Everyone, my name is Dr. Karen Drexler. I serve as the medical director for the American Academy of Addiction Psychiatry. And on behalf of the Academy, I am delighted to welcome you to Psychedelics in the Treatment of Substance Use Disorders, What Clinicians Need to Know. Next slide, please. This presentation is accredited for continuing medical education for physicians and other health professionals. Next slide, please. And here are the learning objectives. I won't review them in detail, but we hope that this will be an educational experience for everyone and that you will have a deeper understanding of the research and limitations of psychedelic research to date and potential risks and benefits of psychedelics in the treatment of substance use disorders. Next slide, please. We have a distinguished panel of both presenters and discussants. And without any further ado, I would like to move on to the first presentation and to introduce Dr. Charles Pittenger. Next slide, please. Who serves as the Mears and Jamieson Professor and Deputy Chair for Translational Research in the Department of Psychiatry and a professor of psychology in the Yale Child Study Center. He serves as the director of the Yale Program of Psychedelic Studies Science, the Yale Center for Brain, Mind and Health and of the Yale OCD Research Clinic and of the Neuroscience Research Training Program. Thank you, Dr. Pittenger. Thank you. It's a pleasure to be with you today. Do have some disclosures which are here. They include working with a couple of companies working in the psychedelic space, but none that are relevant to any data that I'm presenting today. Next, please. And here's some of my research support and other relationships. Next, please. I should say at the outset that I'm not an addiction psychiatrist. I'm known primarily for my work in obsessive compulsive disorder, but I have done some work recently on psychedelics. And I was asked to be with you today to give an overview of sort of the state of the field and where the work is with a particular focus on recent work in addictions. It's gonna be a bit of a lightning tour because of time. And so I wanna start with this question, what is a psychedelic? That's actually a fairly complicated question and you'll get different answers from different people in the space. One way to define psychedelics is in terms of particular molecular structures or pharmacological actions in the brain. And that's gonna be my focus here. But other people will use the word psychedelic to describe an effect, a phenomenological effect of the drug, a particular type of consciousness alteration. And still others will use the word psychedelic to describe a mode of treatment delivery where a consciousness altering substance is used in conjunction with supportive or structured psychotherapy. And the synergy between the two is thought to be required for benefit. And all three of those meanings are of relevance. But what I've done on this slide is illustrate many of the drugs that are called psychedelics by either everyone or some people and are of relevance, some of which are of relevance to our talk today. Very briefly, what you see on the left, the tryptamines and the ergolines are what is typically known as the classic psychedelics and they are agonists of the serotonin 2A receptor. You're gonna hear a little bit more about that later. And you'll see some familiar names there, LSD and psilocybin, and then perhaps some less familiar ones like dimethyltryptamine or DMT and ibogaine. We'll be talking about some of these molecules as we go along. On the right, you see atypical psychedelics, drugs that have overlapping phenomenological effects but different pharmacological effects. I tend not to call these psychedelics but others in the field do. The most relevant one there historically is mescaline, which is found in a cactus illustrated there. And the most relevant in terms of current work is MDMA, also known as ecstasy. And then down in the lower right, you see a heterogeneous group of compounds that work in a variety of different ways in the brain but all have effects on consciousness. And I won't be talking about those today. Next, please. So I think everyone here knows, and I think this is why you're here, that there's been an absolute explosion of interest in work in psychedelics over the last 10 years and especially the last seven or so. And that's illustrated in two different ways here in this slide. On the left, we see a graph of the number of clinical trials registered in clinicaltrials.gov that have used psychedelics. Psilocybin, MDMA, and LSD are color-coded there. And you can see a number using MDMA. That's primarily trials by the MAPS Consortium looking at post-traumatic stress disorder up until about 2016. Then there were some key papers published in 2016 that led to an explosion of interest in psilocybin. And you can see that in the number of gray squares in the last few years. And this only goes up to 2021. I'm sure that these numbers have just continued to go up since then. Relatively small number of studies in the modern era with LSD. There's an interesting history around why psychedelic research, what happened in the 60s and 70s, how it went into abeyance and why it exploded into popular and consciousness as well as into clinical attention at this time, which I don't have time to go through today, but you can see the pattern very clearly in this graph. On the right, you see a similar story, though the data are different. This is the number of people who have participated in trials of psychedelics, registered trials of psychedelics going back to 1996. And you can see some nothing prior to 1996 and some studies in healthy controls shown in green starting at that time, and then an increasing number in clinical populations shown in blue, telling basically the same story. This is something that a lot of attention is going into. Next slide, please. So I'm going to talk about a few of the key psychedelics, beginning with LSD. As I mentioned in the last slide, LSD is not getting nearly as much research in the modern era. It's more been about psilocybin and MDMA. But back in the 50s and 60s, LSD was the primary focus, not only in a cultural and sociological context, which, you know, the hippie and counter-cultural movement in the 1960s, which ultimately led to a backlash and restriction on the research, but also in mainstream psychiatry. There were a really good research by the standards of the day, was done with LSD in the treatment of addiction and depression and other conditions. LSD was discovered serendipitously by Albert Hoffman at Sandoz Pharmaceuticals, and he's illustrated there. He was sort of lauded by many psychedelic enthusiasts as a godfather of the entire field. Next, please. For today's purposes, I focus... Next slide, please. Thank you. For today's purposes, I focus on some controlled trials that were done in alcohol use disorder in this era. Among the better trials done in this era, these were mostly done on incarcerated men, though not exclusively. There were six rather good trials by the standards of the day, where men were randomized. Everyone received some sort of behavioral treatment. Some received LSD and some did not. You can see the numbers there with follow-up ranging from three to 12 months. And these were nicely summarized in a review article Krebs and Johansson referenced at the bottom back in 2012. Next slide, please. And in summary, Forrest's plot is shown here. This shows the six trials and the benefit that came from the addition of LSD to the other behavioral treatments, which varied a little bit between the trials. And what you can see on the right, that the diamond on the right is the meta-analyzed effect size. You can see that those who were treated with LSD did better on average across all of these trials than those without. And again, while these may fall short by the methodological standards of the day, they were really very rigorous and well done by this. I'm sorry, may fall short by today's standards. This was mainstream psychiatry and rigorously done work by the standards of the day. Next, please. Next, thank you. There was only a single trial from this era in opiate use disorder. That's shown here, 78. Again, in the incarcerated population, 78 addicted male inmates. And they were treated in a residential treatment with or without LSD. And you can see in the bottom right, this is the percent of patients who achieved abstinence at three, six, and 12 months. And you can see an abstinence level of approximately 30% in those who received LSD in conjunction with their trial. Single trial, relatively small and some methodological flaws by today's standards, but promising. So this is a historical background for the current interest in the use of these substances in the treatment of substance abuse. Next, please. The large majority of the studies that have been done in the last 15 years for substance abuse, as well as for other indications, which I'm gonna briefly summarize, have been with a different molecule, psilocybin. That's illustrated here in the upper right. Psilocybin is a naturally occurring substance. It's found in the psilocybe mushrooms illustrated on the left. There are about 200 species of these mushrooms worldwide. It's best known for its use in several, historically best known for its use by indigenous groups in a number of places in the world, but especially in the Sierra Mazateca region of Mexico. My red circle highlighting the Sierra Mazateca region isn't showing up, but it's in the mountainous region in Southern Mexico, adjacent to the Southwest corner of the Gulf of Mexico. And people in this area have used psilocybin as part of their cultural rituals and religious rituals going back centuries, if not millennia. And psilocybin was introduced to the West by basically pharmaceutical tourists in the 1950s visiting this region. I