So some collaborators who have worked on some related projects with Hiromas Bradbury, Paul Appelbaum, Steve Locke, who may be somewhere in the audience, and the fine institutions at which I work. So thank you for your attention. Great. So thank you, Natalie. We're going to hold questions until the end. We'll have a block of time reserved for it. We're delighted that so many of you are here and willing to stand, but you don't have to stand. At least many of you don't have to stand. There are seats up front as well as seats scattered in various places in the audience. So if you want to come take some open seats up here, please don't be shy about doing that. Our next speaker is Amy McGuire. And Amy is a JD, PhD, who is the Leon Jaworski Professor of Biomedical Ethics and Director of the Center for Medical Ethics and Health Policy at the Baylor College of Medicine. She's conducted research and written about a wide variety of issues in medical ethics, but they include the use of psychedelics in medical and non-medical settings. And we're just reversing the order a little bit here. Amy, you'll come now and then I'll finish up talking about some of the other issues. So Amy. Thanks, Paul. All right. Welcome, everybody. It's so great to be here. Thanks for joining us this afternoon. I'm going to be focusing a little bit today on thinking about and talking about the access to psychedelics outside of the health care system and how the health care system sort of intersects with these unregulated uses. So just a couple of disclosures. I'm a paid consultant for Lycos for their assisted therapy manual for PTSD. And also I have organized and facilitated a psychedelic retreat myself with Andean Path Journeys to the Amazon in South America. So as Paul mentioned, he gave you a little bit of background of why we're here talking about psychedelics today. And as he mentioned, on February 9th, Lycos Therapeutics announced that the FDA had granted its new drug approval for MDMA assisted therapy for priority review. This is for PTSD. And we have an expected decision coming about whether this new drug approval will be approved probably by August 11th, 2024. So we're anticipating knowing if we're going to have access to the first FDA approved psychedelic medicines or drugs in the United States by the end of the summer. So one of the things that we're very interested in is sort of how is this going to roll out when psychedelic assisted therapy gets FDA approval? And what are people like you who are practicing medicine going to do with that when your patients start coming to you and saying, I would like to explore this therapy as an alternative? One of the things that I think we need to anticipate is that FDA approved therapy is very likely going to be extremely time intensive, expensive, and potentially difficult for patients to access. And this is because the ways in which psychedelics have been studied in clinical trials to date, which is in the context of a psychedelic assisted psychotherapeutic setting, right? So this is FDA guidance on psychedelics for clinical investigators of psychedelic drugs. And what they require in their draft guidance document that they issued in June of 2023 is that safety monitoring for the administration of psychedelic drugs should include observation by two monitors during the duration of the treatment. And they suggest that the treatment duration can last up to 12 hours. The lead monitor under the FDA draft guidance needs to be a healthcare provider with graduate level professional training and clinical experience in psychotherapy. And then the assistant monitor has to have at least a bachelor's degree and one year of clinical experience in a licensed mental health care setting. And then there needs to be a physician who is licensed that is on call within 15 minutes of the clinical site. So this is very, very intensive for a very long period of time and will likely cost quite a bit of money to implement. And this is just for the administration session. Again, the protocols that have been used for psychedelic assisted therapy sessions have included also intensive preparation sessions as well as intensive integration sessions. So the estimated cost in a couple of different publications that are out there for psilocybin assisted psychotherapy is going to be somewhere between $7,750 to $9,670 depending on the price of the psilocybin that you access. And there was a publication that reported that the phase three trials of MDMA cost over $11,000 per patient. So I think that this is in part going to potentially lead to diversion to unregulated non-medical use of psychedelics since it is and will continue to be available in that setting. And we're already seeing articles like this talking about the rise of psychedelic retreats. Sometimes they're luxury retreats that are often offered to individuals and they're increasingly popping up on the market, sort of the gray market or even the black market depending on where you are. And one of the things that's driving people to unregulated psychedelic retreats I think is going to be the high cost of access and limited access within the healthcare setting. Also people are seeking out more sort of authentic experiences that might be grounded more in indigenous traditions and beliefs and practices as well as accessing in countries where this has been used for a very long time, et cetera. So we recently conducted a study called the Trustworthy Responsible Integration of Psychedelics in Society or the TRIPS study. This was funded by the Ordis Foundation. And I'm going to present some data from this study. I'm just going to ask, these are pre-published data so I'm just going to give you kind of hot off the press view of what we're finding. But please don't post this to social media or cite it just because we're working on the papers that are going to come out of this. So what we did was we did a landscape analysis to try to understand what's currently being offered outside of the healthcare setting in a more organized fashion for psychedelic treatment. And we identified 338 potential psychedelic retreat organizations online. Our inclusion criteria were that they had to advertise their materials through a website where it was at least partially in English and that they offered at least one retreat with a psychedelic focus. Forty of those