E204 - The PsychopharmaStahlogy Show: How Do Psychedelics Work Anyway? with Dr. Roger McIntyre

Welcome to The Psychopharmistology Show, a special NEI podcast series. In this show, Dr. Andrew Cutler interviews Dr. Steven Stahl on the most controversial, novel, and exciting topics in psychopharmacology today. Hello and welcome to another edition of The Psychopharmistology Podcast, featuring the one and only Steven Stahl, Steve, how are you doing today? Just great. How are you? I'm really excited about this one because we're going to be talking about something a little controversial. We're going to kind of kick the, put the stick in somebody's eye here a little bit. And who better? Who better to stir the pot than our friend Roger McIntyre, Roger, how are you doing? Great to be with you and look, I'm always open to stirring pots as long as it moves us all in the right direction. I hope that's first going to move us. Well, I think good science, you know, is to have hypotheses into question things. And of course today, we're, this is in our series of psychedelics. We actually usually do three part series here at The Psychopharmistology Podcast, but this one was so important and interesting. We've expanded into a four part series. And so this is actually the second of our four parts. And what we're going to be doing is really focusing today on a little bit of neurobiology. And how do we actually think these darn things work anyway? So there has been a lot of work in this area. And unfortunately, it crosses over from science into what I would say is almost religion. There's kind of these faith-based belief systems around how these drugs work. And Steve and I in our introductory podcast kind of scratched the surfaces a little bit. But Roger, let's start out with a kind of a big picture and then zoom in a little bit. Some of these reported mental health benefits of the psychedelic treatments. Yeah, absolutely. And it's, it's a great place to start the conversation because I think that we are really in a new frontier. And we now have treatments that are not just your usual sort of serotonergic drugs. So to speak, serotoner re-uptake inhibitors in the frontier is not just different. But you know, it seems like it could be better. And that's exciting and that's hopeful and long overdue. Psychedelics, as you probably covered in in in previous discussions yourself and Steve, is really a, you know, it's a category that has a fairly broad definition. I think we typically are talking about serotonergic psychedelics, you know, going back to the early days of, of course, LSD and then of course, psilocybin being the well-known serotonergic psychedelics. And I think if I was to summarize the answer in a nutshell, what I would say is where we've seen the greatest advance with the serotonergic psychedelics in general, at least from randomized, adequately controlled studies, is an adult who live with major depressive disorder and it's, it's cousin adult who live with treatment, resistant depression. Separately, as you know, Andy, we have replicated phase three data with the so-called intact origin or empathogen MDMA for treating post-traumatic stress disorder and that's a separate conversation. But typically, we talk about psychedelics, we're typically talking about serotonergic psychedelics. Other areas, Andy, you should know are being looked at at substance use, tobacco use disorder, other conditions, including not limited to eating disorders, certainly anxiety disorders, broadly. So, and the list goes on, but certainly the major depressive disorder and TRD subpopulation are furthest along with respect to adequate and well-controlled studies. Do we run the risk here, though, of kind of being too good to be true? We're almost talking about treating a large. Psychiatric penicillin! Exactly! Exactly penicillin! I mean, we're talking about a large chunk of the DSM here, Roger. You know, look, I think that the field has really landed on where the data have been forever. That being that psychiatry is composed of syndromes that are really, you know, in these syndromes are made up of psycho-pathological domains that are transdiagnostic, clinicians know who are joining us that medications in psychiatry are not, you know, specific to any particular psychiatric disorder. They really treat symptoms and dimensions of pathology. So, my first reaction is that when we have a new treatment, targets the brain, targets the brain and regions that we now know are relevant with respect to originating symptoms, then I think all cards are on dead possibilities are a good deck. In other words, this could apply in many conditions right across the developmental trajectory, but I think we cannot be historical. In other words, we do know that despite our aspiration, despite our hope, the site, as penicillin for psychiatry, it's not typically how it works. And we know that mental disorders are, yes, similar in psychopathology, but they're not the same. And so I would not surmise or hypothesize