All right. Good morning, everyone. Thank you for joining us on day three. We have one more day of the conference. Hopefully it's been a good conference. But please give us some feedback if you have any thoughts. Today we have a very exciting day, and I'm going to be discussing the schedule for today in a second. But first, let me give you some announcements. Let's start with tomorrow, actually. Tomorrow is going to be the last day of the conference. We're going to have the high-impact publication of 2024 session. This was the most attended session last year. That was the session that got the highest reviews. It's really good. Please come and attend it. The other event that we have tomorrow is the symposium by Dr. Gordon on fentanyl. It's going to be great. And then we also have something new that we're introducing this year, which is the community event. We're connecting with local partners here in Florida to help us give back to the community and connect with local partners here. It's going to be an interesting event. Today, the exhibitor hall ends earlier than yesterday and the day before. It's going to end at 12.30, so stop by. And then a couple of fun things. We have the scavenger event, the scavenger hunt. We have two winners, Dr. Laura Samnder and Bak Hassan. Congratulations. And for all of you who didn't participate, you're going to regret when you hear what they won. They won either a dinner at the restaurant, which is fun, or a spa treatment for two, which is even more fun. And then we also have the winner for the networking bingo, and it's Dr. Henrique Oliva. And he also won the same thing. He has to choose between a dinner or a treatment at the spa. And everyone else who participated in the bingo will get a goodie bag. So please stop by the information desk to get your prizes. Today, we're going to have the poster walk, the award ceremony. Remember, the award ceremony is earlier than it usually is, and there's the reception and the party afterwards. The party is disco-themed. Wear your most fun clothes and be ready to dance. It's not going to be a very formal party. And then I'll remind you of the same housekeeping notes as I did yesterday. The information desk is your best friend if you have any questions. Don't throw away your badges. The tickets on the back, the red tickets on the back, is your tickets for alcohol for the reception tonight. And then during the symposium, if you have any questions, please save your questions until the end, and you can use the microphones in the aisles to ask the questions. And keep your phones on silent, please. Thank you. So it is my pleasure to introduce the first symposium for today. This symposium is called Psychedelic Therapy for Substance Use Disorders, Neurobiology, Evidence-Based Regulatory Considerations, Unintended Consequences, and it's chaired by Dr. Steve Ross. Dr. Ross is a professor of psychiatry at NYU and the associate director of the NYU Psychedelic Medicine Program. He has 24 years of experience treating addictions and doing research focusing on treatment for psychiatric disorders. Dr. Ross, thank you for joining us today. It's a real pleasure to be here today. I've been coming to AAAP meetings for over 24 years, and this feels like a real home to me. So it's so great to see so many people I've known over so many years and to see what's happened over time. So I'm really excited to be presenting this symposium. And I hadn't presented at AAAP in a number of years and recently got some communication from AAAP leadership about suggesting that perhaps I pair up with Dr. Bertha Madras at Harvard to do this symposium. And when I heard about that, I jumped at the opportunity in particular to do it with Dr. Madras. And the goal of the symposium today, we're at an interesting moment in the field of psychedelic medicine, and I think it's really important to be able to shine a light on this and to educate the addiction psychiatry and addiction medicine community about this. Because the concept of using psychedelics plus psychotherapy to treat substance use disorders creates a lot of cognitive dissonance. I mean, as an addiction psychiatrist, to hear that, you would wonder why a drug that we consider a drug of abuse, a drug of harm would be leveraged in any therapeutic way in particular to treat substance use disorders. And this is a field that historically is sort of like filled with polarization. You have some people thinking this is the most wonderful thing ever. The first, I'm going to talk about the first wave of psychedelics, psychiatry, how they were first considered wonder drugs. And then after that, they became demon drugs and demonized and prohibited. And there's a long history of people having kind of hyperbolic reactions to these drugs. And I think we want to steer away from that and want to be able to look at them in a really rational, straightforward way and understand what the evidence is telling us, you know, in terms of relative risk versus harm. And so the symposium today is going to be really interesting. There's going to be three speakers. I'm going to be talking about the evidence base of the use of psychedelics to treat substance use disorders and the gaps. Dr. Madras is then going to talk about the neuroscience and neurobiology of how these drugs work and really importantly, unintended consequences. I would say the big focus of this symposium is to really focus on the potential harms of these drugs for individuals and for society. And I really want to make sure that we spend time on that. And Dr. Madras is the perfect person to do that. And then we have Jack Canningfield of Johns Hopkins and Pinney Associates to talk about the really interesting regulatory pathways here, both with FDA and there's some psychedelic drugs that are getting close potentially to being approved and prescribable, which is really, really interesting and interesting for our field to consider. And then we're going to talk about the state legalization efforts that have kind of bypassed the FDA and are moving forward these medicinal psychedelic acts in various states and to talk about how kind of problematic that can be in particular. These are our disclosures. My only disclosure is that I get grant support from USONE Institute, a company developing psilocybin for major depressive disorder. So the history of psychedelics is really interesting. Long before western medicine discovered psychedelics, they've been used by indigenous cultures for thousands of years. There's documented use of psilocybin mushrooms going back tens of thousands of years. Same with peyote and Aztec populations. But the west discovered it with this guy Albert Hoffman. Albert Hoffman was a Swiss chemist. He was working at Sandoz Pharmaceuticals. He was studying ergot derivatives to try to come up with a vasoconstrictor to help women who were hemorrhaging during childbirth. And he accidentally got this lysergamide on his skin in 1943, went home, and had the first LSD experience. And it wasn't a good one. He kind of went psychotic. He thought his neighbor was a witch who was trying to possess him. He went home, he called his physician, and he thought he's most certainly dying. And the physician examined him, found nothing wrong with him. And he had like a dark night of the soul. He woke up in the morning and felt refreshed. He had these novel insights and realized that he had discovered something really interesting. And so Sandoz Pharmaceuticals LSD is made a legal drug. It's sent to psychiatrists and researchers throughout the world. And it starts this really interesting period in psychiatry that goes on for about a quarter century. And it's considered a wonder drug. Psychiatry really takes it up. There are APA conferences focused on this. And it's mostly LSD during this time rather than psilocybin. And the idea was that this is going to revolutionize psychiatry. It's going to cure mental illness. There's all this kind of hype about it. Psilocybin was synthesized in 1958. And at the end of this quarter century, I mean, there were over a thousand published studies. There were over 40,000 participants. The most studied indication by far was the use of LSD to treat alcohol use disorder. The second most promising data was the use of LSD treatment in end-of-life cancer pain and existential distress. And that was actually the first study that our group did. And I'll talk a little bit about that. But at the end of this period of time, all of this was sort of erased. When I was in medical school, when I was in general psychiatry training, when I was in addiction psychiatry training, I learned nothing about this history. Completely absented from the history books. And I was curious, like, how did this huge part of psychiatric history, like, how can I never heard about it? Well, it started with a guy, Timothy Leary. He was a professor of psychology at Harvard. He started the Harvard Psychedelic Research Group in the early 1960s. He did some really interesting studies. There was the Concord Prison Experiment, giving psilocybin to people with antisocial personality disorder. He conducted the Good Friday Experiment, giving psilocybin to divinity students. And it had some interesting results, but he kind of went off the rails. The Harvard faculty said, whatever you do, don't do this with undergrads. And in fact, that's what he did. He did the drug with undergrads. So did Richard Alpert, who became Ram Dass. And Timothy Leary gets kicked out of Harvard. I think the only professor at the time to ever be kicked out of Harvard. And becomes a Pied Piper of psychedelics. He gets the youth in America to take this drug. He gets caught up in the counterculture movement of the 1960s. And we start to see the real harms with these drugs. At my hospital, Bellevue Hospital, people came into the emergency room having psychotic episodes. We realized people with psychotic spectrum illness, these drugs are quite harmful. But it most becomes concerning for the political establishment at the time. Richard Nixon really thought this was a threat to the political establishment. And so the whole war on drugs that we have, that's been such a horrible thing for our field that started in 1970, was a war to suppress these consciousness-expanding drugs. It led to the criminalization of addiction. It led to addiction being one of the worst taught disorders in all of medicine. It's something we struggle with all the time now. And there's really interesting history. But the Controlled Substance Act always had a loophole to do clinical research. And so Rick Strassman in the early 90s did just that. He got approval. It was kind of a crazy first place to start giving IV DMT to normal volunteers. And they had these alien abduction situations. And it was kind of weird. But after that, Roland Griffiths at Johns Hopkins in the late 90s and Charlie Grubb at UCLA began a program of research. And one day in 2006, I had been at NYU at Bellevue for six years. I was running the substance abuse division. And a colleague, Jeff Gus, came in my office. And he started talking about he was going to visit Switzerland to commemorate Albert Hoffman's 100th birthday. And I didn't know what he was talking about. I didn't know who Albert Hoffman was. I didn't know why this was an issue. And he kind of clued me in. This had been a big part of psychiatry. So kind of out of nowhere, we started a research group in 2006 at NYU. And we've been conducting psychedelic research ever since. Our first study was in advanced cancer with psilocybin. And after that, we were looking for another study. When I first heard about this area, I thought, oh, we'll go back and do research with LSD and alcohol addiction. But that created too much cognitive dissonance. And so we started with psilocybin. But we've tacked back. We've done a study in alcohol use disorder. We recruited Michael Bogenschutz. And I'm going to talk about the results of that study today. So this was a really unique and interesting model in psychiatry. Rather than one patient and one therapist, you had two therapists. It was delivered as a dyad therapy team. And the model here, and I think this is the right model, is that this is medication-assisted psychotherapy. This is not just taking the drug and some magic happens. This is facilitated psychotherapy with two