that we identified did not meet these inclusion criteria. So our final sample was 298 psychedelic retreat organizations. And we looked at a couple of things related to the information that they had available online, both through their websites and through social media pages. One of the things we looked at is where were these organizations based? Like where were they headquartered? And you can see here that 189 of them were based outside of the United States, but 85 of them were based inside of the United States and 24 didn't specify where they were based. We then categorized these organizations based on what kinds of services were they purporting to provide. And we categorized them into wellness, religious, and medical organizations. And this was based on what they themselves put out there on their websites and social media pages. So we defined wellness organizations as those that referred to general notions of healing, mentioned health and wellness activities, contained descriptions of psychedelics benefits in terms of personal growth and development. And the vast majority of those that we identified would fall into the wellness category. So they were sort of talking about general wellness in quasi-medical terms, in terms of healing, well-being, wellness, but not making specific medical claims. And I'll point out that organizations could have more than one categorization. So we may have had some that were speaking about wellness goals within their organization, but also might have characterized themselves as a religious organization, for example. Religious organizations were self-described as such. So they said were either a religious organization, a church, a temple, or they said they provided religious services and then they displayed other features of a religion such as providing a statement of beliefs or other religious literature, having non-profit status or including a membership requirement. Now this is an interesting category of organizations. You'll see here that most of the religious organizations that we found were located in the United States. And I think that there are probably strategic legal reasons that people or organizations are categorizing themselves as religious. In the United States, we have a federal law that allows for religious exemption for religious organizations to provide psychedelics in some cases or substances or different things that are aligned with their religious use. Very interestingly, to get a religious exemption under the Controlled Substances Act, you have to get an exemption from the Drug Enforcement Agency, the DEA. And to my knowledge, I think there's only been three organizations in the United States that have successfully gone through that process and are using psychedelics within a religious exemption in the United States. So most of these other organizations are not religious organizations from that perspective, but they're holding themselves out as religious organizations perhaps with the intention that they can make the claim that the state can't intrude on their right to offer a psychedelic ceremony. Finally, there was a much smaller category of organizations that self-described as a medical organization, or they provided psychedelics explicitly for therapeutic purposes for specific conditions, or they were using sort of a more formal psychedelic assisted therapy format. So much fewer of those out there, although one thing that I will say that's interesting is I'm not presenting data from this today, but we did do interviews with 26 retreat participants from some of these organizations, and I would hypothesize that many people are self-treating medical conditions through participation in retreats even if they're not medical organizations that they're going to. So that raises a whole host of ethical issues about sort of self-treatment and the safety around that in these non-medical retreat settings. We also looked at where these retreats were located, and altogether from these 298 retreat organizations, they were holding 648 retreats. So they held multiple retreats from each organization, and these were held in 440 distinct physical locations across the globe, and 7 online locations. 130 locations were inside the U.S., and 310 were outside the U.S. So very interestingly, inside the U.S., you can see that these are being held across the United States, much more in the West, but also in the South. They are not only happening in Oregon and Colorado where we have looser state laws, but they're happening all over the place in sort of the underground space, or the, I guess, the quasi-underground space. So very interesting to see where these retreats are being held and located. The substances that were being offered on these retreats, the vast majority of retreats offered ayahuasca. So 74% of our sample were offering ayahuasca retreats. 26% offered psilocybin, and 20% offered San Pedro, and then you can see here there were a host of other substances that were offered much less frequently. One thing that was quite interesting that we found is that some retreat organizations offered multiple different substances, and they might have done that, like we have an ayahuasca retreat, or you can go on a psilocybin retreat, but very often they combine substances on a single retreat. So we heard anecdotally that there was oftentimes you would go on a three-day retreat, for example, and you would do ayahuasca in the evening, San Pedro during the day, and you would repeat that several times, which raises very interesting questions about interactions between these substances and sort of dosing and the safety issues associated with that. We also looked at the price of these retreats, and there was great variability in how much they cost. So I apologize, this is very weird to see, but I think I messed up that slide, but anyways, you can see that the one-day retreats ranged in price from $336 to $3,625 I'm sorry, from $20 to $3,625, the average price for a one-day retreat was $368. So that's how you can look at this graph, although I see that this graph is showing twice here for some reason. Anyways, the cost of the retreats ranged from $20 to $23,500 for one-week retreats, one-to-two-week retreats. We did look at retreats that were greater than two weeks. And what we found there was that the price went up to $150,000 and we had one outlier