was written up in an article in Life Magazine in 1953 and kind of exploded into Western popular consciousness at that time. The molecule was purified by Albert Hoffman, the same guy who synthesized LSD and it was studied in the 60s, though not as intensively at that time as LSD itself. In the modern era, psilocybin has been the drug of choice because it's a bit of a cleaner drug than LSD. It interacts with fewer receptors. It has a shorter half-life. The mind-altering experience lasts four-ish, four to six hours rather than 12 to 15. And so for these reasons, among others, it's been the primary focus of recent work. Next slide, please. So just a word or two. Oh, I'm sorry. Much of what I just said is listed on this slide here. And there you can see the CRMS tech region circled in red. That's where my red circle went. Next, please. So just a slide or two on mechanism. All of these molecules, as I said, psilocybin is a little bit cleaner than LSD, but it still does interact with a number of different targets in the brain. Prominent among them is the serotonin 2A receptor, the crystal structure of serotonin 2A as shown on the left, and its distribution in the brain as determined by PET imaging is shown on the right. We are fairly confident that the interaction of psilocybin with serotonin 2A is necessary for its effects on brain activity and brain network organization, as well as for its effects on consciousness. Because when you give psilocybin, or for that matter, LSD, together with a relatively specific blocker of the 2A receptor, the effects on brain activity and the effects on consciousness go away. That doesn't mean, however, that interactions with other receptors are irrelevant, and this is an area of active study. Next, please. We know from... So this is a study using brain functional imaging. What's shown here isn't brain activity, but rather brain network organization, basically how connected different nodes of the brain are with the network as a whole. And at a very broad level, what you can see is an increase or a denser connectivity in the occipital cortex, which is the primary visual cortex. One can make up a story that this may be associated with the visual illusions and distortions that happen when people are taking psilocybin. And you see a disconnectivity through the frontal lobe, including particularly the default node network, which is that light blue area in the medial part of the brain shown on the bottom. This is a fairly consistent pattern. You see something very similar with LSD, and these patterns of change contribute to theories about how the drug activities lead to network changes, lead to their psychological effects, though we don't have time to go into those theories in depth today. Next, please. We also have increasing information about what these drugs are doing at the molecular level and cellular level. This is work from my colleague Alex Kwan here at Yale, but is representative of other similar work done by others with various drugs. Here, what Alex and his colleagues did is they gave psilocybin to a mouse and they visualized the apical dendrites of the individual layer five cortical neurons in the frontal cortex in a living mouse over a month. And the key thing that we're looking at is the production of dendritic spines. Those are in the lower left. These little protuberances from the dendrite, which is where synapses are thought to form. And you see, as you see on the right, the number of spines when mice are treated with psilocybin increases. That's shown in red on the right, compared to mice that were identically treated but didn't receive psilocybin, received saline instead. This matters because we see a similar effect with antidepressants, chemical antidepressants, including ketamine, but also older chemical antidepressants. And this increase in plasticity, in connectivity, which lasts many days, long after the psilocybin itself is out of the system, is thought by many to be an important substrate of its effects. Next, please. So with that background, I want to talk about the clinical work that's happened. There's been a large number of clinical studies, starting with open-label studies, going back to 2005 and then 2012. Controlled studies in various indications began to appear in 2016. That was part of the impetus for the huge growth in interest dating to that time. And then we started to have large multi-center controlled studies with hundreds of patients, especially in major depressive disorder, just in the last few years. I mentioned when I was talking about the definition of psychedelic, that one of the senses is a mode of treatment. So not the drug, not the phenomenological effect, but the mode of treatment, where a drug that causes, or other manipulation, I suppose, that causes a profound effect on consciousness is paired with either a supportive or a structured psychotherapy. Almost all of the trials that have been done in the modern era follow that mode. This is an image of a room at our center where we treat people with psilocybin, and you can see that it does not look like a typical medical context. It's made to be comfortable. The person who takes psilocybin reclines. There are typically two people sitting with them throughout their experience to provide an environment of psychological support, as well as physiological monitoring. There's usually music played. Many steps are taken to make this a comfortable environment. We don't know what of those matter, and we don't know how much that they may contribute to expectancy effects and complications with clinical trial design. Those are important open questions that I know that others on this panel are going to address in greater detail. Next, please. So there have been, the earliest studies were not in substance abuse. The earliest studies, and the controlled trials published in 2016 were in existential distress, anxiety, and despair associated with hospice care and with advanced cancer. This is one of the indications in which LSD was investigated back in the 50s and 60s, and this is where the modern era of controlled trials began. I'm not going to be showing the data for these trials outside of substance abuse, again, for reasons of time, but just to note that this is where the two good controlled trials from two different research groups, one centered at Hopkins, the other at NYU and UCLA, published their work in 2016, and it was good quality controlled studies. Though again, there are some difficulties with placebo control in this field, which is another challenge. We'll be hearing about those more later. So these were the first studies. Next, please. The most robust studies in the modern era have been in major depressive disorder. There was an open-labeled study from Robin Carhart-Harris's group in 2016. Controlled studies began to appear in 2020 from the Hopkins group, as well as from Robin Carhart-Harris. And then two large groups have done multi-center studies with over 200 patients. Compass Pharmaceutical Study was published in the New England Journal of Medicine in 2022, and the USONA Collaborative's large study. We are still waiting to see the publication, though I've seen the data. So now this is kind of a major step that studies in psychedelics have crossed from small, single-center tens of patients to multi-center hundreds of patients as the field moves forward. And there's, I think from this evidence, strong evidence from these studies, strong evidence that there is some benefit in major depression, though with many caveats about methodology, blinding, and expectation, which will be discussed. Next, please. So I'm gonna spend just a little more time and show some data on studies in substance use. And the most robust studies are in alcohol use disorder. Next slide, please. And the leader in these has been Michael Bogenschutz at NYU. This is the first study from their group. It was an uncontrolled study, just to sort of lay out the methodology. But what you can see on the left is percentage of drinking days and percentage of heavy drinking days, heavy in red, drinking days in blue, in individuals with severe alcohol use disorder who came into a structured psychotherapy and then received either psilocybin, well, in this case, it was open label. Everyone received psilocybin. And so you see some benefit from the first to the second data point. That was with no psilocybin. That was just because of the structured psychotherapy began with motivational imaging. I'm sorry, interviewing, going into a CBT approach in the latter half. And then between the second and third data point here, there was a dose of psilocybin. And you see a dramatic drop in the number of drinking days and heavy drinking days at that time. Of course, uncontrolled, and so it's difficult to ascribe causality. But Dr. Bogenschutz and his group went on to do a large study, 100 plus people, who went through the same paradigm with placebo control. And this is the best study in the modern era in substance use disorder. Next, please. This was published last year. And what you see here is individuals with severe alcohol use disorder went through the same paradigm that I've just described. And we see heavy drinking days on the left, on the Y-axis. Everyone went through a structured psychotherapy for 12 weeks. And so everyone had some improvement, but then they received two doses of either psilocybin or placebo at weeks four and eight indicated by the arrows. And what you can see is an improvement in both groups that was sustained, but a significantly greater improvement in the group that received psilocybin treatment. So this is promising data, subject to the caveats that I've mentioned, that there is benefit in alcohol use disorder. And I wanna put this in the context of the studies of LSD that I reviewed before, which, as I said, there were six studies, primarily in incarcerated males back in the 50s and 60s, that