skilled psychotherapists. And the model, let's say, was alcohol use disorder or end-of-life existential distress, that there would be a lot of time spent with the participant, maybe 6 to 12 hours, to prepare them. You would go over their history of present illness, the distress related to the disorder. You do an extensive life review. You would prepare them for the sessions and go over the safety parameters. These sessions are unusual in that they take place in living room-like settings. People lie down on couches. They state their intention. And they focus internally. They have eye shades on and pre-selected music. This is nothing that I had learned about in psychiatry. And so there was a kind of an interesting model. So the resurgence of psychedelic research over the last 25 years has focused on three major areas. It's mostly been with psilocybin. And it's focused on psychiatric and existential distress in advanced cancer and other medical illnesses. Major depressive disorder actually has the most data at this point. There's been over 500 people treated. There's two phase three companies that are in phase three trials for psilocybin for major depressive disorder. So it's possible in the next couple of years, three to five years perhaps, the FDA will be considering applications for psilocybin for depression. And then potentially it could be used off-label to treat other conditions. And so this thing is sort of like around the corner. And the other major area has been substance use disorders, in particular alcohol use disorder. So the drugs we're talking about here are the serotonergic psychedelics. These are drugs that all activate the serotonin 2A system. And we're going to hear more about the neurobiology soon. But they include natural compounds like psilocybin mushrooms, where there's over 180 species. In the middle here you have ayahuasca, the Amazonian brew that has DMT. This is the Bufo Fraud that has 5-MeO DMT. And this is the peyote cactus. And these are synthetic psychedelics over there. The two main classifications of the serotonergic psychedelics are the indole alkalamines. These include the simple tryptamines, which interestingly their ring structure is very similar to serotonin. And it was the history of research into psychedelics that actually helped discover the serotonin receptor. The lysergic acid diethylamide is an ergoline. And then you have the phenyl ethylamines. And these are the infataminergic psychedelics. Their ring structure is very similar to norepinephrine. And the prototype here is peyote. So let's talk about risk of these drugs. This is really important to focus on. From a physiologic perspective, these drugs have very low toxicity in animal studies. And in humans, their safety profile is very favorable for the most part. They're not associated with organ system damage. They're not carcinogenic or teratogenic. They're not associated with overdose deaths or enduring neuropsychological deficits in clinical trials. The most common physiologic AEs from clinical trials are, because they have mild sympathomimetic effects, you can have some cardiovascular AEs. Nausea and headache are very common as well. And in terms of risk mitigation here, these drugs are certainly not for everyone. We'll talk even more so from a psychological perspective. But it's really important to have careful screening and to exclude people. For instance, cardiovascular illness. If somebody has significant cardiac pathology, like they've had an MI or arrhythmias, you would be concerned. There's some data that higher-dose psilocybin prolongs the QTC. And so you want to check for that and make sure, especially in the addiction world, people on methadone as an example, drugs that prolong QTC, you'd want to be careful. From a neurologic perspective, you wouldn't be wanting to give this to people who are delirious, who have advanced dementia. CNS tumors, we've never crossed that threshold, although I have some neuro-oncology colleagues now that say, why don't we study psychedelics to treat something like glioblastoma multiforme? There's enormous existential distress. We can control the seizures. And so people are starting to kind of like wade into certain areas that they wouldn't have considered before. And certainly if someone has unstable, severe medical illness, you wouldn't want to include them. Psychologically, these drugs really do have harms in the psychiatric realm. They can create enormous anxiety and panic and distress, this bad trip. People can feel like they're going crazy. And in our controlled trials, even with optimal preparation and support, about a third of people can have significant anxiety. It tends to be transient, and oftentimes there's a therapeutic valence to it. But yeah, people can really have anxiogenic reactions. There can be acute dangerous behavior. You hear about these stories, somebody using psilocybin and going out and murdering somebody or hurting themselves. And persisting adverse psychological sequelae, we know that people with psychotic spectrum illness should not take these drugs, and they can sort of occasion the onset of schizophrenia in those that are vulnerable or lead to a psychotic exacerbation. There are some people, even though I'm going to talk about reductions in anxiety and depression, there are some people their anxiety and depression gets worse and can endure. And we really have to make sure we understand all these risks. These drugs also create highly vulnerable situations, and people can be quite suggestible. And you can create epistemic risk and harm. Somebody could develop a new belief system that is not helpful. HPPD is pretty rare in the research setting, but I've treated a bunch of cases in my private practice, and it's damage to the visual system. And these people can be highly distressed. It typically happens in teenagers that use a lot of high-potency psychedelics. And there are people that misuse, overuse these drugs, you know, chase some experience. In terms of risk mitigation from this, you want to do careful screening. You want to rule out people with psychosis, people with active suicidality, HPPD, people with severe personality psychopathology that are unable to form rapport, people that have unstable social factors. You know, the typical Bellevue patients like homeless and having trouble finding a meal. I don't think this would be a good treatment for a patient like that. The social component is probably the area we could do the most to help people with addiction. And the therapy model here, it's important to have a robust therapy platform. It's important to prepare people for these sessions, to support them during sessions, and to afterwards to do psychotherapy, to see how you can leverage these sometimes very intense experiences into behavioral change. We video record all the sessions. We have a fidelity team that reviews it. We have psychotherapy manuals for for everything that we do. It's really important to talk about boundaries. There was recently a company trying to get MDMA approved for PTSD and there was a serious ethical sexual misconduct situation where one of the therapists in a study this was a woman that had PTSD and the therapist at the end of the study developed a sexual relationship further traumatizing the person. It was the worst kinds of boundary violations. So it's really important to be aware of this and to mitigate these. If we look at clinical trials of psilocybin the data comes from studies ranging from open label to randomized controlled trials there is at this point over 900 people treated with psilocybin in the United States and for the most part there are no treatment related SAEs in terms of medical toxicity prolonged psychosis HPPD addiction. The one caveat there was a study done by a pharma company that found in a TRD population some increases in suicidality and a psilocybin group. So you know there may be some some harms that emerge in these bigger populations. This is considered a Schedule 1 drug so we know what a Schedule 1 drug means it means no accepted medical use not safe for use and highest addictive liability. But if we were to really look at the neuroscience to see how addictive these drugs are it's very interesting. So we know in preclinical models right we have self-administration and we know that all drugs of abuse that produce dependence syndromes you will self-administer over and over again like you know alcohol and cocaine. The serotonergic psychedelics fail in this paradigm. Same with the operant conditioning paradigm condition plays preference all drugs of abuse will induce this classical and operant conditioning. Psychedelics don't do it here either. We know the nucleus accumbens is robustly activated with all substances of addiction. It's weakly activated with these drugs. They do have some mild dopaminergic properties but but pretty weak. And these drugs are called heaven and hell experiences. Some people can say it was the most ecstatic mystical transformative experience of my life and other people say that was the worst experience ever. I would never want to repeat it. So it's not reliably rewarding. The 2A receptor was repeated use. You also get very rapid tachyphylaxis. And so after a couple of days of doing these drugs there is no effects. So they really don't behave like typical drugs of addiction like alcohol or cocaine in any way and epidemiologic studies find very low rates of hallucinogen use disorders. If we were to actually design a rational system around drug policy we'd look at relative harm of the drug to the individual society. This was an expert consensus done in the U.K. and it looked at you know ranked drugs and relative harm and you can see you know like on the worst end of the spectrum you would imagine like alcohol and stimulants and opiates and towards sort of the least end of the spectrum are the psychedelics. Now that could change if they're you know made available and more people people use them. But yeah their classification system was for political reasons at the time rather than a rational one. And we know the big problems in our field it's tobacco and alcohol and opiates. We have an opiate epidemic that just you know continues to be unmanageable and terrible and it's not just opiates. Don't forget the stimulants you know. So alcohol use disorder has been a big focus of my research over time. It's arguably the most damaging drug of abuse of them all in terms of morbidity mortality economic cost and its causal link with suicide and violence and preventable death. We do have very good treatments for this disorder with three FDA approved medications but we basically don't use them because the stigma of addiction we don't prescribe these drugs and abuse my favorite drug of all time like is the least prescribed medication of all time. And you know our field only 10 percent of people in a year get treatment. So we actually don't need psychedelics as a new treatment for addiction we just need to use all the things we already have and use them on a system level. But that's a different topic. There does remain a high unmet need in alcohol pharmacotherapy and so there is room to develop novel interventions. The use of peyote and the Native American church is really interesting. There are peyote religions going back tens of thousands of years and the use of peyote in the United States has been documented for a couple hundred years. The Native American church legally can use a peyote. This is so interesting that if you want to use a psychedelic United States it's illegal but if you use it for religious freedom it's it's OK. And interestingly I love this quote from Carl Manger peyote is a better antidote to alcohol than anything the missionaries white man the American Medical Association the public health services have come up with. He saw in these communities that peyote used as a spiritual sacrament was actually helpful in keeping people sober and kind of like had a recovery component to it. I learned about spirituality addiction from Mark Gallanter. Mark Gallanter you know recruited me to NYU 24 years ago and I had never heard anything about spirituality and medicine. What does spirituality have to do with medicine. But Mark taught me that addiction has a kind of like spiritual malady domain and he taught me about the importance