retreat that was offered for more than two weeks that was $500,000. So, great variability in the cost of the retreats. But you can see on average that the average cost of these retreats seems, you know, for a one to two week retreat is $2,394. That's the average cost. That's still significantly lower than what we just talked about with regard to medical administration of psychedelic assisted therapy. Okay. So, we also did some informal interviews with psychedelic retreat organizers to try to find out some more information that wasn't available online. So, we contacted 81 of these retreat organizations and we interviewed 50 of them. Twenty-six didn't respond to us. Five of them said, no, thank you, I'm not talking to you. And the rest were very, very happy to talk to us and give us all the information that we needed. And we tried to capture sort of how are they intersecting with the Western healthcare system and what does that look like. So, one of the things we asked them is, do you screen your participants for certain medical conditions? So, you just heard Natalie talk about some of the potential risks associated with pre-existing medical conditions and we wanted to know if these retreat organizations were screening for those. So, of the 50 organizations that we spoke to, 36 said they did screen individuals for medical conditions and they screened out certain individuals who did not, who had medical conditions. Thirty-two of them listed specific medical conditions that they screened for. And the majority of those that screened for medical conditions screened for mental health conditions. Schizophrenia was the most common mental health condition that they screened out for. But they also screened for bipolar disorder as well as several other mental health conditions. And then 19% of the sample screened for, of those that screened, screened for neurological conditions and hypertension was the most common of that. And then also, I'm sorry, heart conditions, cardiovascular conditions, hypertension was the most common of that, neurologic conditions, epilepsy was the most common of the ones that they screened out. So, interesting questions about sort of the evidence base for doing these screenings and these are also self-report. They're not actually screening them medically as far as we could tell. They're asking participants to self-report their medical history. So, there could be a lot of deception associated with that or lack of information being provided. Next, we asked them what they require in terms of medication washout. So, this is one thing that has really garnered a lot of tension in psychedelic-assisted therapy is, of course, in clinical trials, the practice has been to try to get patients off of existing SSRIs for a variety of reasons. One reason being that you don't want to dampen the effect of the drug while they're on it if that has a dampening effect. A second reason is that you don't want to have confounding factors when you're trying to understand what the efficacy of the drug is. And a third reason might be some concern, mild concern, about safety issues related to serotonin syndrome and other interactions. So, very interestingly, I thought that most of our retreats that we spoke to actually do require medication washout before participants can participate in the retreats. So, we spoke to 22 organizations that offer ayahuasca retreats and 95% of them or all but one of them required SSRI washout before participation. Of those that offered psilocybin retreats, 18 of them offered psilocybin retreats and 14 of those are 78% required washout. And then those retreat organizations that offered both psilocybin and ayahuasca, all of them required washout that we spoke to. The length of time that was required for washout varied significantly from, you know, just a week prior to going on the retreat or a couple days before doing the retreat all the way up to over six weeks of washout prior to participating. What's really, really interesting is that they don't necessarily provide support for, or medical support for getting off of your SSRIs. So, 65% of the organizations that require medication washout say on their website or told us in the interview, we require involvement of a medical professional for patients to wash off, wash out of their medication. Good, right? But only 15% of those organizations then actually had a physician on staff to help patients in that process. Another 93% said they required participants to work with their own physician. So, this has implications for those in this room because, you know, patients may be going on a psychedelic retreat and then they're coming to their clinician saying, I have to get off my SSRIs, what do I do? And I have to be off for X number of weeks. And there may be a difference of opinion about whether that is safe, whether that is advisable, but it might be required if they want to participate in these retreats. We also asked about involvement of medical professionals in the retreat organizations. So, 78% of those that we spoke to had a, reported that they had a medical professional on staff, but oftentimes this was a firefighter, a paramedic, an EMT or a pharmacist, not necessarily a licensed healthcare therapist or physician or nurse, but they did, there were some that had physician, nurses and therapists on staff. And then interestingly, 68% of them had a medical professional in attendance at the retreat, but it wasn't entirely clear if these were people who were in attendance in their role as a medical professional or if they were participants in the retreat themselves and just happened to be there. So, it's not entirely clear what that, how that played out. Finally, we asked about integration. We know that integration is a really important part of the process of psychedelic assisted therapy. And we were very curious, like, okay, people have these experiences on retreat, then what happens? And so we asked them if they offer integration of any type and what that looks like. And you can see here this, the type of integration they offer is probably quite different than you would get in a medical setting. Oftentimes it was sharing circles with the group. It might be one-on-one integration meetings, supportive modalities like yoga or breath work, or custom apps or books that they give you online. So not really the type of