suggested benefit. So we're beginning to have convergent evidence of benefit from a combination of psychotherapy. I also wanna note most of the studies in late life anxiety and depression or in major depressive disorder have been done with the pairing of psilocybin with simply support, psychological support. This study, however, paired the psilocybin with structured psychotherapy, embedded the psilocybin in the middle of a structure, of course, a structured psychotherapy. And this is an active issue of discussion in the field is what's the best way to administer these drugs for therapeutic benefit. Next, please. The literature in other substance use disorders in the modern era is much more limited. I'm gonna show a few data slides. There's a lot of studies underway, but the published literature is much more limited. Next, please. The group at Hopkins has done a study in nicotine addiction, and there are two pieces of evidence to suggest there may be benefit. The first done by, again, the Hopkins group is done using surveys. And summarized here in this slide, the individuals who self-report use of psilocybin have a reduced rate of nicotine dependence. Interestingly, as is noted, there's the LSD may be the reverse. Survey data of complicated population, very difficult to draw a lot of conclusions. Slightly more compelling modern study was a naturalistic study of 358 individuals who specifically used psilocybin in an effort to quit smoking, and had, as you see, about a third had pretty persistent, had abstinence, and another approximately a third had some reduction. Again, self-report from individual experience, not controlled data. Next slide, please. The group at Hopkins has begun to do controlled studies with nicotine, and the first is shown here. This was published back in 2014. A study of psilocybin and the treatment of nicotine addiction. You can see in the bullet points, what's shown here is open label to only 15 people. So very limited study, but early promising data, and a controlled study is underway. Next, please. Here's ongoing work in other, including other substance abuse disorders. And you can see there's a lot of interest in the treatment of opiate use disorder, no published data yet. Group at Alabama studying cocaine use disorder. There's work in methamphetamine abuse, as well as in the number of other non-substance abuse disorders lifted here. My own group is doing the work in obsessive compulsive disorder. Next, please. I'm gonna go very briefly, very quickly through these next two slides, these next two slides, because of time. But just to note, there are other psychedelic substances that are of relevance to addiction psychiatry, and you may be hearing about in the coming years. One is ayahuasca. Ayahuasca is a tea that was developed by people of the Northwest Amazon. And it contains two molecules, dimethyltryptamine above, and then one of several monoamine oxidase inhibitors, such as harmin below. The monoamine oxidase inhibitor is needed because the gut breaks down dimethyltryptamine very quickly, and it never gets to the brain if it's just taken by itself. Next slide, please. And ayahuasca is interesting because it is increasingly widely used in a quasi-religious setting, there are ayahuasca churches around the world, as well as in in treatment settings, especially in South America, and you can see there's a survey study of 441 ayahuasca users who used ayahuasca to treat smoking. There's very little controlled data here, and I don't know of any large rigorous studies underway, so this is something that may take a little longer to mature, and it's hard to know where it will land, but it is being actively used in South America for substance use disorders. Next, please. And another molecule that's being actively used in some clinics outside of this country in substance use contexts is ibogaine. This is one of those atypical, perhaps, antipsychotics that was in the lower right corner of that image I showed you before. It has complex pharmacological actions. Next slide, please. And no controlled data. I just mention it here because it is being actively used in clinics in South America. I suspect in other places, South America is where I know of them, and therefore is worth having on one's radar, but they're no controlled trials. There are some concerns about cardiac toxicity, and the pharmacology is very complex. It interacts with a lot of the sectors. We don't really know how it may be affecting the brain. Next, please. Final topic I want to mention, just in one or two slides, is this question. Are psychedelics addictive? Back in the 1970s, psychedelics, LSD, and psilocybin were lumped in with clearly addictive drugs like cocaine and heroin in the Controlled Substances Act, but there's been an active discussion about whether that is really an appropriate categorization and whether they are in fact addictive. Next slide, please. One study to address this question recently was a survey-based study done by David Nutt and his colleagues published in 2010. I will say this is based on a survey of experts, and so it's just basically summarizing current opinion, but you can see that people were asked how harmful are various substances of abuse. Blue is harm to others. Red is harm to others. Blue is harm to the users themselves. You can see that alcohol, heroin, and crack cocaine and methamphetamine were seen as most harmful at the left. You can see that mushrooms, meaning psilocybin, LSD, and ecstasy are all the way over the right. They're not perceived as being in the same category as these other substances, for what it's worth. It's a survey of experts. Next, please. Next slide, please. It is that these drugs have relatively low reinforcing effects. Most people we treat with psilocybin are not asking to come back quickly for another exposure. The experience can be rather challenging. There is tachyphylaxis with these drugs. Frequent use leads to reduced response. I know of no evidence for dependence or withdrawal. Now, I want to caution that that absolutely does not mean that they're without potential harms. Some of those harms are shown at the bottom. The safety record in controlled studies in the modern era has been very, very good, but that's with controlled doses of controlled substances in a very safe, controlled setting of a highly screened population. I do have some concerns about what additional harms will come to light as Luce expands, as I suspect that it will in the coming years. You can see a list of some obvious potential harms at the bottom, dysregulated behavior, psychological distress, how will this interact with a predisposition towards psychosis, I don't think we know very well. Cardiovascular effects aren't profound, but they do happen. And then, persisting perceptual disturbance, or HPPD, which is a DSM diagnosis for persisting hallucinosis, has not occurred in controlled studies in the modern era, but at less controlled settings is absolutely something that needs to be carefully considered and we need to keep an eye on. Next, please. So, that's the end of my overview. My thanks to my collaborators in my own work and who've helped me learn about this field, especially Ben Kelmandy, pictured here, now an assistant professor at Yale and the leader of our studies in OCD, who's really been instrumental in bringing me into this field, which has become a source of great interest and professional satisfaction. Next, please. My funders listed here. And final slide, please. Thank you all for your attention. I hope this overview has been helpful, and I hope that it will nicely connect you with the stage for some of the discussion to follow. Thank you, Dr. Pittinger. That was a wonderful overview. We've already received some questions in the Q&A function. So, I'd like to highlight for other participants that if you have questions as we go along, please feel free to enter them. And without any further ado, I would like to introduce Dr. Muthukumaraswamy, who's an associate professor at the School of Pharmacy in the University of Alkaline, and he's going to be presenting at the University of Auckland, where he also leads the psychedelic research there. Because of the time difference, he requested to pre-record his presentation, but he will join us live for the question and answer and discussion period. Thank you. All right. Welcome to this talk, which is titled Reviewing the Design, Outcomes, and the Limitations of the Studies and Data Collected from Large Randomized Controlled Trials with a Focus on Psychedelics. And my name is Associate Professor Suresh Muthukumaraswamy from the University of Auckland. And as a disclosure, I've received previous research funding from a couple of pharmaceutical companies. So, the objectives of this talk is that learners should be able to identify the compounds that are key limitations in psychedelic randomized controlled trials, discuss how these manifest depending on the randomized controlled trial design, and then try to apply these understandings to the nascent field of psychedelic clinical research, so that when you see new papers come out on psychedelics potentially in addiction, that you're able to kind of deconstruct what's going on and be able to critically evaluate the data that's in these papers. So, in order to do that, we really need to understand the nature and purpose of the randomized controlled trial. And so, the purpose of a randomized controlled trial is to try to establish a causal effect between a treatment and an outcome. So, here we have treatment, and it's linked to our outcomes. So, this is a causal diagram. And so, we establish efficacy this way, and we also establish safety this way in clinical trials. And this hides, there's a way of formalizing this logically, and it's called the fundamental, and it's called the Rubin Causal Model. And so, ideally, what we would like to do in any situation is be able