of 12 step and that really had a profound impact on me. Mark taught me about William James. William James was Harvard early 1800s. He's the father of American psychology and he noticed that in the Boston area there were these people with severe alcohol use disorder that were homeless individuals who he noticed were able to get into recovery by having these religious conversions. And he was the first person to realize that religious spiritual conversion can help people with alcohol addiction. And then there's obviously the story of Bill Wilson although I'm going to tell you about as part of this story that I never knew about which is fascinating. So Bill Wilson is a stockbroker. He's living in Westchester. He's hopelessly alcoholic and really having a hard time. And he ends up getting treated at a hospital in 1935 and there was a financier who would develop a hospital in the Upper West Side giving Belladonna alkaloids anti muscarinic agents to individuals. And Bill Wilson had this mystical vision under the influence of this drug and had a vision to form AA and what I never knew about is he went on later to undergo LSD psychotherapy at six sessions at UCLA under the auspices of Sidney Cohen and he thought that these spiritual experiences were akin to his original experiences and he actually wanted to introduce LSD into AA and of course we know that that never happened but Bill Wilson thought that psychedelics could be part of 12 step recovery which is just a really interesting thing to consider. The use of LSD to treat alcohol addiction was centered in Canada. There was a program there led by Humphrey Osmond they treated several thousand individuals clinically. This was not in research. Their initial model was that they would be scared straight they would create these aversive DT type situations but people started reporting these positive mystical type experiences and so he changed his model and reported up to 70 percent improvement which you know uncontrolled so we really couldn't believe this data but it was interesting. But there were the best designed trials during this era there were five single dose LSD versus placebo to treat alcohol use disorder studies. Each of them like showed no effect but a meta analysis in 2012 combining them suggested that there was an actual treatment effect a medium effect size a doubling of the quick rate of the LSD group versus placebo. So this data was really interesting and something that Michael Bogenschutz and I picked up on I'll tell you about in a minute. There was a couple of studies in opiate use disorder there was one at the Lexington Narcotic Farm that included 30 individuals with opiate use disorder receiving high dose LSD to one of five treatments that included inside oriented psychotherapy hypnotherapy some control groups all of them at two months showed improvement in psychological measures they didn't measure drug use here. There was another study this is about 80 individuals that were incarcerated at the time with heroin use disorder randomized controlled trial of LSD in a residential setting and the results here it appeared that the psychedelic group had improved continuous abstinence at long term follow up Matt Johnson who had been at Johns Hopkins developed a program of research using psilocybin assisted cognitive behavioral therapy to treat tobacco use disorder he did a pilot study that included three doses of psilocybin plus CBT ended up publishing this you know in 15 individuals 80 percent abstinence you know in early studies things look so much better than they end up being. But this was interesting data and Matt has been able to leverage this data into a grant from NIDA. He actually did a comparative efficacy study of psilocybin versus NRT in about 80 individuals and that study is I think done and the data is being analyzed and is interesting but Matt also a couple of years ago got the second grant ever from NIH in 50 years for psychedelic research it was from NIDA it was a U01 psilocybin assisted psychotherapy in tobacco use disorder and includes three sites Hopkins NYU and Alabama and that study is going on and we should get readouts from that but I want to focus today on psilocybin assisted motivational interviewing for alcohol use disorder. After we did our cancer study we really wanted to do something in addiction and Michael Bogenschutz and I both part of the NIDA CT and started having discussions about this and we had two different models Michael wanted to do psilocybin for motivational interviewing. I want to do psilocybin plus 12 step facilitation. So this study occurred at University of New Mexico included 10 people open label two high doses of psilocybin mixed with MI and there were reductions in percent heavy drinking days pre post and this served as the impetus to do a bigger trial. We recruited Michael Bogenschutz to NYU in 2015 and over the next seven years we did a study that we recently published in 2022. It was a double blind randomized control trial of two doses high doses of psilocybin versus diphenhydramine was the control we thought that there provide some blind integrity didn't do a very good job. We haven't found a good way to have an active placebo in the field and these are people with moderate AUD at least four heavy drinking days a month. The primary outcome was percent heavy drinking days and you can see that this was the design of the study here. There was a lot of preparatory psychotherapy focusing on MI you know seeing what stage of change people were at and the idea was that these experiences might catalyze change and get them you know for pre contemplators and contemplators along the continuum. So what what we found is this is the two groups here you can see this is the psilocybin group there's an 83 percent reduction in drinking for baseline to a primary endpoint here. The control group has a 50 percent reduction which is probably what you expect from MI. MI has a decent evidence base but there's a clear separation between the two here that's statistically significant and the between group effect size was about point five. So you know decent in terms of the outcomes. We also looked at some dichotomous outcomes like abstinence and no heavy drinking and these favor psilocybin over the control group that these dichotomous outcome measures people appear to improve. We also looked at some of these potential mediators of improvement and we found reductions psilocybin group versus placebo in functional impairment problems related to to drinking. We found reductions in craving improvement in confidence and self-efficacy reductions in temptation. We found self-compassion as well that these individuals reported improvements in self-compassion. And interestingly we looked at personality changes and found that the psilocybin group versus placebo led to greater reductions in neuroticism improvement extroversion increase in openness. We know that these are personality constructs associated with driving addictive type behavior. So all of these secondary outcomes were really interesting to maybe point out if and it's a big if this actually works and is efficacious within how what are the mediating psychological or neurobiologic mechanisms. We have recently looked at the subjective experience we wanted to answer the question does this mystical experience matter for reduction in drinking. And here what we did is we measured a total MEQ over the dosing sessions we added it up and we looked at a correlation with percent heavy drinking at months three to eight and you can see here that the intensity of the mystical experience is correlated with reductions in drinking. And we also looked at this altered states of consciousness scale that has this oceanic boundlessness construct which is similar to the mystical type experience and the data there showed in those constructs related to mystical type experience there were positive correlations with reduction in drinking. So you know it may be that there's something about the subjective nature of these experiences that may have a spiritual component that can have value to people and so this has emerged as a kind of psychological candidate mechanism of action. So in summary this is a small trial. These trials are this is very early days in the research only about 100 individuals and suggested robust and persisting improvements in both continuous and dichotomous drinking outcomes and it pointed to some domains that may mediate the effects like craving self-efficacy self-compassion some of these personality facets and the mystical type experience potentially being a psychological candidate. But we need to do so much more here. We need to firmly establish safety and efficacy. I mean just like with every drug we have to try to figure out who are the responders and who are not. And we really need to understand how this works and we need to design trials where we can really query both the neurobiologic and the psychological components of how it may work. And just to end here there's a trial that's about to be published. Peter Hendricks did a trial of psilocybin assisted CBT and mostly African-American men in Birmingham Alabama suffering from crack cocaine use disorder and and he's the data there is interesting and and you know cocaine use disorder never found any pharmacologic treatment so it's interesting that it's being tried for that. There are some studies of psychedelics for opiate use disorder methamphetamine use disorder. So the gaps here there's enormous gaps in the data. There's also big gaps in funding for years. The NIH wouldn't fund these studies but now the NIH is funding these studies. I talked about the UL one from NIDA a couple of years ago got an R01 from the National Cancer Institute to do more work with psilocybin in advanced cancer. And my colleague Michael Bogenschutz just got two really amazing grants from NIH. One is from NIH triple A to continue our work with psilocybin and alcohol use disorder. That study is going to include neuroimaging and Michael also got a big grant from NIDA to study psilocybin assisted psychotherapy and people with opiate use disorder who are methadone maintenance be a really big trial. So really interesting that it's the most important that NIH funds these studies. That's really sort of pure. You can do pure science and you can also like look and understand the mechanisms behind it as opposed to drug companies or private philanthropy where you know the money always has some kind of strings attached to it and it gets complicated and there's huge gaps in implementation. A lot of people ask me well how can I refer a patient to this and the answer is you can't. These drugs are illegal. There is no clinical implementation yet and thinking about that will be really interesting. So this is promising pilot data but it's certainly not enough to convince the FDA or the addiction treatment community. There's a potential for false discovery in these early studies you know you have bias over enthusiastic people you know the same user drug early on in research because it's like you know lose its efficacy over time and we need more research to establish safety efficacy and mechanisms of action and if these drugs are ever going to be used and Jack Canfield is going to talk a lot about this today they'd have to be rescheduled from one to something else. The FDA most certainly is going to constrain their use through REMS programs and I hope that there would be a lot of oversight here and monitoring and ultimately the thorny issue of how do you deliver this care and how do you pay for it. I mean we don't know how to do that in medicine period so I don't know how this ultimately gets to people and this is really interesting for the addiction community like where would it be used with an inpatient rehab ever give somebody psilocybin. So it's kind of interesting to think like a Betty Ford or some of these places the Karen Institute. Interestingly the study that Michael Bogenschutz is going to do funded by and I triple A is going to happen at Silver Hill which is an inpatient rehab in Connecticut and the idea there is people are going to go for alcohol use disorder get detoxified and they're going to be testing psilocybin versus placebo to see if it reduces relapse afterwards and very interestingly with the 12 step