intensive psychotherapy that we talk about in the clinical setting. Regardless, the people who were leading these integration sessions, 33% of the organizations that had people leading these integration sessions had somebody who was a licensed healthcare provider of some sort, but most of them were either a non-medical coach of some sort, a religious shaman or religious leader, or some other type of person leading these integration sessions. So, I just wanna end, that's a lot of data, but I just wanna end by kind of thinking about what is the implication of all of this for people like you who are going to be seeing patients who may be attending these retreats, either to treat a particular medical condition or just for general wellness purposes. And I think that it's really important for all mental health professionals to be prepared and knowledgeable about psychedelic-assisted therapy and psychedelics as a potential therapeutic modality, because we will see an increasing number of individuals who are seeking out these treatments, both in a medical and in a non-medical setting. And clinicians, licensed clinicians are gonna be involved, I think, in both settings in some ways. And they could be involved in a variety of ways. So patients may come to you and say, and you might already have had the patients who have come to you and said, I'm interested in this, what do you think? Tell me how you would advise me on this. And I can tell you, I have had, I mentioned before that I help organize one particular retreat, and I've had several people who have inquired about participating in our upcoming retreat in September, and I've said, maybe you should talk to your physician about it, and tell me what they said, I'm really curious. And they report back very, very different responses. It's like some clinicians have said, you're crazy, no way, do not do this, this is contraindicated. And others have been like, that sounds pretty cool, you should try it, let me know how it goes. So that's interesting. Your patients may come to you asking about medication washout, saying, I have to do this, because I'm going on this retreat, help me get off of my SSRIs, how do I do that? I need to do it, and I'm going, you know, for a certain amount of time, is that safe? Those sorts of things, and you may ask for help with that. They may ask for help for preparation. We know that sort of the efficacy of psychedelics increases the more you kind of prepare. People talk about set and setting, the importance of set and setting, so the mindset going into the sessions, and the setting that you're in is really important to sort of the therapeutic effect. And so patients who are either going on a retreat, or are looking to use psychedelics in a state, you know, legalization setting, or under personal use, or adult supervision use in Oregon, or if they're looking for it in a medical setting, they may be coming to you asking about helping with preparation, psychological preparation. Some of you may be involved in actual treatment, so administration of the psychedelics themselves, and then again, on the flip other side of preparation is integration. So even if you're not administering the drug, there may be downstream integration implications if your patients are taking the drugs. And then finally, once you come back from retreat, or once you finish your administration sessions, there's a lot of questions about follow-up medication and medical management. So if you've been on SSRIs, you go on retreat, you take a, you have an experience with psychedelics, you come back, you may need to go back on the same dose of SSRIs you were on before, you may need a different dose, you might need a different medication, so there's gonna be a lot of follow-up medical management and potential adverse event management that's gonna be required as well. So I'm gonna end there. All of this raises a million issues that we could talk about for three days, but this is kind of a teaser, and I hope we can have a good discussion about it during the Q&A, but I just want to acknowledge our fantastic collaborators on this particular project, and our Ethical Legal Implications of Psychedelics and Society program at Baylor College of Medicine. Thank you very much. Thank you. Great, thank you, Amy. Let me reiterate for those of you in the back, there are seats up front. If you're getting a little tired, feel free. So I'm going to talk about a selection of the kinds of challenges that I think about when we talk about the imminent arrival of psychedelics in the clinical setting. And let me say, I have no relevant financial interest to disclose. And I want to start by thinking with you a little bit about informed consent. And what informed consent to this treatment, set of treatments, they're not all the same. That's an important thing to keep in mind. MDMA is not the same as psilocybin, which is not the same as ibogaine or ayahuasca. And we're going to have to, over time, tease out those differences so we understand them better. But how are we going to go about getting meaningful informed consent from patients? So I would suggest that for patients to provide meaningful consent, they really need to understand and appreciate the likely effects that the treatment is going to have. But there's a challenge here, right? Because some of the effects of psychedelics, and you heard Natalie give some examples from one of the scales that are used in these studies, are inherently difficult to convey. There are terms used to describe these ineffable experiences, like oceanic boundlessness. There's actually an oceanic boundlessness scale that's used in psychedelic research. Dissolution of awareness, dissolution of ego, shifts in values or personality. Now I want to suggest that it's inherently difficult for any of us to understand what it would mean for us to have a different set of values or a different personality than we have today, much less what it will feel like were our ego to dissolve or to be submerged in oceanic boundlessness. How do we deal with the reality that these are very difficult experiences to convey and to appreciate? One way to deal with it, of course, might be to have them meet with someone who's already been through it, who can describe that experience to them, although that's then just one person's view. Another might be to put together