to understand what effect an intervention has on any individual. And we would like to be able to describe for an individual the individual treatment effect, which is equation one here. Unfortunately, though, because there's only one of us in only one universe, we can never collect data on both what happens with the intervention and what happens with a control intervention. And this is known as the fundamental problem of causal inference. So, what we're left with problem is that we can't actually estimate individual treatment effects. So, what we do instead is try to describe the effects at the level of the population, and that's what equations two and three get us to. And that, so that in equation four, we now describe what we call the average treatment effect, which is the estimated value of the individual treatment effects across a group of individuals in a population, and we achieve this through sampling that population. So, this gets us around the fundamental problem of causal inference. And so, we're describing the average treatment effect, and that's the effect size that we typically see reported in our randomized control trials. In order to make this unbiased causal inference, we require several things to happen. The first thing is that we require our participants to be randomized into our two groups so that they're essentially what we would call exchangeable. We require the sample size to be sufficient so that the statistical estimation is accurate, and we require the allocation to be concealed to the investigators and the participants. And critically, in terms of this talk and also some of the weaknesses that we see in psychedelic RCT data is we require double or potentially triple blinding. And the ICH, who basically set the global regulations for drug trials, have nicely described what double blinding is, and so I'll just quote it here. So, blinding or masking is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence which the knowledge of treatment may have on the recruitment and allocation of subjects, their subsequent care, and the attitudes of the subjects to those treatments. So, that last part is particularly important. That blinding or masking limits the occurrence of bias that it will have on the attitudes of subjects to the treatments that they receive. So, and the thing with psychedelics is that they have really large psychological and psychoactive effects on people. So, this could be grabbed from almost any psychedelic research paper. Here is the effect of LSD on various psychometric scales. This is the 11D-ASC, which is very commonly used, and you can see that there's dose-dependent increases in audiovisual synesthesia, elementary imagery, complex imagery, blissful state. So, they create a really strong and powerful psychological experience in the participants that receive these substances, and this creates a pretty fundamental problem for maintaining blinding in psychedelic RCTs. And so, that can be summarized in the quote below. So, given the obvious psychoactive effects of psychedelic drugs, those in the active intervention group will likely know that they've received the treatment, and therefore, they may show a greater treatment response due to the expectancy effect. Those participants, on the other hand, that receive a placebo intervention, they may realize that they've received the placebo intervention, and therefore, they may be disappointed, and that may actually decrease their placebo response. And so, this is something I like to call the perils of abstraction. When we talk about data and we see papers being presented to us and summarized in kind of logical form like this, or maybe you see a graph in a paper that looks like this, we see data points and dots. And maybe after numerous studies we conducted, we see a meta-analysis where the dots get aggregated into ever and ever more abstracted ways of thinking about data. But it's really important to remember that these data points have actually come from people with biases and expectations. And so, rather than just considering things from a data point of view, what I'd like to do is next show you a video of actually people's experiences undergoing a psychedelic clinical trial. So, hopefully, this works technically. I'll try and press play here. So, this comes from a documentary from the BBC about a cytosine clinical trial. There may be some swearing, and I apologize for that. I didn't say it. It's really interesting to observe how the investigators interact with the participant. And it felt okay. I was lying there, and I just, the tears were pouring out of my eyes, but they weren't sad tears. They were joyful tears. I felt really happy, and I just, I remember thinking I could die in this way. So, now we see the experience for a different participant. So, You become extra sensitive to yourself, or am I feeling anything, or is that just a suggestion? Who knows? But for Nadine, there are no noticeable effects after about 20 or 30 minutes. I realized that really, if anything, it was very, very minimal. I couldn't really tell. If there's too much anxiety, or stress, or anything, it's very easy for it to tip over quite quickly into a position where I feel I need to kind of shut down or remove myself. And at that point, I was encouraged to kind of stay with it for quite a while. Nadine is in the Essatelipram group. I was very, very upset. Oh, yeah, extremely disappointed, angry at the trial, you know, like I'm not in a great place. So here you can see, you know, she describes being angry at the trial. So obviously, when we think about an accumulation of data points that we read might be our control group, that these people may be disappointed to realize that they're even angry that they realize they've been allocated to the control group. Whereas those who are maybe in the active psychedelic group, that maybe they were having expectations that this would help their treatment, and then when they realize that they're in the treatment group, this may amplify their response. So what we get from the two flip sides is we get actually a double separation of bias where disappointment and expectancy could potentially serve to amplify the observed treatment effect that we're trying to capture in the clinical trial. So another kind of issue with abstraction is that some of the ways that we actually evaluate the clinical trial data in psychedelics may not be appropriate for psychedelic RCTs. So one of the common ways of evaluating clinical trials is to use the Cochrane risk of bias tools from the Cochrane collaboration. And actually, the authors in this paper, it's a really good paper, they applied the Cochrane risk of trial, risk of bias tools to psychedelic RCTs. And what you can see is actually using the tools instructions, the actual risk of bias in these trials appears really low. And that's really counterintuitive when you consider the video that we just saw. And it's because probably the tool isn't a valid way to evaluate the psychedelic RCT because it just clearly seems to lack facility when we know participants are coming unblinded, yet when we're in the abstract, things seem to look okay. So there's sort of further troubles when we start to think about the evaluation of data, and that not only will the participant become unblinded to the intervention, is that the therapist and research team can actually become unblinded to the intervention. And you can all basically see that in the video I showed that the therapists were very much engaged in the active participant, whereas for the control participant, there seemed to be quite a lot of isolation for that participant. And this creates potentially differential therapy, where the two groups may not actually receive the same therapy or therapeutic input from the therapists. And this differential therapy could lead to kind of a bias in the therapeutic alliance that is generated between the investigators or the therapist and the participant. And we know that therapeutic alliance is one of the strongest mediators of a successful outcome in psychotherapy. So it may just be that the fact that everyone's kind of expectations have been fulfilled in the psychedelic group, both the therapist and the participant, and that helps them create a stronger relationship, which would amplify the average treatment effect that we're trying to observe. And finally, sometimes these psychedelic therapies, they can be a little strange, the content of them, if you actually received a placebo, when they ask about things like mystical experiences, and actually you haven't had any, this can be a little strange for those participants. So when we now come back to think about our causal models, in our ideal clinical trial, we have a link between treatment and outcome, which is really nice and clear and direct. Actually in the psychedelic treatment model, there may be some direct influence of the treatment on outcome. And there may be quite a bit of it that's actually mediated through psychotherapy. The problem is, though, is that there are other pathways that can actually get us from treatment to outcome. So there may be that the patient unblinding allows a causal pathway to be generated from the expectancy of the patient can now influence the outcome. And also the expectancy of the therapist can influence the outcome. And this is potentially not an ideal scenario, because we would like our treatments to really not depend entirely on the expectancy of patients and therapists. And also those expectations can potentially be manipulable and may not be stable over the time when a therapy is approved, if it is approved. One of the things that we could potentially do, and isn't happening very much, is that we could begin to start to measure some of these things. So arguably, things like therapeutic alliance can be measured, the blinding of participants can be measured, and the expectation of