community I mean 12 step is a very conservative community. The idea of using any drug there other than let's say caffeine is you know like frowned upon the idea of somebody in 12 step recovery using a psychedelic just seems crazy to consider although Bill Wilson certainly considered it. So the last thing I want to say is caution. I think the history is repeating itself. The first phase we had this like hype going to cure everything then it was demon drug then it was shut down and we've seen in the last bunch of years all these media articles hyping this up psychedelic revolution is coming psychiatry will never be the same. There's really a lot of bias here and inflation of efficacy minimization of harm. I'm very concerned about the state legalization programs Oregon and Colorado legalized medicinal psilocybin in Oregon high school students can administer psilocybin to people with severe mental illness. I mean that's just seems like something very bad is going to happen. And you know this doesn't go through the FDA process and they regulate it in a proper way. I mean there could be all kinds of unintended consequences. So that's the next segue for our next speaker Dr. Modris. Can you please come up here and I'm really excited to hear your talk. Thank you very much for inviting me. It's a delight to be here. You know, I can't even see the screen, so I'm gonna move over here. Today I was asked to talk about the neurobiological mechanisms of psychedelics as well as the unintended consequences. Having worked in public policy for short phases of my life, the unintended consequences are always very important and uppermost in my mind. These are my disclosures. So, none of you have to be introduced to what psychoactive drugs are. The therapeutics are atypical hallucinogens, which include the dissociative anesthetics like ketamine, the intactogen, MDMA, and deliriance. And then we have a group of hallucinogens that are designated as psychedelics, which include LSD, psilocin, psilocybin, mescaline, N, N-dimethyltryptamine, et cetera. The word psychedelic comes from the Greek, psyche, which means the mind, the soul, and delune, to manifest, so mind manifesting. The giants in the field who really promulgated what I would consider both the scientific research as well as the hype about psychedelics, the first person that comes to mind is Richard Schultes, who was a Harvard botanist and he was a brilliant researcher. He spent a great deal of time in Mexico and in South America trying to excavate the origins, the different characteristics of drugs that were used for psychoactive purposes by Amerindians. And then along came Alexander Shulkin, who had more of a love affair with this class of drugs. And this dichotomy between being a scientist and being a purist and also being an advocate permeates the entire field of psychedelics. So Shulkin wrote his chemical love story. David Nichols, who's an excellent, extraordinarily good chemist who has focused his life on hallucinogens. And finally, a friend of mine, Brian Roth, who I think has done more to bring the state-of-the-art science to apply to this classification of drugs. My lifetime adventure with psychoactive drugs begins at the Allen Memorial Institute of Psychiatry, where I was a 20-year-old graduate student. And I was asked by my mentor to uncover how psychedelics work in the brain. I should leave that last phrase out, not in the brain. He just said, here's a group of psychedelics and I had every single one of them. I had aboga alkaloids and psilocybin, bohembine, cornanthine, harmala, you name it. Ergots, ergotamines, tryptamines, and mescaline and other phenethylamines in my lab, including LSD. And I was given a tray of LSD and asked to investigate it. My mentor said, find out how these work, but you can't work in the brain. So that was quite a problem, that was quite a challenge. The other challenge working with these drugs is that at that time, the only radionuclide available was carbon-14 to measure the biological mechanisms or targets of drugs. And carbon-14 has a very long half-life, so that if you have very high-density proteins like enzymes, it's very easy to identify them with carbon-14. But in order to identify receptors and receptor mechanisms, you need a radionuclide such as tritium, which has a much shorter half-life that gives off a much higher level of radioactivity in a shorter period of time. And it was the breakthrough of incorporating tritium into drugs such as LSD or DOI or haloperidol and so on, or spiperone, that enabled the discovery of the receptors in the brain. That technology did not exist at the time. So I did not make the great breakthroughs that I dreamed of as a graduate student. What I would like to just begin with is some of the biological mechanisms. And we begin with a few topics on the biological mechanisms. First of all, the history of serotonin itself. It's billions of years of history. It's history of receptors, neuroplasticity, neural networks, and mind-altering drugs, and whether or not that is the mechanism of therapeutics. So let's go through a little bit of the history of serotonin. G-protein-coupled receptors, which are the target of many of the psychedelics as well as neurotransmitters, are ancient, ancient. Because in order for life to develop from a single cell to multi-cell organisms, there had to be a method of communication. And the method of communication was very simple. You squirt out a chemical message, and another cell is able to receive and interpret the message. And without receptors and without transmitters, there was no possibility of assembling single cells into multi-cellular organisms. So we find evidence of G-protein-coupled receptors about a billion years ago. We find serotonin in single cell, such as paramecium and so on, that were critical for swimming for behavior and for growth almost 700 million years ago. And then receptors, there's evidence for them about the same frame of time. And then multi-cellular organisms clearly had both serotonin receptors and serotonin. And finally, we have them in human beings and the human brain. And humans have about 14 different subtypes of serotonin receptors that receive serotonin. And after 1.2 billion years, in 1950, just about 75 years ago, serotonin was discovered. So the long, long evolution of serotonin and serotonin receptors resulted in a huge diversity of function. We can say the same thing for the cannabinoid system. If it's very ancient on an evolutionary scale, it subsumed a number of functions. With serotonin and its receptors, it was appetite, aggression, sensory perception, mood, anxiety, depression, cognition, sex, sleep, development, endocrine, cardiovascular, gastrointestinal, temperature regulation, and immune system. And we can understand why serotonin is such a complex biology to acquire, to learn, and to master because of its ancient origins. The pathways of serotonin, I'm sure most of you have learned these in psychopharmacology courses. The neurons of origin are the medial and dorsal raphe nuclei in the brainstem. They have terminals all over the cortical regions, as well as thalamus and hypothalamus and multiple others. There are a number of subtypes of serotonin receptors, the 5-HT1, 5-HT2, of which the 2A is critical in terms of our discussion, the 3, the 4, the 5, the 6, the 7, and all of these receptors are in play in trying to understand it. The most interesting thing about the 5-H2A, which is considered a primary target of psychedelics, is that their distribution in the brain is massive. They're located in many, many, many different sub-regions of the human brain. And because of their ubiquitous location, it makes complete sense to understand that if you target this receptor, you can target a multiplicity of brain functions with it. These are just images taken from PET imaging labeling the serotonin 5-HT and a number of receptor subtypes, as well as transporters. And what's interesting is it is the most widely distributed. It is more dense, not only is it wider distribution, but it's denser, with a few exceptions, the insula, the temporal pole, and the hippocampus. What is also really interesting in terms of biology is that hallucinogens and psychedelics bind to multiple receptors. They bind to multiple serotonin receptor subtypes, as well as to biogenic amines. For example, LSD is probably the most promiscuous of the lot, and it binds to not only serotonin receptor subtypes, but dopamine, adrenergic, histaminergic, sigma, and the trace amine receptor 1. And so how did we ever discover that this is an important target for LSD, for psilocybin? In Gadham in 1953 noted that the core structure of LSD had elements of it with a serotonin molecule. What he did not contribute to was the remarkable discovery that LSD has remarkable potency. The potency of LSD is about 50 to 75 to 100 micrograms per individual, not on a per kilogram basis. And this would suggest that the potency is so overabundant that you can actually try to correlate the potency of these drugs with serotonin receptors and see whether or not there's a correlation between potency and binding, as well as potency in terms of producing psychoactive effects. And indeed, this correlation was done in Richard Glennon's lab. I remember when this graph came out, there was so much excitement that finally, people have nailed the targets of hallucinogens. In terms of, in this case, it was total human dose correlated with binding potency at these receptors. Then it became clear that it's not just generic serotonin receptors. With the advent of cloning, it was possible to clone and identify multiple receptor subtypes in the brain. And of these emerged 5-HT2A receptors. What do they do? Essentially, from the brain stem neurons, there are terminals that terminate in deep cortical layers that cause activation of the 5-H2A. This activation promotes glutamate release. It promotes serotonin 2A activation. And in turn, these cascade of events gives rise to a change in brain-derived neurotrophic factor which promotes neuroplasticity. It promotes changes in a number of ways which I will quickly show you. So the question was, why not 5-HT2B or 2C or some others? What are some of the few points that we can make in terms of identifying this receptor subtype as opposed to the others? So, all classical hallucinogens bind to 5-HT2A. There are no, there are no, there are very, very few exceptions. The mouse het which is used as a surrogate or a proxy for hallucinogenic effects produced by an N-dimethyltryptamine or LSD. If you delete, if you can delete any receptor, any protein currently that we know exists, if you delete it by genetic modification, you eliminate the het which after you administer LSD or DMT. So if you restore it and you can do conditional restoring of the receptor, you restore the het which. If you block the 5-HT2A with catanserin, you block the het which. And the het which, as I said, is a surrogate for hallucinogenic effects in humans. And catanserin blocks the occupancy of this receptor and by doing so, it blocks the effects, the so-called psychedelic effects of these compounds in humans. So here's an example of psilocybin occupancy of the 5-HT2A receptor. And what we see is that the intensity that users self-report under the influence of this drug is correlated highly with occupancy of the 5-HT2A receptor. And occupancy is just displacement of a radioactive compound from the receptor, a selective radio probe for the receptor. And you can also see, let me just go back here because the animation isn't working well, that the plasmacyllicin concentrations correlate very highly with the intensity of the effect, although there's huge variations inter-individual. So there are two competing hypotheses on how this actually works. One is that the, because we know that drugs that are not psychedelics produce, activate 5-HT2A receptors. So how is it possible that some drugs can activate the receptor, not produce hallucinations, and other drugs activate the receptor and do produce hallucinations? So let's focus on the receptor first, and then we'll even look at some alternate biochemical explanations. Psychedelics bind the 5-HT2A receptor via what's called bias signaling. We must also recognize in this age of bioinformatics and computational docking