a reel of patients who've been through this talking about a different variety of reactions and experiences that they had. But the challenge isn't going to go away. Even with that, it's going to remain, and it is an inherent complexity that we will need to deal with as psychedelics move into the clinical realm. Another challenge in consent is getting people to think about the session itself and what they will want to have happen to them during that session. So you heard from Natalie about the use of therapeutic touch designed to calm people who may be feeling anxious or fearful in the course of the psychedelic experience. Of course, touching patients is something that we are all discouraged from doing in our training. It is not concordant with the usual mainstream approaches to treatment, particularly in psychotherapeutic settings. And there are good reasons for that. Touching introduces concerns about boundary violations, including a history of boundary violations in the psychedelic space, which have been anti-therapeutic, exploitative, and abusive. And so finding out from patients what they would prefer is considered standard practice in this realm. But if you've never been through a psychedelic experience, which will be true for most people who are ultimately treated with psychedelics, how do you know what you would prefer if you find yourself in an unanticipatable panic on a bed or a couch in a psychedelic treatment room? Moreover, how do you know that your preferences won't change? Touch? No, don't touch me. I don't want you to touch me. But when I'm in the middle of a psychedelic trip and I'm terrified, touch might be incredibly reassuring to me. A difficult challenge, again, there's no great answer to this other than to be respectful of what patients indicate both prior to but also during the session and to be sensitive to changes in preferences during the session. Advanced planning also needs to include some discussion of the fact that unlike a TV show that you start watching and then get bored with and you just click and it's gone, the psychedelic experience is not that easily terminated. Once a session has begun, it can't easily be aborted. Changes in preferences due to adverse effects, adverse experiences can't easily be accommodated. There are rescue medications that are used. Natalie alluded to these. They include benzodiazepines as well as antipsychotic medications, but they may control anxiety or fear. They don't completely reverse the psychedelic experience. Expectations are going to be another challenge here. As Anderson and colleagues wrote a few years ago, psychedelic medicines carry a truly uncanny allure. You've all seen this in the media coverage of the studies as they come out. Here's an example. This is from Ezra Klein, who I usually think of as a fairly sensible data-oriented person in writing in the New York Times. The piece was called Can Magic Mushrooms Heal Us? He wrote, it would be one more option for those who need it. Both evidence and anecdotes suggest it would be life-changing for many. That would be enough. That would be so much. This is essentially prior to the publication of any of the major studies on the efficacy of psychedelics in the treatment of psychiatric disorders. It is very easy to be drawn into the hype in this area. As part of the informed consent process, you, I, all of us will need to monitor those unreasonable expectations and address them with our patients. Another challenge in the consent process comes from not what we know, but what we don't know. There is a great deal of uncertainty, many unanswered questions at this point in time. They are likely to exist to some considerable extent even after the approval of these medications for clinical use. One of those areas is uncertainty about the immediate or longer-term effects, both good and bad, of psychedelics. For patients with a positive response, and we know that many patients do appear to have a positive response, current data don't tell us how long that's likely to last and whether if they relapse, they will again have a positive response to repeated administration. Those are critical questions that we need to have answered. There are studies underway now with MDMA, also with psilocybin that will address some of these issues, but these are very important things that we don't know the answers to today. Regarding adverse effects, as you heard again from Natalie's presentation, psychedelics seem relatively safe, but what the long-term consequences might be of repeated administration, although it certainly has gone on in the underground use of the medications, are unknown in any scientific way, and we need to be very upfront with patients about this. We often deal with unknowns in psychiatry and in all of medicine. We just need to be honest with patients about what we don't know, and if they don't know the questions to ask, then we need to tell them upfront. We don't know what the duration of effect on average is likely to be. We don't know, if you need a second round right now, whether that's likely to be helpful to you. There's a great article I just want to refer you to by Will Smith and Dom Sisti in the Journal of Medical Ethics, which presents a model for talking with patients about the use of psychedelics, and we don't have time to go through the table here today, but I commend that to you, and you might want to track that down, Journal of Medical Ethics 2020. A second set of challenges I want to talk about, in addition to the challenges in the consent process, are challenges in what happens after the consent process. That is, ensuring that these medications are used appropriately. And that's always an issue when medications transfer from the research realm into clinical settings, because it's inevitably accompanied by a diminution in oversight of utilization. It's important to remember, I don't know that we've clearly said this yet today, psychedelics remain illegal in the United States under federal law, although some cities have declared that they're essentially not going to arrest and prosecute people for possession and use, and you've heard that a couple of states, Oregon and Colorado being out in the lead here, have developed approaches by statute to regulate and authorize their use. They're still illegal under federal law, but we know that there has