participants around their treatment can also be measured. So that would lead one to question, well, are psychedelic randomized controls actually measuring these important things that may be influencing outcomes, such as expectancy and blinding and also alliance? We did a review of this, and we found that overwhelmingly no, well, very few next to no studies are actually recording the expectations of participants going into the clinical trials. And some are recording the blinding, but not very systematically and often informally. So even just collecting the actual information of where the participants de-blinded is actually being poorly reported in the literature at the moment. There's a few tables in the paper that you can refer to. So I'll just skip over that. But there is a slight paradoxical thing when we start to thinking about the actual measurement of blinding, is that in many ways, the purpose of the clinical trial is to become unblinded because we want interventions that are efficacious and heal the patient. And the participant, therefore, realizes in the clinical trial with an intervention that works, that they've gotten better, and then they can attribute that to the actual therapeutic effect, perhaps not the malicious effect of the psychological experience that they're having. This gets rather philosophical, but from a practical point of view, it does ask us the question of when we should actually measure blinding. And we have previously argued that this should be done relatively soon after the dosing session, but well before the outcome on the person's outcome assessments. So that gets us to the next kind of set is, okay, so we have these things that we think we should, that trials should measure, but what is the context of the trial that we should actually be measuring it in terms of trial design? And there are a lot of clinical trial designs out there that one could use. We would argue that some of them really aren't very optimal for psychedelic studies. So the placebo lead-in trial is probably not very optimal. The reasons for this can be found in the paper, but actually you don't want people that are easily influenced to be removed from the trial in this particular context. The crossover trial is probably not a very good idea for these kind of trials, not only potentially the treatment effects long lasting, but if you're in the treatment group, for example, you're in a crossover group and you realize that you got the drug first, you'll know that you're in the placebo group second and vice versa for placebo and drugs. So not only can the treatment effects carry over, but one's knowledge of the allocation can carry over. So that's potentially not a very good treatment design. The delayed treatment design is pretty much in our view useless because it doesn't control anything and you can have these really neat factorial type designs, but they're very complicated and running forearm trials is not many investigators are going to do that because it creates real power issues. So the potential designs that probably should be being used in psychedelic trials are using active placebos to try to at least begin to mask what the actual intervention is. Using dose response designs, we use low or potentially low and medium doses of the drug in the intervention and potentially using a pretreatment design. We provide a pretreatment that blockades some of the effect of the drug. And these are probably three of the better type designs. So when you're thinking and looking at data, you could ask, is the design of the study optimal for a psychedelic trial? When you're also reading paper, it's important to remember that often not reported in trials is that participants get told a lot about the intervention. They get, they respond to study advertisements. These are just some advertisements from a study of mine that is now completed. They're just here as an example to show you that, for example, participants are primed to the study by responding to the study advertisement. And when they come and enroll in the trial, they sign a participant information sheet and consent form where they're informed all about what's going to happen in the trial. And this will shape their expectancy. That shaping is particularly important because they're probably going to get de-blinded during the trial. Unfortunately, though, in many psychedelic, I would say almost most psychedelic RCDs are not actually reporting what the participants are actually told about the intervention. And this leads, there's a whole host of biases that can potentially contaminate the data. And you can see a lot of these, that they occur in different parts of the trial. And it's summarized here that you can go back and look at. So the biases that can happen due to these blinding effects and unblinding effects can happen throughout the RCT. And so just to kind of finish off the talk, although it's really, there's a lot of interesting and exciting data coming out on the use of psychedelics in psychiatry and in addiction psychiatry, arguably there's some questions about, do we actually have the experimental methods, the tools and the designs of RCTs to actually demonstrate causal inference or efficacy for psychedelics that we can say for sure isn't just due to de-blinding issues. And I guess I would argue at this case that we probably don't have those tools. That leads us to think about other approaches that we might need to use and whether we need converging evidence beyond RCTs to actually bolster the efficacy of these interventions. And I guess finally, as a kind of cautionary note, I would kind of ask what happens if psychedelics are improved for medical use based on low quality evidence and what might be some of the unfortunate consequences that such as indication bleed or other substances being approved that maybe aren't appropriate for use as medical interventions. And that is the close of my talk. So thank you very much. Right, welcome to this talk. All right, thank you, Miriam in the background. And now I'd like to welcome Dr. Paul Appelbaum who is the Dollard Professor of Psychiatry Medicine and Law at Columbia University. He has received numerous awards for his work in ethics and in psychiatry and the law. And we are delighted that you can join us today, Dr. Appelbaum. Well, thank you so much. It's a pleasure to be here. And I guess I can't control my own slide. So let me ask for the next slide, please. I have no relevant disclosures. Next slide. These are the educational objectives, but you'll see more about them in the next slide. So let's go there. So the question that I'm gonna be addressing in a broad sense today is what could be different about the ethics of using psychedelics compared with the ethics of any other psychopharmacologic medication or for that matter, medication in general. And I'm gonna suggest, first of all, that there are some challenges in informed consent to psychedelics that don't exist with other medications. Next, please. That there are difficulties that are looming on the horizon as these roll out into clinical use in ensuring that that use is appropriate based on the existing evidence. Next. That we need to anticipate adverse effects of these medications in ways that we really haven't done to date. And I'll get more specific about that next. Next. There are unique boundary issues associated with psychedelics and next, finally, there are issues related to commercialization, which is another, sometimes less than visible, but profound force in shaping psychedelic research and use today. And I will touch on those as well. Next slide. So let's start with informed consent. As you all know, to provide a meaningful consent, a patient needs to understand and appreciate what the likely effects of a treatment will be. Next. But with psychedelics, that's not necessarily so easy. Next. Because some aspects of psychedelic effects are inherently difficult to convey to people who've never consumed a psychedelic. People who have often talk about ineffable experiences, transformation of their awareness, dissolution of their egos, profound shifts in what they value or in aspects of their personality. And my favorite, oceanic boundlessness, which sounds like a consequence of global warming, but is sort of a blending of one's ego into the entire universe. How to convey those changes to an individual who's never experienced them seems almost impossible. And as part of the consent process, we may in fact have to tell people that. Next. And it might be helpful in some cases to have them meet with someone who's already had the treatment, although effects vary from one person to another and what one person's experience is may not mimic the experience that a particular patient will have. But this is gonna be a tough discussion to have with patients. Next. A second challenge regarding informed consent is the need to plan in advance for interventions that may be required during the psychedelic session. Next. Particularly therapeutic touch. Next, please. Touch, one person laying hands on another is often used to calm down people who become anxious or afraid as a result of the trip that they are on when they consume a psychedelic. Next. But of course is not in accord with what we all learned as psychiatrists and what all therapists learn about restricting touch very severely so as to maintain boundaries and prevent exploitation of patients. Next. Which of course introduces concerns about the potential for boundary violations that are anti-therapeutic, exploitive and abusive, all of which have been reported unfortunately in the psychedelic community. And so patient's preferences need to be ascertained in advance as part of the consent process. Next. A third challenge in informed consent is dealing with the expectations of potential participants. Next. And we've already heard about this already in the context of research, but it will be