that they're going to be good for everything, although right now that seems to be some of the vibe that's out there right now. Is there a unifying, either set of symptoms or single symptom that cuts across all those things that makes it make more sense? To say instead it works for everything in psychiatry, to say it works for such and such symptom profile, in depression, bipolar, unipolar treatment system, substance abuse, eating disorders, PTSD. Is there a symptom that seems to shine out there that really these psychedelics hit hardest and best? You know, I think it's such a great question, and I think if I was to embrace the sort of the RDoC nomenclature and that framework, we all, just for everyone, just to kind of level set again on this, our colleagues joining us. So the RDoC is a, authored by the NIH. It's meant to be a matrix to look at the symptoms of psychiatric disorders. I was referred to as kind of a prism. If you put all psychiatric disorders to a prism, how does the light, not as the colors spread out? And in simply put, you can reduce all psychiatric disorders to a relatively finite number of domains or dimensions of psychopathology. And every clinician knows this, fear, problems with cognition, social and general, problems with eonodowny and motivation, problems with your circadian rhythms and some of your internal sense or motor functions. And I wouldn't say for me if I was to step back and say, okay, just to your point, Steve, where do psychedelics, where are they actually really affecting? We just recently published a paper looking at an RDoC approach to psychedelic outcomes. You know, I would say that, you know, we get signal here on all these areas of looking interesting. But the one that's sort of catching my eye a bit more is the area of reward, reward function or deficits thereof. In other words, people who have motivational deficits, adhedonia, noshwa, devive in their life. And what's interesting, and this is where one has to sort of be a good detective on this, making for all these pieces of circumstantial evidence. And if you go back to some of the trials that I published with psilocybin as an example, the depression outcomes on our usual metrics, mattress and quids is looking pretty interesting. But what's really more interesting is the benefit on patient reported outcomes, quality of life, well-being, the sense of engagement in their life. And again, these don't lend themselves to a simple one-size-fits-all dimension. But I sort of see that area as being especially interesting. I don't think it's less interesting, the benefit we're seeing on fear and anxiety. And of course, we know this as ubiquitous in psychiatry. So I think- Well, can I say something here? This reminds me of a conversation I had with a colleague, you may know from Belgium, current in the air? Current in the media, yeah. And so we wrote a couple of papers together, and he had some, of course, several others. And what he's saying that patients don't want the same thing doctors do. Exactly. Doctors want to get rid of all this nasty stuff. So if you have a terrible thing that really is awful, let's get rid of it. Let's reduce it. The patients say, "No, no, no, no, no. I want the positive stuff I used to have to come back." So we want to reduce negative stuff. They want to enhance positive stuff, and it may very well be that the psychedelics are enhancing the positive stuff, is that what you're maybe saying? Yeah, absolutely. In fact, there was a clinical trial, it's a randomized controlled trial with psilocybin, compared to acid talopram in a non-treatment-resistant depressed population. And on the primary outcome, which was the quid's SR, both treatments improved, but there's no difference between the two groups, so it was a relatively small study. What really caught my eye, though, is the secondary outcomes. In the secondary outcomes, you know, I always see sort of secondary outcomes as sort of future prospects, like a college football team, kind of see some future kind of potential here on those secondary outcomes. They had about a dozen and a half secondary outcomes, which was, I think, fair, it was exploratory and all that. What they found was, most of these secondary outcome measures, which tapped into aspects that we're talking about, positive mental health, well-being, not just taking away my illness, but giving me a sense of purpose and a sense of function. Interlude psilocybin beat acid talopram in a lot of these measures. So again, some might say, well, that secondary don't reach a much end to it. I'm not, but I think we always keep our eyes and ears open. That just caught my eye. Yeah, I'm not terribly surprising. Well, Steve, you know, it's interesting, you mentioned that condomediae, of course, has published some very interesting. interesting stuff on the differences between what a provider, a physician, if you will, sees as a goal and a good outcome versus the patient. And our friend Mark Zimmerman has also published on this