been considerable underground use for many years, and one question to think about is when psychedelics emerge from this underground community, with its vast and unregulated heterogeneity of practices, what's going to happen at that point? How faithful will clinicians who are using psychedelics be to the database, all the research data that are currently being generated? Will their own experiences with psychedelics and their enthusiasm for them shape how they use them in contrast to what the data might say? So here's a study last year in psychedelic medicine which showed that of 32 therapists who admitted to doing psychotherapy, I'm sorry, psychedelic-assisted psychotherapy today in the United States, its illegality aside, 88% of them had themselves taken psychedelics and all had highly favorable views of its use. Such clinicians may convey to their patients unrealistic expectations of benefit based on their own personal experiences. Again, Anderson and colleagues, even conservative individuals can become wildly enthusiastic about the potentials of psychedelics to heal and transform. How might we try to deal with something like that? Well, maybe this is one of those instances where the therapist, him or herself, should not be conducting the consent process. Maybe having a neutral colleague who can take a more objective view of the risks and benefits for a particular patient would help mitigate this effect. There's an example that's worth thinking about out there today which may tell us something about what we can expect when psychedelics move into the clinical realm. And that's ketamine. You all know about FDA-approved use of esketamine under highly controlled circumstances for the treatment of depression. But that is not how most ketamine in the United States is being prescribed for psychiatric indications today. It is being prescribed off-label. It's being administered typically, although not always, intravenously, with varying doses at varying intervals, largely by commercial clinics serving a pay-out-of-pocket group of patients since insurers won't cover the unapproved treatment. Most clinics have no psychiatrist on site involved. The drug is typically administered by an anesthesiologist or a nurse anesthetist. And it's used for a variety of non-evidence-based indications. Anxiety, PTSD, subsyndromal depression, you name it. It's also being prescribed orally, remotely via videoconference, sent by mail, with no oversight of how it's being used. And two years ago, the Wall Street Journal really had a terrific expose of these practices and the consequences that it has had for patients. Ketamine is not an innocuous medication to use on an ongoing basis. One of the most serious side effects is paralysis of the bladder. So there are 20-something and 30-something-year-olds out there who will be catheterizing themselves for the rest of their lives several times a day because their bladders have been paralyzed by the continued use of oral ketamine. And one of the most remarkable aspects of it is that in many cases, they're continuing to use the ketamine even after experiencing that horrendous consequence. How can we think about ensuring, or at least encouraging, more appropriate use? So here, the FDA has some role to play. The FDA can impose what's called a Risk Evaluation and Mitigation Strategy, or REMS, on new medications. Esketamine has a REMS. You're probably aware it's gotta be administered in person in a therapeutic setting. It has to be registered with the FDA prospectively. You have to watch the patient for a period of time after administration, et cetera. REMS can limit indications for which psychedelics could be used, impose training requirements, restrict dosages and frequency, require in-person administration, all of which may be positive and necessary here, and may make a good deal of sense, at least in that rollout period when there will be a lot of inexperienced therapists out there eager to try the new medication. There is likely to be a REMS. Almost certainly, there will be a REMS for MDMA if that's approved later this year, and we will have to see how far the FDA goes with that. But of course, one of the problems in constructing a safety-oriented REMS, which is the FDA's role here, is they have to know what the risks really are. And although that's true to some extent, we do have some sense of the risks, and Natalie went through many of them with you, the existing database comes from research studies that have looked at highly selected populations. So these are the exclusion criteria from one of the major studies of psychedelics from Carhartt Harris and colleagues in the New England Journal in 2021, and I just highlighted several of them for you. Immediate family or personal history of psychosis, history of serious suicide attempts, suspected or known presence of a preexisting psychiatric condition like borderline personality disorder that could jeopardize rapport. And I just wanna suggest to you that you roll out a new drug for depression, which has been shown some efficacy in treatment-resistant depression, and you're gonna get people with family histories of psychosis who have made serious suicide attempts and are comorbid with borderline personality disorder. And today we have very little, or in some cases no knowledge in any systematic way of what the consequences of that are likely to be. So we ought to be looking for that before these medications roll out into treatment. And I'm just gonna skip through this. These are just the data to suggest how the comorbidity will appear, and we really need to be collecting those data. And I will point out to you that when you look, you see things, right? So when Goodwin et al. in a phase two study of psilocybin in 2022 looked at the adverse effects in their high-dose psilocybin group, which was the group that got the efficacious treatment, the lower-dose 10-milligram and one-milligram groups did not show the same level of efficacy, they found a surprisingly high rate of suicidal behavior associated with that group. Well, that is something we need to be looking at carefully. Moreover, they found that all of the patients who manifested suicidal behavior turned out to have past histories of suicidal behavior. So maybe that is an important exclusion criterion, but we need to know that with more than three patients, which