true in the treatment setting as well that as Anderson and colleagues noted in Lancet Psychiatry, psychedelic medicines carry a truly uncanny allure. People are drawn to them in an almost mystical way. Next. Indeed, as an example from the media contributing to this potentiation of the overestimation of the benefits of psychedelics is a quote from Ezra Klein, a level-headed data-oriented commentator for the New York Times in a piece he wrote called, Can Magic Mushrooms Heal Us? And he wrote the following, it would be one more option for those who need it, talking about psychedelics and both evidence and anecdotes suggest it would be life-changing for many. That would be enough. That would be so much. These kinds of encomiums in the press can't help but heighten the expectations of people, particularly people who may have failed other treatments before they come to psychedelic treatment. Next. And therefore, as part of the consent process, unreasonable expectations should be monitored and addressed. Next. The fourth challenge in informed consent is uncertainty about the longer-term effects of psychedelics, both good and bad, and how to deal with that. Next. Even for patients who have a positive response to the medications, we don't know based on current data. We just don't know how long that positive response is likely to last. And if it fades, whether it will be re-invoked with repeat administration of psychedelics. Next. Moreover, regarding adverse effects, although, as you heard, psychedelics seem to be relatively safe, the long-term consequences, particularly of repeated use, are just unclear at this point. Next. This is a table from a piece by Will Smith and Dom Sisti in the Journal of Medical Ethics, which I commend to you on suggested ways of presenting information in the informed consent process. It's written specifically for psilocybin, but it's actually more broadly applicable to psychedelics as a group. And I note in particular the box on information about the experience at the top, and the statement, hence, we can't tell you exactly what this is like, and you may have trouble understanding it before you experience it yourself, which I think is the challenge of getting consent from people in this context. Next. The second issue I want to sketch out for you are the challenges to ensuring appropriate use of psychedelics. And in some sense, this is a common problem when psychopharmacologic agents move from research to the clinic, and oversight is necessarily reduced. There are no prospective protocols. There are no IRBs watching what's going on. There's no compliance office looking over your shoulder. Next. Just to remind you, possession of psychedelics is still illegal under federal law, although a number of states and localities have declared that they will not enforce their own legal restrictions on some or all psychedelics. But they've been used for decades by what is often referred to as an underground community of psychedelic enthusiasts, with many therapists having led psychedelic therapy for years with substances obtained, usually by the patient, in the illicit market. Next. The fact that psychedelics emerged from this underground community has led to a broad heterogeneity of practices, many of which have no evidence base, at least not beyond the experiences of an individual therapist. Next. Treaters, in fact, often seem to base their judgments on their own positive experience with psychedelics. A recent paper in the new journal, Psychedelic Medicine, which tells you how this field is expanding, studied 32 therapists who do psychedelic-assisted therapy in the underground world today, and found that almost all of them, 88%, had themselves taken psychedelics, and they all had favorable views of its use. Next. So there's a risk of over-enthusiasm and advocacy, and of subsequent overuse and improper use of these agents. What can we do about that? Next. Well, the experience we've had recently with off-label ketamine is not particularly reassuring here. Next. Ketamine is currently, although approved for intranasal use, also being administered, and maybe even more so, administered intravenously, with varying doses at varying intervals by commercial clinics that serve an exclusively pay-out-of-pocket group of patients. Next. These clinics have no psychiatrist in many cases, and the drug is administered by an anesthesiologist. Indeed, they may have no mental health professional at all on site. Next. And they're using ketamine for a variety of non-evidence-based indications, such as anxiety, PTSD, and subsyndromal depression, about which we have no evidence of its efficacy. Next. It's also, as you may have seen in the media, being prescribed orally via video conference, sent by mail, with no oversight of how it's being used, and there are clear indications that at least some people are overusing or abusing ketamine with serious consequences. Next. How can we ensure appropriate use? Well, if psilocybin and or MDMA are soon approved for clinical use, as many people think they will be, the Food and Drug Administration has discretion to impose what are called REMS, risk evaluation and mitigation strategies. And those of you who use buprenorphine are well aware of how REMS work. Next. REMS can limit the indications for which psychedelics can be used, mandate training of various sorts, restrict dosages and frequency of use, require in-person administration, as they do for esketamine, and set other limitations. Next. And at least while psychedelics are relatively new in the clinical world, and while experimental, and while experience accumulates, those kinds of restrictions may make very good sense. Next. Whether they will in fact happen, however, we don't know at this point. Issue number three, dealing with the risk of adverse effects. When the FDA approves a new medication for a specific indication, some data on the potential adverse effects are usually available from the clinical trials. Next. Although for psychedelics, that's true to some extent. Psychedelic studies often exclude participants with personal or family histories of major psychiatric disorders like schizophrenia and bipolar disorder, or histories of substance abuse. Next. So these are the exclusion criteria, and I've highlighted several of them in a much publicized study from one of the leading psychedelic research groups. And I put it here not to criticize them, but just to use this as an example, because it's really quite typical of what's been going on in psychedelic research to this point. They excluded people with immediate family or personal histories of psychosis, histories of serious suicide attempts, and suspected or known conditions that could jeopardize rapport with the treaters such as borderline personality disorder. Next. Whether such precautions are necessary or whether in clinical practice they'll be adhered to are questions at this point. But I think it's clear that not having data on vulnerable populations prior to the approval of clinical use of these substances will make it very difficult to formulate guidelines on that use. And yet some of those excluded groups are very likely to be seeking psychedelic treatment. Think about suicidal patients, and think about the many patients with borderline personality disorder who have concomitant depression and substance use problems as well. So it seems to be really important to be collecting data under controlled conditions about the use of psychedelics in these populations before they roll out into clinical use. Yes. Next, please. Issue number four, boundary issues. And I alluded to this earlier, but psychedelics may induce states of extreme suggestibility on the part of the patient who's consuming them. Next. And there are reports of sexual exploitation during unregulated use in the 1960s, but also reports more recently of sexual exploitation even during at least one current trial of a psychedelic MDMA. Next. To date, the usual way of trying to prevent this has been having a male and female therapist team in the room for the entire six to eight hour session. Next. But that may not be feasible when you roll this out into clinical settings and therefore exploitation of vulnerable people will be a concern. Next. Let me just mention briefly the final issue here, which is commercialization. As an academic, I can attest to the fact that we academics tend to imagine that everybody will be as cautious and desirous of adhering to guidelines as we are. But when prescription of psychedelic medication becomes a profit center, there will be incentives to prescribe more broadly for less severely ill patients who might respond to standard treatments, to treat patients with less clearly diagnosed conditions who are of course quite common in ordinary clinical practice and to shed the precautions that have been used in research settings but that raise the cost of treatment. Extensive pre-session preparation, post-session debriefing, and as I mentioned, the presence of two therapies. Commercialization also implies, particularly if the ketamine clinics are an example of that, that access may be limited for poorer and less well-insured groups when pay out of pocket becomes the dominant model. Next. So to conclude, psychedelics raise concerns that are in some sense similar to those of ordinary psychoactive medications but also very different as well. Next. And these ethical concerns I submit to you are going only to increase as they move from research settings to clinical use. And although we didn't have time to talk about it today, even to public availability as various jurisdictions are talking about now, simply legalizing access to psychedelics without a prescription. Next. Regulatory restrictions may be needed. Next. And it would sure help to have clear guidelines from our professional organizations to mitigate the risks of ethical improprieties in their use. So with that, let