that we can actually visualize with extreme accuracy what happens when a drug binds to a receptor and the change in shape of the receptor that that drug produces. And if the change in shape of the receptor goes in one direction, the tail of the receptor that's inside the cell is going to bind to a different set of proteins than the tail of the receptor that is shaped different, the receptor shaped differently if some other compound binds to it. So that's what bias means. It means that certain drugs are gonna change the shape of the receptor and trigger binding of a signal transduction mechanism in the cell that's different than the ones that don't produce hallucinogens. And in this case, it is thought that binding to the 5-HT2A by psychedelics produces a bias in signaling to the beta-arrestin protein over what's called G-coupled signaling. So the bias is one theory. The second theory, so that hallucinations require this bias, the second theory is that in order to develop the psychedelic effect, you have to have a huge threshold of signaling that is going to trigger the G-protein. And forget about the beta-arrestin, that's not critical, it's just the signal that has to be strong enough to twist the serotonin receptor sufficiently to get a huge G-protein response. So these are two theories on how this could work. Second, now we move on to synaptic plasticity. So you say, well, all these happen at the level of receptor, but so what? What happens next? How do we construct from these molecular detailed, detailed observations into the whole body, into a person's response. So what we are aware of is that synaptic atrophy is potentially a characteristic of depression. And one of the hypotheses is that by binding to the serotonin receptors you trigger via the 5-HT2A BDNF brain-derived neurotrophic factor which promotes synaptic plasticity and strengthens connections and restores the connections that have atrophied in depression. So is the structural remodeling integral to learning and memory storage? Is neuroplasticity critical and integral to these experiences? So psilocybin does increase spine density and spine size in frontal cortical pyramidal cells in layer 5. Psilocybin produces structural remodeling that can last as long as a month. So this fits the profile of perhaps we're able to restore some synaptic integrity and connectivity. Again, there's a but. And the but is that certain types of, and we'll get to this in one moment, so the psychedelics induce rapid production of spines in the cortical neurons. They may be preserved for weeks. Could this explain long-term antidepressant effects? And then the caveat comes in. There are compounds that produce these psychoplastogenic effects but have no hallucinatory effects whatsoever. So there's a problem because this is a nonspecific response that could or could not account for any or component or all of the psychedelic experience. So spinogenesis is not hallucinogenic specific and that's quite important to recognize. Altered consciousness of psychedelics via these receptors is a barrier to widespread use. It requires special medical supervision. It may trigger HPPD, which has already been referred to by Dr. Ross. They may trigger reversible or irreversible episodes of psychosis in susceptible populations, especially in individuals who take them multiple times. They may be critical in terms of triggering people with a family history of bipolar disorder, schizophrenia, or suicidality. They have to be excluded from psychedelic trials. So is there a psychedelic therapy? Is there a possibility of being effective while minimizing altered consciousness? Is it possible to retain psilocybin benefits but minimize this barrier to widespread use? So Brian Roth recently, because of computational biology and chemistry, he screened 70 million chemical structures to look at the docking of 70 million different chemical structures on the 5-HT2A, looking for signaling that was according to his model of not being biased towards beta-restin. Of those, a few came up positive. He synthesized a few and of these 70, 75 million, there's others that have done the same, there were some that produced antidepressant effects in mice without having the head twitch. So the second caveat is that there is one paper that just came out last year that said that psychedelics also bind directly to tropomyosin receptor kinase B. Now this receptor is the receptor for BDNF. So it may be possible that some of these drugs circumvent the 5-HT2A completely and bind directly to BDNF and produce the neuroplasticity that may be therapeutically relevant. All of these are still up in the air. What I would like to conclude this small section is that psychedelic biology is complex. It's likely to be far more complex. Once you begin to take a large panoramic view of what these drugs produce, instead of looking under the obvious targets, but look at proteomics and transcriptomics of different cell types, you find that there is a vast amount of change that we never recognized in the past, of different targets that we never imagined occurred as a result of the use of these drugs. So I just want to leave this segment of the presentation with the knowledge that although we have hints, we have some data, we have some targets, we have some mechanisms, we are still a long way off to being definitive about how these drugs work. The next level of organization is altered functional connectivity. Does that explain the psychedelic effect? So many of these studies, of course, have been done with magnetic resonance imaging and what it shows is that the modularity of the brain, in other words, very discrete areas that are functioning almost alone, is reduced. That network connectivity goes up dramatically, flexibility goes up dramatically, and possibly that's associated with insight acceptance and the mystical state. So what we find is that global connectivity increases dramatically. The connectivity between the thalamus and specific cortical regions, the insula, and so on, they can account for visual alterations and blissful state. The connectivity between the thalamocortical, the hyper connectivities associated, again, with certain subjective effects that are self-reported in the individual in terms of insightfulness, in terms of disembodiment, and so on. Also, the increased connectivity within the somatic motor cortex is associated with religious experience, thoughtfulness, experience of unity, and so on. So these, again, are very early stages in trying to understand how, once you alter receptor cell signaling, once you alter neuroplasticity, once you alter a wide array of biological functions that are embedded within the cells, you change brain connectivity. It's very easy to understand how because the 5-HT2A is everywhere in the brain at very high densities. This could produce some of the biological effects and some of the self-reported spiritual effects that we see. So acutely, they alter synaptic function. Is enduring synaptic plasticity related to durable changes? We simply can't answer that definitively. Psilocybin massively disrupts functional connectivity in the cortex and subcortex. The frontal cortex changes, dissolves network distinctions. The networks that are normally identified under certain stimuli, there's no longer those networks. There seems to be a far greater integration. The changes are strongest in the default mode network, which involves sense of time, space, and self. Psilocybin causes persistent decrease in between the frontal cortex and the anterior hippocampus default mode network. Is this persistent reduction connected to an anatomical and mechanistic plasticity? We have all these possibilities. There are papers that have been reported every week, and I was trying to modify but couldn't in time. There's a meta-analysis that has said that the subjective effects are correlated with regard to depression and substance use disorders. With psilocybin, it's about 24% correlation. With depression alone, it's about 18%. With substance use disorder, it is actually much higher, about 60%. So there is a correlation between these psychoactive effects. They have a modest role in mediating therapeutic outcomes for depression, but for substance use disorder, the data is quite robust, but only two studies, so that too leaves us with a very temporary conclusion. Is the biology relevant to therapeutic outcomes? Long-term antidepressant benefits attributable to psychedelic experience? It's actually quite difficult and challenging to know if psilocybin and therapy are critical because there's been no treatment arm receiving the drug alone. Again, is the drug sufficient? It's clear from many studies and also concerns about allowing it to be used alone that we have not really done these definitive experiments. Patients who receive psychedelics and therapy seek support outside of study protocols. So is there an unmet therapeutic need? Are biological changes insufficient or temporary? Is it safe to reduce or omit psychotherapy and rely on the drug alone? That is probably one of the critical questions because I don't think we're going to be able to adhere to the rigid protocols that the FDA standards would permit. Now we quickly move to the history, medical recreational use of psychedelics and the unintended consequences. Hallucinogens as medicines. The reason they were introduced in 1950 was because psychiatrists were desperate. They were desperate to find something, anything, that could alleviate the symptoms, the anguish, the torment of people with schizophrenia or bipolar disorder or major depression and some of the other symptoms associated with them. So we have to be very understanding of the reasons why this class of drugs was embraced so dramatically at that period of time because the public health burden was massive. It continues to be massive at the present time. There are many treatment needs that are inadequate or still unmet and the indications, almost universally, are conditions of internalizing disorders. And so with regard to drug policy now, all our premises are being questioned. There are millions of people with major mental illness or substance use disorders or both. Millions. These are very recent data. The early use of hallucinogens in psychiatry were used to alleviate depression, anxiety, alcohol use disorder. We've already heard this. And they wanted, the hope was to reveal unconscious traumatic memories in a thread that goes back to Freud. Unconscious content to reflect the orientation of the therapist. Most of these were uncontrolled case series and they were poorly designed and poorly executed and poorly controlled with biased outcomes. I can go through many of the history of the literature. I've done this as a graduate student when it was published originally. I wasn't a graduate student in 52. But there were a lot of caveats early on. 1952. Drugs are important in producing schizophrenia-like reactions in normal individuals or magnifying symptoms in people with schizophrenia and so on. The early medical experiments. Rosenthal was very honest in 1964. The assertion has been made that just four side effects are the result of poor technique on the part of the person administering the drug. But he refused to accept that. He thought the drug itself can produce pain, explosive anger, hallucinations, illusions, delusions, paranoia. These experiences are short-lived in some but others they last much longer. These were early cautions for medical use. The use carries a danger which is not sufficiently recognized of prolonged adverse effects. I can go on with the literature. But then we get back to the Allen Memorial Institute where Dr. Ewan Cameron was a psychiatrist in chief at the Allen. He was also the president of the World Psychiatric Association and the American Medical Association. He performed CIA funded LSD experiments on patients. I inherited that LSD. I was given a hundred vials of the Sandoz LSD when those experiments were canceled. One day on the day of my birthday somebody came into my lab and smacked me in the back and said happy birthday birth as a joke and I dropped the entire tray and I said no one will believe me that half of these vials will disappear and what I did for the next five hours was assemble every single vial back into the tray. I