as well, who's another sort of homogenee pot stirring kind of guy. But what they both show is that we tend to be very symptom focused. And I think we're trained. We have to use symptoms to make a diagnosis and a lot of our rating scales, especially for registration trials or symptom-based. But what patients care about is what you're talking about. It's quality of life. Vitality, it's wellness. You know, it's engagement. And I think our serotonin-based and reuptake inhibiting in a depressants don't do very well in that area as you're talking about. Certainly not in Hedonia, which is another topic, Roger, that you and I are involved with. But let's zoom in a little bit. Let's, since we're talking about serotonin, you mentioned serotonergic, and this actually may be part of the controversy here. So let's say the classic psychedelics is opposed to the antagonist and the dissociative ketamine, we have been taught that they work through agonism at a specific serotonin receptor or receptor, but principally the 5-HT-2-A. So tell us a little bit about that. Yeah. You know, this has been a well-characterized pharmacodynamic profile of, for example, psilocybin and related serotonin psychedelics. And there are differences that you know, Andy, between some of these serotonin psychedelics, especially their KIs and dissociation and affinities and all that. But as a summary statement, they are 5-HT-2-A agonist, and there are now preliminary data to support antidepressine efficacy in non-treatment resistant and treatment resistant. We should also state that the benefits seem relatively rapidly, and it seems to be sustained at least in the near term, we can't say long term, we can say near term. And so the pharmacol, when you look at rank order, we like the rank order, we all have these slides, when we look at a drug, we rank order, it's affinity, and whoever is king of the hill or queen of the hill, that's the one we sort of like look at first, and it's the king of the hill, or the queen of the hill, it's the top one that they're abining for most of them. Again, there's differences. Right. And there's been a number of studies that have been done and trying to bridge this to the laboratory, looking at 5-HT-2-A agonism, and many people have said, well, 5-HT-2-Agonism also has, in of itself, beneficial effects on animal behavior that is thought to index to some extent what we're calling antidepressine effects in humans, so all kinds of comes together. The plot thickens a little bit, and gets a bit more confusing, because you know, it's just wonderful, every data point was all in the direction of this thought, but it doesn't kind of work that way, because when one looks at the studies now, these are the one looks at cellular and molecular studies, this is very laboratory and very scientificy, it's turning out that the antidepressine effects, at least the antidepressine effects that we are inferring in rodents and otherwise, those antidepressine effects may not necessarily depend on the 5-HT-2-A. Also we love brain-derived neurotrophic factor, brain fertilizer, who doesn't want brain fertilizer? We love amontor, the latest fertilizer we're talking about, well, these types of fertilizers are boosted if you give some of these serotoninetic psychedelics, but you don't need to bind to the 5-HT-2-A recipe to get that effect. We also love plasticity, neurons that fire together, wire together, and again, that effect, along with the molecular effect, may be dissociable from the 5-HT-2-A receptor. What is very much agreed on, though, and is now, is that the psychedelic effect, which in the rat, is a head twitch, and the psychedelic effect, which is a head twitch in the rat, is definitely mediated by the 5-HT-2-A. So, I think we came at this with a very reductive understanding, 5-HT-2-A is where the psychedelic trip happens, that's where the antidepressant behavior happens, but we now have to somehow reconcile a fairly rigorous and replicated finding that the, in quotes, molecular and cellular behavioral effects that we think are in line with being antidepressant are dissociable from that psychedelic effect, which is more 5-HT-2-A. Well, let me ask you something, are you now convinced that all 5-HT-2-A agonists are not created equal? And the reason I'm saying that, of course, is that probably all 5-HT-2-A antagonists are more or less equal, they just block receptor, and you know, there's nothing very interesting about it, they're all the same, and what characterizes most 5-HT-2-A antagonists by their differentiation is they're non-5-HT-2-A concomitant off-targeted properties, but at the 5-HT-2-A, we said that they're all the same. Now, pivot that to 5-HT-2-A agonism, and I also trying to teach that to all of our listeners, we're in a brand new era of trying to look at agonist pharmacology, and that ain't the same thing as antagonist pharmacology, you're talking of muscarinic 1, muscarinic 4, or 5-HT-2-A. So, Roger, what do you think about the differentiation of different