me stop and thank you for your attention. Thank you, Dr. Appelbaum. And thank you to all three presenters for some very thought-provoking and informative presentations. I'd like to transition now at this point and invite our two invited discussants. We are delighted to have Dr. Nora Volkow who serves as Director for the National Institute on Drug Abuse at the National Institutes of Health. NIDA is the world's largest funder of scientific research on the health aspects of addiction. And Dr. Volkow in her own scientific research has been instrumental in demonstrating that drug addiction is a brain disorder. She's received numerous awards from her colleagues in the research world as well as in the popular press. And so thank you, Dr. Volkow for joining us today. We'd like to hear your impressions. Well, Karen, thanks a lot for having me. And it's a pleasure to be here with my colleagues and in particular with Dr. Berta Madras because she and I have navigated so many spaces and landscapes of the changing drug use and misuse and addiction in our country. I think that the presentations really eloquently illustrate the challenges and complexities that we have, but also the tremendous opportunities. And to me, this is actually quite an exciting area, really ready for research. When I listen to it, and obviously because of what we have seen happen in the past, and most recently with cannabis, we have to, of course, I mean, I am concerned, like many others, about the hype that is coming along with the use of psychedelics, because of all of the reports, and because of, I guess, this magical thinking that we all have of encountering just almost like magical treatments that are going to address the challenges that we have in treating patients. I think that that is my concern, that we basically have right now, the data is quite limited. The evidence is quite interesting and the way that I view it is the evidence is not sufficient in any way to start to implement psychedelics for treatment of patients with mental and including substance use disorders, but the data is sufficiently intriguing to justify the need to investigate it, so that we can understand much, much better what are the potential of these psychedelic drugs and how to optimally utilize them, and I also think in order to do that, to do the research that gives us an understanding of how they work, and so to me, what I find fascinating at psychedelic drugs, if we look at it in terms of what the data has shown, is we have compounds that are able to produce long-lasting changes in the brain or in behavior after one or two administrations, and open up the possibility of having, on the one hand, an intervention that, by shifting the landscape of the neurocircuitry, the interactions of networks in the brain, can result to modifications in our consciousness that may have therapeutic benefits. On the one hand, that's one of the proposed hypotheses. The other one, and they are not exclusionary, the possibility of having a drug molecule that you can tie it with a psychotherapeutic intervention to maximize the neuroplasticity changes, so that the effects of the psychotherapeutic intervention can be much stronger and longer lasting and achieved in a much more constrained time period. So, it shifts the way that we've been looking at in terms of drugs that we use in psychiatry in general, where we think of them, you do repeated administration, and then you see benefits in some of them, like for ADHD, you give a stimulant medication, and you have to be under the effects of the drug to have the therapeutic benefit. This is not the case here. The effects of the drug for psychosis may be six to eight hours long, as it relates to the intoxicating effects of the drug, and yet its therapeutic effects actually linger afterwards. And therefore, the major question of why it becomes so crucial that we understand what are the mechanisms that are driving these potential therapeutic effects. I also, I mean, as based by the discussions that were very, very much in detail presented, is we have here, more than in any other type of medication, how crucial and impactful the effects of expectations, which of course we have it with placebo. But here, that expectation, if we can even manipulate it in a way that it can maximize therapeutic benefit, maybe something that we want to work with, and as pointed out, is not just the expectation of the individual, but the expectation of the therapist. And again, that is not an area where we have been controlling on clinical research. I also resonated very much with the questions of, yes, we are used to randomized clinical trials, which of course are the gold standard, but it may, the current situation, as well as development in extracting knowledge from other sources apart from randomized clinical trials, is forcing us into thinking what alternative ways we can use to obtain that knowledge. So clearly, there are many things one can say about the psychedelics, but I do not want to go on, because I do want to get time for answers. I do think, questions and answers, but I do think that we cannot basically in no way neglect, under no condition, all of the ethical issues that were discussed, as well as the responsibility that we all have to take this as we go on in doing research, that we disseminate that information in ways that is not misinterpreted. Because the worst thing that we want to happen is that we start to see, as more and more people are being given the psychedelics, with no oversight, we, just by numbers, we may see more adverse effects. And those adverse effects may be then used to stop any further development of these therapeutics. So it could backfire to the whole field, if we actually don't provide the structure that's necessary to do this in a safe and responsible way, and ethical. And importantly, also, as mentioned, in a way that is not going to expand disparities, so that only some people can afford it. And finally, we have to tackle with the issue that for us, and I do want to highlight it, because I think that we need to communicate, it is important, these psychedelic drugs are Schedule I substances. Even though for the classical psychedelics, there's not really evidence that they produce addiction, but they are Schedule I, which means that research with these substances is much harder to do when those that are not are Schedule I. And I would hope that despite these obstacles, investigators would be willing to take the effort to actually explore the value of these agents in the treatment of substance use disorders, and in the treatment of other mental illness. So thanks very much for letting me be part of this panel. Thank you so much, Dr. Volkow. And thank you for those insights. I would also like to introduce our other distinguished discussant, Dr. Bertha Madras, who is a professor of psychobiology at Harvard Medical School. She's based at McLean Hospital, and the Massachusetts General Hospital as well. In public policy, she served as deputy director for demand reduction in the White House Office of National Drug Control Policy. And I learned just yesterday, though, that as she was starting in her research career, she actually did research on psychedelics as well. So thank you, Dr. Madras. We are delighted to hear your impressions. Thank you very much. I'm delighted to be here and in the company of Dr. Volkow, who is not only a national but an international treasure. So I have three perspectives that I would like to deal with very quickly. And I know the timing is short now. The first is advice to everyone working in the field. Number one is do not ignore history. The history of psychedelics in the 1950s, 60s, and 70s is sordid. It was a raucous period of clinical trials with inadequate controls, bias, charges, and counter charges by psychiatrists who castigated each other for poor study design and unethical practices. And if you even look at some of the citations that were provided by Dr. Pittenger on the use of LSD and substance use disorders, you'll find some sordid components of these trials, including the fact that, you know, the Smart et al. trial actually proved that there was no effect on alcoholism. The Savage and Cage trial used, which was also alluded to, they actually had the LSD responders in intensive inpatient residential therapy, whereas the non-LSD treated cohort was an outpatient without any intensive psychotherapy. So it is really important for people to familiarize themselves with the past, because the past should also help to inform the future. Our standards have changed, but have they really changed as much as we would hope them to change? Just one other thing following up on our first speaker is that we don't have any mentions of what the publication showed in terms of LSD as a counterproductive or perilous clinical trials for certain populations or their risks in terms of public use. And I would also like to focus on the mention of the Controlled Substances Act. The fact that hallucinogens are in Schedule 1 is not based on their addiction potential, but their abuse potential, and there are very good definitions trying to distinguish those two categories. So I would like to just go on very quickly with my other remarks with regard to Dr. Suresh Muthukumaraswamy's excellent presentation on the confounds and challenges of conducting these studies. It is really important to understand how we define some of these diffuse terms, such as boundlessness, spiritual experiences, and disembodiment. And what is really missing in the literature is the data on the percent who respond with spirituality and the percent who respond with fearful hallucinations and terror. Is there predictive measures of these dichotomous responses? In 1967, Dittman said, why is it that some people, sometimes after only one LSD experience, become victims of depression, paranoia, psychosis, and even suicide? Whereas