didn't wear a mask which was rather foolish at the time but just to make sure that I counted for every one of these. But he hoped that these experiments would cure patients illness by erasing memories and reprogramming their brains. The end result was survivors and families of these experiments sued, brought class-action lawsuits, horrendous horrendous cases and what we saw is a number of books written about it. One of them by a Stanford psychiatrist who happened to be my colleague in the honors biochemistry program. He was so quiet and silent and suffering because of what happened to his father that I never knew about it until I read his book and then I contacted him and we've been in touch since. So psychedelic research was abandoned some claimed that it was because of the Controlled Substances Act in 1970 but the factual history is that the research was started to decline seven years before because of terrible outcomes including psychosis, suicide attempts. California banned LSD in the mid-1960s and the federal regulations began to kick in because of the thalidomide experiment in which one FDA examiner was the wisest person in the U.S. by preventing thalidomide from being used in pregnant women. And so I think there's been a misreading of the Controlled Substances Act because this was a real problem long before it came about. And then we had a renaissance of psychedelic research. For those of you who wish to know what the origin of this painting is, I looked at the Primavera by Botticelli and decided that I was not going to get concerned about priorities and licensing agreements, so I asked artificial intelligence to make me a springtime painting, and it did. So the science versus the reality is how solid is the science? We must bear that in mind, that's uppermost. Can protocols be scaled with fidelity? Critical. And what is the reality of unintended consequences? The reality is that the hype, there are current beliefs that this is settled sides, and that's why we have so many ballot initiatives in the country, as well as huge investments in not necessarily legitimate medical purposes, but in promulgating rogue clinics and in promulgating the sale of psychedelics to the public. And that I think is quite a problem. To move ahead without FDA approval, I think, is irresponsible. The FDA approval is contingent on high quality data, safety, efficacy, unbiased data, and REMS. The media is complicit in the hype. I can go on and on with the Vice and Rolling Stone and Forbes and the New York Times, the Guardian, Business Insider, Bloomberg. The hype is much more interested in investment, use, and not as much in consequences. Unregulated medical clinics are as an alternative to the medical model have sprung up in Oregon, and there's a lot of problems with the Oregon medical clinics in terms of informed consent, in terms of appropriate diagnosis, medical records, safety monitoring, risk screening, long-term follow-up, and so on. And the financial investments right now in this whole field are vast. We're trying to, in many cases, medicalize and legalize via ballot initiatives, and we are losing the battle in some cases. We won the battle in Massachusetts, and I would have to go in hiding to outline my role in one of these, in this case. The surge of hallucinogenic use is increasing in recent years amongst 19 to 30 year olds and even older people. Poison control centers are reporting much higher levels. Emergency department visits associated with hallucinogens is increasing as well. We see adverse consequences in youth that are associated with the use of this class of drugs. I'm not going to get into all the details of it. If you look at a hallucinogen use disorder amongst youth, they are most vulnerable. And you look at DSM-4 criteria, you see that with MDMA in particular, there is an addiction potential, especially among young people. We see the prevalence of mental health status. There's a greater risk amongst young adults using LSD, and days unable to work and engage in normal activities because of mental health conditions associated with its use. The hype is driving beliefs that medical use has settled science, and these non-medical psychedelic clinics are exploding. The United States failed to prevent conflation of biomedical and commercial marijuana enterprises. The pattern should not be repeated with hallucinogens is my stand. And I'll give you one final example. This was the famous, notorious five-sentence letter to the editor of the New England Journal that addiction is rare in patients treated with narcotics. Of course it's not rare. It's on average between 8 and 14 percent. And this was weak science, weak scientific literacy. Advocacy reigned and skeptics were ignored. These are the dark blue bars are the affirmations that opioids are not addictive in people who are receiving them for pain management. It was only, and everyone followed, just followed the leader and bought into this myth until 2017, when finally there was no affirmation left when the data were so clear. And this letter, this five-sentence letter received 600 citations in the literature. It received affirmation for decades. So what are the lessons to be learned? Ignore history, ignore generational forgetting. Medical and public education on negative consequences is weak. There's inadequate or absence evidence for safety. I can go on and on with all of the ways in which we've corroded our system of objective scientific discovery. And with hallucinogens we're on the same pathway as opioids. So whether or not you are Aldous Huxley mindset, which says that psychedelics are the chemical opening of doors into the other world and a belief that drugs can procure, what Catholic theologians call a gratuitous grace, or whether or not you're a skeptic like Arthur Kessler, chemically induced hallucinations, delusions, and raptures may be frightening or wonderfully gratifying. In either case, they are in confidence tricks played on one's own brain. I thank you. Dr. Modris, thank you for such an incredible talk. I think we learned so much and so important to hear everything that you said. So our next and final speaker is Jack Henningfield of Johns Hopkins and Pinney Associates. Jack is one of the world's experts on regulation around drugs and abuse liability and is going to talk today about the regulatory pathways including at FDA. Jack, please come up. Thank you, Steve. It's a pleasure to be here. I'm so glad this Academy is taking this up because I'm gonna go rather quickly and highlight some things on my slides because the last slide I think is most important and it's an invitation to all of you and hopefully the Academy to comment to a congressional inquiry that is going on on what we need to know to address the issues that Dr. Modris raised because she stated the facts. They're all correct and there are the concerns are legitimate and the only way FDA can approve a drug is if there is a safe pathway and a favorable benefit to risk ratio. So these issues have to be addressable. Let's see. That's right. I keep looking up that way out of hopefully I'll know how to work this by the time I finish. By disclosure, through Pinney Associates, I consult in this area and in medications development. I've been doing abuse potential assessment work for half a century. I've contributed to most of the approved medicines for treating addiction either in research or regulatory work except methadone. That was before me. I'm consulting at present through Pinney Associates on gosh probably a dozen or so potential psychedelic medicines in psychiatry, neurology and our group has met with FDA dozens of times over the last 10 years or so and one of the things you should be reassured is that FDA is really taking this area seriously and with a fine-toothed comb. They've given four accelerated pathways, breakthrough therapy pathways and that gets FDA actively involved with the sponsors. You're probably aware that the first one to come to NDA submission was MAPS, Lycos, MDMA for post-traumatic stress and it went down in flames in the advisory committee and really left FDA no choice but to say that we need more work. So it's probably a couple of years off before we see that again. So let me quickly cover what is the approval pathway, how does this work, how do we get from theory and fear and concept to potential medicines that address the promise that Dr. Ross discussed and if you look at the literature as a whole in many different areas there's a lot of promise but as Dr. Madras pointed out there's a lot of risk and concern that needs to be addressed. Adverse event issues, what's the role of abuse potential, how does that fit into the controlled assessment, controlled substances scheduling because any schedule one drug that is approved must be rescheduled. A couple of things about why do we need FDA approval and why is just wholesale legalization a bad idea? Well with FDA approval comes a lot of things, control over the dose, the purity standards, packaging, the REMS and you all know what REMS are and REMS can vary from a label to really comprehensive lockboxes that say nobody can have it in their home, no pharmacy can have it. Training as Dr. Madras and Dr. Ross mentioned, what should it look like, what should be the standards, what should be the oversight be, how long should the follow-up be. A lot of these issues that have been mentioned as potentially important can be addressed. So FDA is also in vital approval to ensure equitable, ethical, safe access. So for example in Oregon where actually things seem to be going better than I would have expected from a safety perspective, guess who's getting the therapy? People with enough money to pay for it and that's not fair and what my group works on and everything is making sure that medicines that are approved are conditions to enhance equitable, safe access. We need FDA approval for that. There's a lot of different paths that are taken formally and informally. The risks of timely approval can vary widely. The MAPS, LICO, MDMA path has been going on for several decades, limping along in part because of lack of funding, but you know pharmaceutical company like J&J that got ketamine, S-ketamine through the system, did it relatively quickly. They had a lot of advantages. They work closely with FDA and they got what FDA likes to refer to as the first psychedelic, which provides a model that we've all learned from that has elements that are good and elements not to do again. You all know that FDA has an approval process that requires multiple levels of study from phase 1 to phase 3 and what's to get to pivotal studies, oftentimes you're talking about thousands of patients. In this category it's difficult to get studies with thousands of patients, so FDA has to work with the sponsors and figure out how do we do it with smaller numbers and get valid and reliable data. What doesn't need to be repeated? So for example meeting with FDA with the so-called classical psychedelics, you may not have to do much in traditional phase 1 if the PK for example is already well characterized. You can move more quickly working with FDA. Phase 2 study with the initial efficacy, how do you do that? What should you collect to maximize your possibility of going into phase 3 with a lot of information that may contribute to your review? In the drug approval process you've heard REMS mentioned many times. The plan for REMS for psychedelics is going to be really important and I hope if you folks comment individually and ideally as an organization you'll comment on what should the REMS look like and that's always a balance in there. The congressional law says they should not be unduly burdensome, but the whole point is burdens to discourage bad things. What's the balance? Let's see, oh good it did. Okay, the most important, by the way all of my slides will be available through the organization or email me and just put triple AP slides in the subject line and I'll send you the slides because my deck also includes hidden slides which provide more background on what FDA says in its guidances and the resources if you're interested in development in this area. The most important thing in planning and safety is discussing with FDA. This has to be a really iterative process with the FDA and that's going to save a lot