ways in which 5-HT-2-A agonists work? Can you have 1, 5-HT-2-A agonist effect that actually is a head twitch, or hallucinations without antidepressant effects, and the other way around, we can have antidepressant synaptic plasticity without the head twitch? Can that happen? And it's still an agonist? Absolutely, and see, this is so true. For example, you know, most of us, when we get our pharmacology training, you know, when you have a ligand that binds to a receptor, it's an agonist, well, it agonizes, it activates, and that leads to signal transduction, and the rest is history. It was a very simple story. Well, turns out the story's not that simple. It turns out that when a ligand or a pharmaceutical, which behaves like a ligand, and dodges ligand, binds to that receptor, well, it turns out a couple of things could happen. Then it's called biased agonism. In other words, it turns out that there's different intracellular pathways. So it's a bit like when you walk into a building, a revolving door on the main, and there's the congear standing there, you can turn left to go to the restaurant, turn right to the front desk, and check into your hotel, go up to your room. These are very different outcomes. One for dinner, check it into your room. So this is a very different left and right. That's biased. So once you get inside that cell, it's turned left and turned right. It turns out that some 5-HT2A agonist, when you bind to that receptor, you turn left and you turn left, at least to a head twitch in a rat, and that leads to psychedelic trips and people. You turn right. There's no head twitch going on and doesn't seem to be, we don't think, the same degree of psychedelic activity, for example, we already have other drugs in medicine that are 5-HT2 agonist. They're better known in neurology. These drugs don't cause people to trip, and it turns out those drugs go down the other. They turn right when you walk in the front door of the hotel, so they're not causing that. So 5-HT2A agonist, it was the revolving door on the main floor of that hotel, that building you walk in. But then whether you turn left to the restaurant or turn right to check into the hotel, it's a very different outcome. Well, can I also add here, there's a drug called xenomaline, which is actually a famous drug now, because it's been filed for schizophrenia and celebrated as a muscarinic one and muscarinic for agonist. But I've got news for you. It is in the serotonin revolving door, but it doesn't go anywhere. It just stays in there. So this drug binds to 5-HT2A and other subsets of receptors, but doesn't activate any of them, so that doesn't make a decision, so you can even have drugs that are agonists that don't trigger any signal transduction. You never get your room or dinner. Well, guys, I'm going to throw another, I'm going to throw another wrench in this. There's also partial allosteric modulation, oh my god, so there's another way, if you will, stimulating without you being an endogenous ligand or binding to the orthosteric site, but you can bind to an allosteric site that changes the configuration of the receptor, so that's something happening on the outside, if you will, and enhances the binding of the endogenous ligand, or it can be, as you said, inside going down different roads, different signal transduction pathways. Boy, this is getting complicated, guys. This is why I use the revolving doors the metaphor, because my whole world turned upside down, because I always had this sort of notion that, you know, 5-HT-2-A receptors are just docked on top of that cellular membrane waiting for a serotonin molecule to come along. I had no idea, they can become intracellular, and it gets complicated, and so in other words, imagine that revolving door of the hotel in the main entry is, it's going, and so it shows, and it goes around, goes back inside the cell, comes back out, this is something very different. And so, not all 5-HT-2-A agonists are the same, and again, once they activate the receptor through the orthosteric site, or the allosteric site, the orthosteric site, I just call it the main site, and the allosteric is kind of like the STP oil treatment, the one on the side, it's kind of helping the engine go. I sort of see, okay, goes inside, you know, I turn left to the restaurant, I get a bite between right to turn, go check in the hotel, and that's a metaphor for some go down this molecular in the 8-dural pathway, molecular cellular behavioral path we have twitching, the rats are twitching, which we think it's a trip and it's a started trip. But others don't do that. So it's a very, very interesting way. And many folks are now interested in pursuing if 5/8/2A so relevant to the end of the present effect, it may or may not be, can I go down that other right to write and not twitch, not at a psychedelic? And guys, no, this is interesting. This is introduced to the new vocabulary for us, a psycho-placigen and a neuro-placigen. You know, and I know Steve, you're written