is the number who manifested suicidal behavior in this study. For reasons of time, because I wanna leave time for questions, let me just say we've heard a little bit about suggestibility and boundary issues already, and those are things we're gonna have to figure out how to deal with, happy to talk about that in the questions. And I just wanna conclude by suggesting that the FDA isn't gonna do it for us. We are going to have to regulate ourselves in this area, and our professional organizations, the APA and others, have a role to play here in terms of developing guidelines that can help the profession structure its own approaches to these issues. And one example of an already beginning process, which you can find online, are the guidelines that the American Psychedelic Practitioners Association issued last year. They're not perfect, but they're a good start, and something that other organizations, I think, will have to emulate. So just to conclude, our ethical concerns about the use of these medications is gonna grow as they move into the clinical setting. They may be even greater in unregulated non-medical use when that is done either legally or despite the law. Regulatory restrictions may be needed, but guidelines from professional organizations may be essential as well. So with that, let me stop, and let me invite your questions. Questions for any members of the panel. Take it away. I would like to thank all the speakers for this excellent presentation symposium. I'm visiting from Lebanon, and we're a very small country, and I can say we have maybe five, six organizations offering psychedelic therapy, and all the agents are not legal in Lebanon. My question is, how much is the effect of the psychedelics, how much is the effect of the therapy? Would these substances work without therapy? And therapy, which seems to be extensive, 12 hours, is the therapy standardized? How do you go about making sure who's doing the therapy, and what happens in the therapy? Is it a type of CBT? And the effect of therapy in somebody who's maybe cognitively impaired? So these questions also are, to me, concerning. Natalie, do you wanna say something about what we know and don't know? This is on, yeah. So I think this is an area that's ripe for empirical investigation. So we don't really have the answer to that question of how much therapy is appropriate, for whom should we have more therapy, when should we do the therapy, what kind of therapy should we do? There are many, many careers worth of studies to be done there. So the general format that we use in a lot of these trials has just been replicated over and over from what seemed to work in some of the earlier studies, inherited in part from the first wave of research from folks like Bill Richards, who helped set up the program at Hopkins, who was actually in the first wave and administered some of the final doses of LSD before it became illegal. So we don't know the answer. I suspect that there are individuals who need less support, right? If you look at the data on just naturalistic use, psychedelic use seems to be associated with some benefits for mental and physical health, and most of those people are not accessing psychedelics with any therapist at all. It's just in social settings or on their own. So we don't know the answer to that question, and we should work on finding out, but also funding of psychotherapy trials, which is essentially what this would require, is hard to come by, so that's a barrier. And again, if you look at the ketamine clinics as an example, they're infusing ketamine and sending the patients home without any psychotherapeutic component at all, and once it's out there and can be administered off-label, I worry that we will see the same thing occur with psychedelics as well. Yes? Hi, I'm Calvin Chalice. I'm an addiction psychiatrist at Rutgers University. I just wanted to let you and the group here, we've developed a psychotherapy intervention that gets the same results as the psychedelics do, and we get it with mystical experiences, and it was short-term in 10 weeks. So it was much less intensive. I would like to talk with you about it because it was pretty dramatic. So it does exist. Anyone interested in knowing later, I'll take you, we'll go out to dinner. Great. Maybe next year you should do this symposium at VPN. They didn't accept my presentation this year. So. Shows what they know. I guess it wasn't politically correct enough. I treat patients with schizophrenia, and I won't be prescribing any psychedelics for them. I think it's kind of a scary fad. That's my own opinion. But the question is, a number of these substances apparently or soon likely going to be approved by the FDA, and I'm out of the loop in terms of knowing what research has been done, but can you just give a brief idea of the kinds of studies that have gotten it to the point of almost being approved because you'd think they must be impressive, and yet I haven't heard anything today so far that would indicate that they are. Well, so let me start, and then Natalie should chime in because she's the real psychopharm expert, psychedelic expert on the panel. So when I started off with that very brief summary of the studies, it was to give you an idea of the range, excuse me, the range of findings that are out there. MDMA is the only medication that has currently been submitted for approval. As Amy said, August 11th is the target date for a decision on that. There are two phase three studies that have been completed and published, both showing superior efficacy for MDMA plus psychotherapy versus MDMA placebo plus psychotherapy. So that's the evidence base on which the FDA is gonna be making a decision about MDMA. To this point, although there are phase three studies for psilocybin underway, they have not yet been, as far as I know, completed or published, but they will then form the data set on which a decision about psilocybin will be made. Natalie, do you wanna augment that? I mean, the studies have been hyped up, I think, for sure. As Paul mentioned, phase three has been completed for MDMA. It's in the process of being completed by at least one entity for psilocybin for treatment of depression. There's another one underway. The studies are smaller than many of the other studies you might have seen for other treatments in psychiatry, but