of the time and money. Also because FDA like all of this is on a learning curve and in our meetings with FDA sometimes it feels like we're in seminars where we're all trying to figure out what's the best placebo, what how do we maintain safety. Expect evolving thinking. Some people will complain, there was complaint after MAPS, Lycos, MDMA failure that FDA moved the guideposts. Well guess what, the FDA is learning like all of us along the way and when they learn about better ways to improve safety and understand potential benefits, they add things. They should be doing that and by working with FDA, it can be part of your plan. Placebo and active comparator, part of the MAPS Lycos, I'm not but you saw in my first slide by the way my group consulted the MAPS Lycos and my focus was on the abuse potential assessment related issues and so everything and I'm going to say is what's in the public domain and a lot of lessons were learned. First with respect to placebo, if though any of you followed the advisory committee last June, there was a lot of discussion by the committee about well it wasn't a good placebo and it was basically unblinded. FDA already knew that and when we discussed with FDA they say well there's a lot of potential paths to placebo, we'd like to see at least one of your studies with an actual placebo and the others may have some type of active or inactive. There are different ways and we'll determine efficacy on the basis of all of the data taken together, not just a simple control test versus placebo. So FDA understands that in an awful lot of drugs used in psychiatry, the blind is broken as soon as the person takes the drug. So that's not novel here. Placebo issues for what FDA defines is well controlled studies. These again are the main point is really simple. You need to discuss with FDA what's a little bit different here and some of the concerns that well placebo might have explained the effects. Remember in most of these studies the drug is only given once or twice, in the case of MDMA three times. It's a little harder to explain a placebo effect that lasts ten months, a year or two years and in some of the depression studies we have data going out two years. Therapy issues. In most of the categories we're working on we refer to this as medication-assisted therapy and is it drug alone or therapy? And at this point, it looks like in most cases, there is a therapy effect that is as important, if not more important than the drug. MDMA, remember the old name, the love drug? Well, it does seem to contribute to a bond between the therapist that is probably helpful. That means there also needs to be guardrails in place to make sure that doesn't become inappropriate. In advisory committees, it's up to the sponsor to explain all this because the advisory committees typically include people that do not have waivers because of conflicts of interest. An awful lot of the experts in this area that have experience, including Dr. Ross, Dr. Reffens, myself, were conflicted and aren't going to be on an advisory committee. So it's up to the sponsor to explain this. In the first round, it's safe to say that either the sponsor didn't do a good job or the committee didn't get it. Adverse events. We all know that psychedelics can cause hallucinations, euphoria that's transient in some people, fear, anxiety. And that's part of the reason that in sessions, literally in some cases, a hand-holding monitor that establishes rapport with the patient before the session is part of all of these studies. And that's for safety. And generally they're not referred to as therapists. That's separate. But there is an interaction. I don't think it's possible to separate the two out completely. And if we had a standard where we have to separate them completely and we have to have a perfect placebo, we'll never have a drug approved. So FDA understands this and is wrestling with it. But the adverse events have to be carefully documented. And you may have heard in the advisory committee in June that Matt said, well, we didn't document the abuse-related hallucinogenic and euphoric effects because that seems to contribute to the therapeutic outcome. Guess what? It doesn't matter to FDA. Those are adverse events. And why does FDA want them carefully documented in a clinical trial? Well, it needs data for labeling, for approval. Was it better or worse in the clinical trial? At this point, with a lot of clinical trials done, it appears that they've demonstrated that there are conditions under which you can get safe use and minimal adverse effects, minimal serious adverse events. But what are those conditions? What are the data? It's the sponsor's job to collect all of that. Going forward, if you're involved, you've got to really follow FDA's guidance. What about events during psychedelic dosing sessions? The idea that the blind is broken when the person takes the drug, that's real. I don't think we're going to come up with a better placebo. In some of the studies, niacin or an antihistamine or a low dose of the psychedelic have been used, and FDA staff are, I think, basically concluding that there isn't any one ideal. But it's been asked the question, yes, but do we have to measure euphoria, depersonalization, et cetera? And the FDA, it's really clear in all of their guidances and statements, yes. Let's see. Spirituality, awe, consciousness, connection. This is also new territory. With a depression study for approval, a ham scale can be sufficient. In this area, we're missing a lot of the boat. And because a lot of other things are happening, people are coming out and the next day they're saying, wow, the garden is more beautiful. You know, before I thought people were all schmucks and I was just angry because I have this disease. And now I'm thinking, you know, the world isn't that bad. Maybe I'm ready for this in the case of people with advanced cancer. In chronic pain that we're looking at and NIH is funding, it's not because the psychedelics appear to be great analgesics, but the preliminary data suggests that they help people achieve acceptance and improve emotional and physical functionality, which is a goal of chronic pain. So you need other instruments. In a paper that we did in neuropharmacology on chronic pain, it was initially rejected because we mentioned spirituality. They said that has no place in neuropharmacology. We said, wait a second. These are reports from people, and we're learning a lot more than just the disease state in these studies. The Johns Hopkins Center in my department is the psychedelic center for psychedelic and consciousness research. It's worth keeping in mind in this area. These drugs are working differently in ways that, as Dr. Madras pointed out, we don't fully understand. Now guess what? The vast majority of drugs that are approved by FDA, we don't understand very well the mechanisms. Even in a lot of the classic antidepressants, we're still learning and debating how do they really work. So that's not a barrier to approval. A barrier to approval is demonstration of efficacy and conditions of safe use that can be incorporated into labeling and REMS and so forth. So this is really cool. How do psychedelics work? One of the things that jumps out is people say, that experience was one of the most powerful experiences in my life. Awe. And the awe experience, it turns out, and David Yadin and his colleagues at Johns Hopkins and elsewhere are studying awe. I did a poster on this at a conference. Image-induced awe. Therapeutic opportunities and challenges. Is this something that can be used independently of psychedelics? Well, we're learning a lot about that through psychedelic research. What about people that can't get out of their rooms or incarcerated individuals? How do you use image-induced awe if you can't get out and experience it in real life like a lot of us can? That's some of what is going on. Maybe that's part of the mechanism. Any of you remember George Valen's work on spontaneous recovery in addiction in the 70s and 80s? And what he noted was that a lot of people spontaneously recover. It wasn't random. What happened? A religious experience or conversion. Birth of a child. Near-death experience. A family member experience. What's going on? That that precipitated abstinence in the person? I'm not going to try to explain it. I'm not a psychiatrist. You understand it better than I do. But the outcome is real. And if you're a researcher, it's really exciting. If you're a drug developer, it makes life a little more confusing. We should include a scale on spirituality. I do abuse potential work. I'm constantly working on drug applications for abuse potential. Well, the liking scale probably misses the boat with psychedelics. To understand why people use psychedelics, an awful lot of people use them but only use them a couple of times to enhance connection, spirituality, appreciation of art and music. One of Roland Griffith's studies focused just on that. But law is a really cool thing in life, and it's worth keeping in mind in this area. A couple of quick notes on drug scheduling. Any drug that has abuse potential that is considered significant, officially by law, high, it's basically considered significant. If it's not an approved drug or commonly accepted for medical use, it's in Schedule I. So when people say, why has psilocybin in there with heroin? Because it's not approved. So Schedule I is the only place. The only exception in modern history is possibly being looked at, and that's marijuana. So to do the eight factor, they had to do a Camus analysis, and they concluded that there's commonly accepted medical use but not FDA approval. It's going to be complicated if it gets through, but that's worth keeping in mind. Abuse potential assessment includes a full assessment of all of the things that Dr. Madras and Dr. Ross mentioned to you today. All that has to be organized and go into the FDA. It's not good enough to say, well, it's low or it's high or whatever. We've got to document it. Adverse events are part of that. And guess what? The FDA has been pretty flexible. The FDA has said with the classic psychedelics, you do not have to do new dedicated animal abuse potential studies. You don't have to do a $5 million human abuse potential study. Me and some others have argued we really don't know how to do them with hallucinogens at this point, and FDA is agreeing we really don't need those to inform our scheduling recommendation. When we take it out of one, if it's psilocybin or LSD, it's probably going to be either two or three. And what would that study add? But FDA, I think, really being pretty flexible. Policy considerations. Sean Bolloin at SAMHSA and was detailed for a while that FDA, to help them work out this area, has done a couple of articles on policies that support safe, equitable access and responsible use. And, again, the issues that Dr. Madras-Wade raised have to be addressed in any approval, and your input could be really helpful there. As he mentioned, clinical trials provide the foundation for safe and effective use, because in the clinical trials we're demonstrating that it's possible to have safe, effective use. But as Dr. Madras raised, how do you scale it up with an approved drug? That's going to take guardrails. Look at the Dr. David Yadin and Roland Griffiths articles. They were mentioned on some of Dr. Madras' slides, where he talked about the cart going off the tracks and guardrails. REMS. REMS are one of the most important answers to fear and providing a path to approval. The Spravato REMS, in some ways, was too burdensome, and that's helped spawn the proliferation of ketamine clinics, and as far as I can tell, most of them are doing good work and helping a lot of people. But to be blunt, who are they serving? Mainly rich white people in big cities. We need FDA approval with REMS that protect people but don't create such burdens that they spawn off label use and more people saying, I'm going to go find somebody that will do it or do it myself. An issue that isn't discussed enough is respecting and supporting indigenous and traditional knowledge practices in the United States and globally. This was addressed in an article in the last year that a number of us worked on. And so over centuries, if not thousands of years, a