about that. Yeah, well, the idea is that these are placegins. It's no question that they can cause neuro-plasticity, you know, in terms of new synapses forming, not so much a neurogenesis, which means brand new formation of new neurons, but connections, yes. And so, yeah, you have the ones that do that without causing hallucination, and we have examples of that. You've got ovality, which is the dexamethorophane, doesn't seem to do that. Asmethodone. These are NMDA antagonists that work at the similar site of ketamine, and yet they don't cause dissociation. And then you've got even, to the extent that Zeranolone, which is a drug that works on GABA receptors, is an additive present. You know, there's some evidence for that. It doesn't seem to cause hallucinations either. So, it's not, I mean, it's not even a necessary or sufficient property. And I want to throw them on the thing into the mix. It's called partnering. We'll call it that, hetero dimerization. So, in other words, maybe we're getting this, and if you've heard our talks on the trace of means, that's one of the first clinical examples of that phenomenon. What does that mean? It means that sometimes receptors bind to other receptors, and when that happens, things change. And so, in the case of the 5-HG-2A receptor, there's now work going on, suggesting that if you have the certain type of agonist, it will then marry, date, caress, hug, bind, whatever you want to call it, another receptor. And maybe even the so-called Turk B receptor, which is the one that is forbidden enough. So, there's a lot of things that can happen. Why does 1-5-HG-2A receptor turn left, why does 1-Turn right, 1-HG-1 hetero dimerized? These are all unknown questions, but it does leave the possibility that you don't have to hallucinate in order to have a rapid-acting antidepressant effect. Yeah, let's get back to that, guys. I feel like our field has been myopic around monoamines in serotonin in particular. So, what we're saying is really going to challenge a little bit of dogma here and blow people's mind, that it may be the way these drugs are working are not even through these serotonin receptors. And we haven't even talked about some of the other serotonin receptors these drugs bind to. And I know, Roger, you've written an article about the risks of 5-HG-2B agonization, which some of these drugs do, as far as valvular heart disease. So, what else are they doing, Roger? Well, that's a great point. I always believe that if you can't explain something on a bumper sticker, you probably don't know what you're talking about. So, we all is like a nice simple story. It almost becomes a slogan. I love slogans. Slogans stick with me. It helps me sort of remember certain things. But slogans don't tell the whole story. And I think we've learned, for example, we've learned in other classes of pharmacologic agents that other activities matter. And a lot of this comes down to where the street light is shining. And many of our colleagues joining us know that, for example, access arise, target the serotonin transporter. But they have effects on other systems as well. For example, they have effects on Sigma-1 systems, which has now been a target of buproprion, dextromethorphane combination. I mean, my goodness. This is an important farther receptor. So, other things are happening. So, but bringing this back to the serotonin or the psychedelic, if we were to create a table, and many of these exist in a literature, where you sort of juxtapose the different serotonin or psychedelics together, you rank, order, all their binding activities, what should bind the appendix for other serotonin or receptors. They have appendix for other systems as well, including other monolimines, like dopamine. But also, other neurotransmitters are, depending on which one we're talking about, are also affected, including glutabate. But coming back to the serotonin or nervous system, and I remember you and I had a conversation about this not too long ago. You and I were talking about, you know, the loxicine, and its history is an antidepressant, and I became a treatment for ADHD, non-stimulant, and you and I were talking about 5-HT2B on that day. I remember that wasn't too long ago. You and I were talking about that conversation over lunch in the media of Texas. And essentially, because we have many medications that are 5-HT2B agonists, and for those who are maybe less familiar, 5-HT2B agonism raises at least a yellow flag for us. Maybe sometimes a red flag, but so the yellow flag, because when the 5-HT2B receptors were looked at, they were located in different parts of the brain and body, but they do populate the cardiac valve and the subvalvular apparatus. And there's been plenty of examples, of course, for fluoramine. Everyone knows fluoramine. There's argotamines. There's other drugs that are known to have effects that are agonistic effects at 5-HT2B, so I'm going to say, well, so what? Well, the so what is is that it could lead to an increase in