others, even after numerous sessions, appear to suffer no ill effects, but even claim substantial benefits in personal insights and functioning. So I think we don't have good data on differentiating between these dichotomous cohorts. Dr. Applebaum demonstrated challenges to inform consent for treatment with psychedelics, and added a number of other caveats. I would like to add the following that I think are really important in addressing three questions. How solid is the science? And we already have heard about what subjects have been excluded, the comorbid psychosis, suicidality, known risk factors, but all of these obviously limit the true risk of the drugs in a clinical setting. It is also important to recognize that prior hallucinogenic use is a common feature of the most recent clinical trials. Of 11 clinical trials, on average about half the subjects were already conversant and have been familiar with using these drugs, and that certainly can shape one's experiences and one's outcome measures. The second question we have to ask is, can or will protocols be scaled with fidelity? And clearly, as Dr. Applebaum highlighted, the REMS, the possibility of REMS risk evaluation mitigation strategies that the FDA can impose. Well, these REMS have been imposed on the ketamine clinics, and yet they haven't, they certainly have not curtailed rote clinics that have very few controls, very few decisions on including or excluding potential patients, very little training, very little oversight by the medical community, and so on. So even if we do adopt REMS, even if the FDA imposes them, the fact that our society is the wild, wild west with regard to drugs is not necessarily going to give us any command over fidelity and implementation with regard to scale. And the costs, of course, of scaling up is terrible. These terrible consequences are not known. The third issue that I really want to delve in, which has not been described in great length, is the reality of unintended consequences. The legalization movement for hallucinogens and psychedelics is being piggybacked onto medical research. And will the states follow California's medical marijuana Proposition 215, which occurred in 1995? Once you medicalize a substance, it becomes, in the minds of the public, safe and effective. And because of this, the legalization movement followed very rapidly after the medicalization movement with regard to marijuana. And I think that what we're seeing now is advocates promoting compassionate access to this group of drugs without FDA approval. And from what the predictions are, the majority of states will legalize psychedelics by 2034, within a decade or so. We already have 74 bills in 25 states considering the reform bills on psychedelics. Most of them are legislative initiatives. They're a lot easier to deal with than ballot initiatives. It's a lot easier to convince legislators rather than the voters. And we have legal medical hallucinogens have been decriminalized in Oregon and Colorado. Clearly, our social movements towards making these drugs available, based and piggybacking onto the current clinical trials is very disconcerting. Because there may be pressures on the FDA, there may be pressures on legislative bodies to move forward in the absence of very solid safety information. The US failed to prevent conflation of biomedical and commercial marijuana enterprises. And I just hope this pattern is not repeated with hallucinogens. Finally, I'd just like to close with a little bit of literary plagiarism. We have Aldous Huxley, who commented that hallucinogens, at that point, that was the term used, was the chemical opening of doors into the other world, and a belief that drugs can procure what Catholic theologians call a gratuitous grace. On the other hand, Arthur Kessler wrote that chemically induced hallucinations, delusions, and raptures may be frightening or wonderfully gratifying. In either case, they are in the nature of confidence tricks played on one's own nervous system. And I think both points of view prevail at the present time. Hopefully, we'll have some clarity through far more intensive research and far more extensive insights into how they function and whether or not they are suggestive drugs rather than chemically induced neuroadaptive changes. Thank you. Thank you, Dr. Madras. And thank you to all the panelists. I would like to thank the panelists, Dr. Pittenger, Dr. Muthukumaraswamy. Y'all have both jumped in and started typing answers to questions that we've received. So, I appreciate that. We're receiving lots of applause, emojis, and thank yous also in the chat. We did get a late start. So, if I know that everyone has busy schedules, but if you have another four minutes, both panelists and participants, AAAP is going to keep the webinar open until 140. So, thank you. Let's see. What I'd like to do is go to the questions and answers and pose. There have been many wonderful questions raised. And as I said, thank you to the panelists for answering them. Some of the remaining, we're seeing patients, Dr. Madras, your comments reminded me of this about public policy and science and the interface. We're seeing patients purchase psilocybin off the street in an attempt to treat themselves and drop out of treatment. This is a growing trend and will increase with legalizations. To you, any thoughts? And then to Dr. Volkov or others, do you know of any studies planned to look at the effect of the drug alone or to the effect of changing policies and public consumption? Well, the quick answer is that we had no policies on consumption in the 1950s and 60s and early 70s. And for those of you who really want to have the most optimistic view, I urge you to read the literature of psychiatric reports, not only with regard to patient trials, but also with regard to the consequences to the public. Because we often try to attribute the Controlled Substances Act and President Nixon's war on drug to the decline and the demise of these clinical trials. But in fact, that wasn't the case. They began to wane because of the recognition that some of these trials were so unethical. And finally, ethical randomized controlled trials came into play in the late 1960s. And it developed a reality check on what these clinical trials had been doing up until this point. I happen to inherit the LSD from the CIA experiments that were conducted at the Allen Memorial Institute of Psychiatry. One of my close friends in our program in biochemistry, eventually became a Stanford psychiatrist and wrote a book about the devastation that his father had by being a patient and a subject to one of these things. I think we have to go back and not have generational forgetting on what happened in the past, and how to develop firewalls and boundaries and barriers to prevent this from reoccurring in the future. Yeah, and I'm going to jump here because I do think and I agree that we need to learn from history and we don't seem to be very good at it. But I also want to comment on the notion that where we were in the 60s or the 70s is very different from where we are now, as it relates to our ability to actually interrogate the human brain and understand what its consequences are. And I would hope that those advances can provide us the background with which to do research that is ethical, that gives us the possibility to actually evaluate whether psychedelic drugs have a potential for therapeutics or not. I think pharmacologically they are extremely interesting drugs themselves. I also think that an aspect, and Berta commented on it, and I do think it deserves also more attention overall is how do we personalize that intervention. And this is relevant not just for psychedelic, for any other therapeutic. Not every patient responds to the same medication or doses. So again, understanding that in the future what we're aiming for are much more personalized interventions where the use of therapeutics may not be seen as isolated, you take a pill, but they may be seen in the context of a very specific combination of interventions, such as is the case of a psychotherapeutic intervention with proper oversight. I do think that it behooves us not to be sometimes just too scared of what may happen, but use that fear generating from past negative experience to ensure that we are doing things safely. But it behooves us. I mean, that's how science advances. And I do think that here we are in psychiatry and in the addiction field in a very exciting time where scientific advances and understanding access to artificial intelligence, large databases, which was the question that you were asking, and indeed we're very much interested in starting to generate registries that can provide the data of people that are taking these drugs because they are taking it and they are not taking them by themselves, which is something that we didn't discuss. Many of these people are also combining psychedelics with marijuana, with alcohol, and understanding these interactions, which may be very negative, becomes extremely, extremely important. So that's why, I mean, my view is that data is very limited, but what we know and the tools that we have really bring it up as something that does deserve research and in a way that will not jeopardize if it does have potential for therapeutics, its potential future use. Thank you so much, Dr. Volkow. I think that's a great way to wrap up the presentations. Again, thanks to you. Thanks to all of our panelists for your amazing presentations and thanks to the audience for your thoughtful questions. We will at AAAP be gathering those questions and answers and we will send them out to participants, so you will have those at the ready. Thank you. Take care, everyone. And one more request on housekeeping, please provide us with your evaluations. We take your feedback very seriously. Thank you.

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