lot has been learned about ritualistic use, in some cases for a variety of reasons, but oftentimes in group settings, and that raises the idea of maybe for some people group settings is not only a way to scale up but might be better. The Department of Defense and Veterans Administration are both committed, in part by the last DOD-approved authorization, to do work research in this area. I'm hoping, and perhaps with your encouragement, they might move more quickly because the VA might be a great place to set up groups and figure out how to do it. Think about it. Right now at Hopkins or any other place, you need one or two monitors there for every patient being studied. For a group of 10 people or 8 people, what's the number? You need 16 monitors? I mean, how are you going to do that? I'm betting that VA would have more flexibility than academic institutions. But there's a lot we can learn, and we also need to respect what they've been doing, and that's already causing some problems with different indigenous communities saying, You're trampling all over us. You're patenting, trying to patent stuff that we use as part of our religious ceremonies. It's just not a good thing. FDA approval. The reality is it looks likely that there will be approvals within a couple of years. Why? Compass is in their Phase III trials. They could have an NDA. I'm not consulting from them, but based on everything I've seen, and they also have a breakthrough designation. That's for treatment-resistant depression. MDMA will be back to FDA. Whether it's 2 years or 3 years, it'll be back, and this time a leader will be the leader of the Johnson & Johnson team that got escadamine approved. He knows how to do it, and most of their work was done well as far as I could see and is going to be acceptable to FDA, but more work has to be done. The Assistant Secretary of Health led the assessment report on policy. NIH, the different institutes, are funding a lot of research. The floodgates are open in a lot of different areas. That'll lead to independent studies that will be important to advisory committees, whether or not they're a part of a formal new drug application. FDA has presented its meeting, its thinking, and its thinking is evolving. Department of Defense and VA hospitals are beginning to move. The Army DARPA is supporting research on the possibility of psychedelics in some areas that do not have hallucinogenic activity. One of the medicines we're working on is for chronic cluster headaches. Does that medicine have hallucinogenic activity? Maybe it's possible in some areas. The Congress has a bipartisan Psychedelic Advancing Therapies Caucus. It's really cool to be briefing a caucus in Congress that's both sides of the aisle working together with the administration. I just came out, I thought, there is hope for the future. Representatives Correa and Bergman are very serious about this. They're retired military. They're concerned about the 5,000-plus suicides that they think some of them could be prevented with psychedelic therapy. So there are some allies that want to get this right. A lot of things are saying, we are going to have approvals. How do we do it right? Addressing everything that Dr. Madras raised. So I hope that AAAP professionals will, a lot of you are already doing research, get more involved. Come up with therapeutic models. How does this work? What are the different models? How much flexibility? How structured should FDA's realms be? Development of group therapy models. Education, training, certification standards. We need societies involved in all of this. Reimbursement models. How does this work so it's not just rich white people in big cities getting therapies? How do we address, is there a place for teletherapy to merge with a local professional to reach people that are in the wilderness? So my last slide. I've got the path at e at path at mailhouse.gov. And this has opened the, it was announced in Federal Register. And if you read their Federal Register announcement, it basically has a lot of issues that they would like comment on. Therapy, public-private sector models for going forward. So I really hope that all of you will address the good, the bad, and the ugly, your ideas, that will be constructive and helpful. And also I hope the academy will come informal. Thank you very much for the opportunity and for being here. Thank you. Yeah, you can hear me, right? So yeah, fantastic, alarming, interesting, just amazing presentation. I just want to ask a basic science question, the 5-HT2A receptor you talked about, Dr. Madras. We know that SSRIs operate on that. We know that psilocybin is for better, for worse, on the launching pad for depression. What's the difference in how it interacts with the receptor? Well, I think the first and most important thing is to remember that SSRIs are serotonin transport inhibitors. They are not per se receptor activators like psilocybin does. So when you administer an SSRI, you are increasing extracellular serotonin across the brain. Of those targets of serotonin, you're going to hit the 5-HT2A, clearly. But you're going to hit it with an endogenous neurotransmitter that could have biased or unbiased signaling. Depends on how it binds to the target. Whereas the way that psilocybin and some of the other psychedelics function is that they are targeting, certainly not exclusively, but they are targeting with very high affinity the 5-HT2A, and they may induce a different shape in the receptor, which leads to different intracellular signaling than serotonin itself does. Does that help? Thank you for wonderful presentations. It was very impressive, and I'm learning a lot. I'm an addiction psychiatry fellow at UCSD. I'm Dr. Jo, and I'm wondering what, so I was so impressed by that the psychedelics can restore neural connectivity. So in terms of that part, so what would be, what do you think is the possible indications of those future psychopharmacological do-it-yourselves from psychedelics? Is it, can we use inertial to restore our degenerated neurons in such as Alzheimer's disease or schizophrenia, or can we use those medications, future medications, to restore the altered reward pathway in addiction patients? And that is my first question, and, okay. Well, I think what was pointed out in one of the slides is that the ability to promote synaptogenesis, neurogenesis, and not neurogenesis, but there are three different ways in which psilocybin and other psychedelics promote increased synaptic connectivity, but drugs that do not produce hallucinations can also do it. The problem is being neuron cell-specific and receptor-specific in terms of other mental disorders. And I don't think that we have, at this point, the ability to target very specifically the precise circuits, the precise connections that are disrupted in some of the major psychiatric disorders. We also have to bear in mind there's a whole different biology that was not addressed at all today, and that is the role of glia in regulating synaptic connectivity. There is a vast, vast area of research that is coming in trying to understand how glia also shape and form synaptic connectivity and how to target them, because glia do have some of the conventional receptors that we're aware of, but certainly not all. So I think your concept is a very interesting and important one, but I think we're not there yet. I really appreciate your insights and experiences. I'm very excited now, because it means that I understand there are a lot of research that is going on, but we are not there yet. It means that there are a lot of future research opportunities for me in early career. And so I'm excited. And then my second question, I understand you are conducting a lot of researches now, so I'm wondering if you can pick just one psychedelic or one mechanism that you particularly think very promising, would you introduce that? And if there is any challenges, also, please share. I'm not sure I understood your last question. Yes. I think the most important mechanisms would be to do proteomics and transcriptomics, single cell, which is being done now. I think that is the way of the future, is to try to understand the big picture, to do a complete integrated survey of how a drug can affect multiple pathways, multiple systems on a cell-by-cell basis. We'd have, and bioinformatics is going to have to clean up the disastrous amount of data that is being generated by this, but that's the future of the field. I think, unfortunately, we are out of time. I think maybe one last question, Karen? Oh, thank you, Steve. Thank you to the entire panel. This was an amazing presentation, and I want to thank you for the balance between potential benefits and risks. I would like to have you say a little bit more about one particular risk that you mentioned briefly, Steve, and that is the most well-known and most notorious case of a patient, Megan Buison, who was sexually exploited as part of a MAP study for PTSD. Richard Jensen, who was a licensed psychologist but let his psychology license lapse, who had had some sexual misconduct previously, was a co-therapist with his wife, and there was a relationship that continued after the experiment in which they continued to have sex with her. She moved in with them. It was pretty awful. But it's not the only one. And back in the Timothy Leary, Richard Alpert days, sexual exploitation of the Harvard undergraduates was part of why they were asked to leave or not renewed in their contracts. So my question to you is, there's some bit of adverse selection of who's drawn to do this kind of therapy, and how can we protect the public from sexual exploitation? I think it's such an important question. That case is so horrible. Yeah, I mean, it's such a terrible case. You had a traumatized woman with PTSD from sexual trauma. You treat her in the model, and then you have a sexual relationship with her after and harm her even further. I mean, terrible, terrible. Unfortunately, it's sexual misconduct and inappropriate contact occurs in our field in psychiatry. Upwards of like 5% of practitioners will engage in inappropriate sexual activity. I mean, we've known about this for years, from psychoanalysts leaping to their patients and on and on. And it always horrifies me to learn. Like, how could you, as a healer, do that? But it happens. And I think here it's compounded even more, because people are so vulnerable, so suggestible, and they're at heightened risk for somebody to take advantage of them. How do you prevent? I mean, I think the most important thing we do when we screen potential people to come to our program is for maturity. If somebody says in the interview, I love psychedelics, I did it the other week, they never come in. We don't want people that are so excited and hyped up. There's a certain amount of ego inflation that can come with this. And there are some people that are interested in this area for not good reasons, having to help people. So I think we have to be on the lookout for this in our field. And I think that was one of the things that undermined Lycos' application. That case was so bad, the company did not deal with it well. It was not properly disclosed in a journal article. There were two of them were retracted because of it. And you have to have something like that come to the fore and to talk about it. It's such a big deal. I mean, it should never happen, but we need to make it safe so that it's exceedingly rare. Let me just add, this is where your comments could be really helpful. Because this issue will not go away. And the fact that the rates are low and appear to be low and happens with other drugs won't be good enough for any approval. FDA must be able to say, this is one of the problems we're addressing with the REMS. How do we manage it? And are there guardrails? And if there is not a consensus that the guardrails are acceptable and it will be tested through an advisory committee, it won't get approved. So please comment. There's no simple answers. I think our time is up. Thank you so much.

psychedelic therapy

substance use disorders

Dr. Steve Ross

NYU

LSD

psilocybin

cognitive dissonance

therapeutic agents

legal background

societal background

clinical trials

alcohol use disorder

neurobiological mechanisms

FDA oversight

psychedelic medicine