fibrosis, an increase in deposition of glycosaminosplichins. The short story is this can lead to a regurgitin valve, and that leads to, well, pulmonary hypertension, and many people have heard of this, with, of course, phenfluoramine. Now, again, one doesn't want to be alarmist. We're not trying to be alarmist. We have to be safe, and we have to know what the safety profile is. And we need to have a full cardiac characterization. Good news is, it doesn't seem like the serenity of psychedelics, prolonged QT intervals or other electrocardiogramic parameters. That's good, but on structure, I think this is still something we need to sort of. The FDA's come up with guidance on this, and they're guidance in very clear languages. People who have pulmonary hypertension, or who have preestablished cardiac valve or disease, should be excluded from serenity of psychedelic studies until we have a better handle what's going on here. I think it's entirely possible that the FDA will not approve any 5-HT2B agonist ever again. And that means that's why you hear about microdosing and limited dosing, because that's going to be the best you're going to get out of these older drugs that are promiscuous, a lot of receptors. But I also will mention another wild card, which is that there are numerous drugs that are 5-HT2B antagonists. We have no idea what that contributes to the price of bread. Well, in other words, to make it work better or not. So 2B is a bit of a or not 2B, that's the question. The question here with these drugs, though, is as you're saying, these drugs are agonists at 5-HT2B to some degree, some more than others. And the question is, which is worse, episodically hitting that, or in microdosing, you're consistently hitting it, a little more consistently. And I think we just don't know. But the interesting thing is that 5-HT2B antagonism, and this is part of our conversation, Roger, that's pretty well emerging as an anti-depressant mechanism, because it disinhibits serotonin release amongst other things. It's very involved with serotonin-neurotransmission. Yeah, it's always, we all know correctly. I was just going to mention very high probability for D3. Well, we don't, again, this is where it kind of like, if I play on a basketball team with LeBron James, no one can make anybody on the team that LeBron James plays. And so, you know, the D3 is the LeBron James, and everyone talks about that with Cripply, but it's also 5-HT2B antagonist. But again, no one doses on the roster when LeBron James plays. As is Vlox, is he in the 5-HT2B antagonist? Yeah. Well, it's interesting you mentioned that, because I sometimes think in terms of teamwork, I know you and I are big sports fans, and the fact is that probably the hole is greater than the sum of the parts. And we know the best sports teams, our teams, well, there's excellent chemistry, and things are in balance, and it's not just one star, you know, driving the whole ship. So, getting back to these agents, what has been found recently, and we've shared amongst the three of us, we have shared an article in particular from Finland, that blew my mind, because it talks about direct effects at that truck B receptor. So it turns out, these psychedelics are actually have very high affinity at the truck B receptor. They act as positive allosteric modulators. So talk a little bit about what's going on there, and we're talking about neuroplasticity as the final common pathway. Yeah, you know, that's such an interesting fight. It was a very rigorous study. You're making reference to the idea. And there's been a, as you know, and there's been a lot of work to show molecular and cellular studies to show that when you activate the truck B system, that can lead to an increase in BDNAF, consequently plasticity. And then that then is in accordance with some of the behavioral changes in the animal that we think are obviously highly imperfect, but is it sort of an index of an antidepressant effect. And what's interesting is that with treatments like psilocybin, maybe the NLST, they may be activating the truck BBDNAF system, which is, in quotes, the antidepressant brain plus city system, independent of the five HD way, independent of serotonin. Exactly. Yeah. Absolutely. So again, I think that that is, that's important. This is, it's always difficult to bridge the lab to the bedside. But that's important because that is a highly replicated model, you know, you know, paranoid as well, you know, described and so on. So I think that, and people may say, well, you know, this seems like a, this seems, you know, what houses really affect the bigger picture? Well, it does because there's a lot of, there's, there's many, many, many drugs that are so called five HT2 agonist or potentially psychedelics. And this is critical because the decision to go forward and developing these needs to be informed by the science. And, and also if it's the case that you don't need the five HT2A for the antidepressant, in fact, and instead, the