the effect sizes are very large. So as an example, SSRIs have an effect size of something like a 0.3 to 0.35 of a Cohen's d, meaning like a number of standard deviations of improvement you can expect to see with treatment, whereas some of the psilocybin trials, for example, have an effect size on the order of two, so a very large effect size, much larger than what you might see for other treatments, and the improvement occurs within one day to one week, in some cases, and the effects can last, in some patients, upwards of a year or longer, which is why there's so much excitement about it. But these are very teeny, tiny little studies that some of those results are based on. The larger studies are not finding effect sizes as large, which is, I think, expected, as patients are less cherry-picked for some of these studies. And you mentioned you work with schizophrenia patients. I've heard of a study that might be being planned right now or even underway of administration of MDMA for people with schizophrenia, so I think they're trying it out in a lot of different people. I'm a little scared of what they might find in that particular study. But as I mentioned, right, there's also an open-label bipolar two-depression study that's sort of pushing the boundary of what kinds of patients this might be appropriate for. So there are a growing number of studies. The literature has really ballooned or mushroomed over the last 10 to 20 years or so. Are they all for depression or mood? Psilocybin for depression, MDMA for PTSD, and now LSD for anxiety, generalized anxiety, I think, disorder. I'll just add that there's lots of challenges with doing these clinical trials, one of which is they're placebo-controlled, but most people know what group they're in. It's hard to not know what group you're in. And so there's, you know, Natalie talked a lot about suggestibility and expectancy effects. I think we can expect that there's been a lot of that as well kind of influencing the trial results. And as a practicing psychiatrist, my concern is not does it work, but does it work better than the alternatives? And there have been very, very few head-to-head comparisons, and one of the ones which I mentioned in my brief overview at the beginning was the comparison with escitalopram, which showed equivalent efficacy, at least on the primary outcome, but not greater efficacy. So we still don't have a great answer. There's suggestive data like the effect size comparisons, but very few head-to-head studies so far. Yeah. Forgive me for my old timer view of things, but I always have it repeating in my head when, let's say, when I see something about MDMA. I could have sworn, maybe I'm wrong, that in my training at that time, which is a long time ago, they were talking about how MDMA, you know, really damages serotonergic neurons and things like that. Now, I might be misremembering, so correct me if I'm wrong, but I've just been having a hard time marrying the, obviously it was a different time, a different emphasis, a hard time marrying those disparate sort of ideas. Thank you. So I think you're referring to a finding that was retracted, published by Riccardi and colleagues, where they found out that instead of MDMA, they were actually using methamphetamine in their experiments, which turned out to spread this idea that MDMA causes brain damage, but actually that's not the case. So I don't know, that might be what you're referring to. I'm either misremembering or the data proves to be incorrect. They ended up retracting it, yes, yes, so there's an update. But certainly, you know, like repeated use, we don't really know what the risks are of that, and the doses, we're still figuring that out, yeah. Please. I'm Joost Mertens from the Netherlands, psychiatrist working for 20 years. Thank you for your elaborate talk, raising important questions. What amazes me, that a lot of the answers of these questions can be found in the knowledge about working with hypnosis and hypnotherapy, which actually I first came across on my first APA conference in 2003 by David Spiegel. And I'm actually amazed that there's nothing about hypnotizability, hypnosis, working with trans state, the do's and don'ts, the when's and how's, there's a lot of knowledge about there, and there's nothing in your talks about that. And I was amazed that this knowledge has somehow vanished, because with hypnosis, which is a sort of non-placebo, non-deceptive placebo, you work with a trans state, you know what to do, if you're trained properly. Is there anyone here in the audience knows about hypnosis, that the chapter in the textbook is vanished, and I don't understand why. Can you maybe have some comments on that? Anybody want to comment on the analogy with hypnosis? It sounds like an interesting and maybe very useful area of research to look into related to this, but I personally don't really know much about it. Yeah, go ahead, Amy. There's some, I think like some folks over at Imperial College of London are doing, like with holotropic breath work, which similarly can induce sort of trans-like states like hypnosis, I think they're looking at that as sort of an alternative to psychedelics. So I think it's an interesting question, but there hasn't been a lot of work done on it in terms of other modalities that can be used within, especially within the field of psychiatry that might induce similar effects. Well, it's especially about what you do as a therapist when you work with the hypnotic state, which is the hypnotic altered conscious state is there. It's nothing magical. And if you're trained, you know what to do. You know what to do with the therapeutic touch. You ask before and you ask in the session and there's no problem. So I would recommend to get that chapter of David Spiegel again in the textbook because it's very useful when you want to work with trans-states. Good, thank you. So it's 3.02, we're a little past time and I think we have to let you go to use up your retirement savings getting another cup of coffee upstairs. But thank you all for joining us today. Thank you.

psychedelic compounds

psychiatric treatment

Paul Appelbaum

psilocybin

depression

substance use disorders

cancer-associated distress

Natalie Koukassian

psychological side effects

physiological side effects

Amy McGuire

informed consent

regulatory oversight