five HT2A receptor is only igniting a cascade of events that leads to trips that may not, may not be relevant, for example. Then let's just focus on where the action is. You know, it's, you know, Willie Sutton, the bank robbers, and I rob banks, or that money is, I think we think the Willie Sutton approach, we just go where the money is. And that's how you do it. Well, don't you think that some of this almost exaggerated hyperbolic interest in psychedelics? Some of it comes from, of course, all of the purulent facts of the abuse and trips. But don't you think some of this comes from the unmet need that our current therapies were posted of the inadequacy of our current psychiatric treatments for a whole host of our psychiatric disorders? And maybe that's why people are getting so excited. Here we have something that may work very fast and on a variety of our conditions. You know, I think you hit the nail on the here, right with that, with where you preface that, you know, the look, I think that when it comes to the unmet need, I think there is a huge unmet need that you hit around the head. And I think if the needs of our patients were, were more than adequately addressed, I don't think there'd be a vacuum to fill. And there is a vacuum. It's, it's, it's, there's a lot of, you know, discouragement and a lot of, you know, gaps in our knowledge. And, you know, it's a fact that many, if not most, people don't knock it out of the park, the first anti-depressant or all the psychiatric drug they take where the condition. So I think, I think that's part of it, even if there has been an unmet need. So the question then, I've always said, I've always said to people, there's nothing wrong with being passed. There's nothing wrong with being hyped up. But that should be moderating. That shouldn't be mediating your behavior. In other words, it should be a background tailwind for, tailwind for you. But we've got to have cognition be the rudder here. We got to think this route carefully. Safety first, do adequate and well controlled trial. And I think, I think in some respects, the psyched deluxe, they're kind of cursed by their history because they were never really developed in a rigorous way. They were put on the back shelf for reasons everyone knows because of rescheduling and all that kind of thing. And they were never subjected to the interrogation that any medication would be expected to be interrogated today. Well, you know, it's interesting. Citad and Michael Burke, who probably won't be listening to this because they're Australian. And I are looking to put together a book called Repurposing Recreational Drug. Nice. And I think that there are almost any recreational drug you can think of. That's right. Yeah. Can be thought of in therapeutic ways as well. Part of that is due to the fact of the unmet need as the Roger Soil suddenly said. But I think also there's a little bit of anger towards the pharmaceutical industry and towards psychiatrists that are too, you know, bound to tradition and payers that have a system in place which excludes certain people from getting better because they don't have other options. So they jump to these. And although there's promise to that, I still think that that the enthusiasm, like you say, as a tale was a nice analogy, but you have to actually be blown towards a scientific proof that these things are safe and effective. You know, I've always said the brain doesn't know the difference between legal and illegal. These are just chemicals that have effects in the brain. And of course, the classics like Adelix, LSD and psilocybin, both, by the way, discovered by Albert Hoffman, they were developed as therapeutic agents, not as recreational agents initially. So I think you're right that a whole stigma has built up around these and a whole belief system that I alluded to at the beginning here. There are some people now who just have this almost fanatical religious belief in how these things work. And I think you're right, Roger, that we have not subjected them to rigorous, rigorous scientific investigation, which is starting to happen now. And you mentioned the FDA's published guidelines on these things. But I think what is concerning is, first of all, this title, this psychedelic assisted psychotherapy, as if it's the psychotherapy that's doing the heavy lifting and all the psychedelics are just helping that. I think, you know, you have been leading the forefront of turning that on its head a little bit, right? Yeah. Well, you know, going back to your comment a moment ago, Andy, I certainly have never tried to be a polemicist or an iconoclast, or someone who's just trying to sort of make noise in the back of the room just for noise sake. I think, look, we have seen all three of us have seen medications, and it ended up in the medication cemetery because they weren't developed properly. And for those who are less familiar, I mean, the spending medications, it just weren't sort of developed with the adequate controls and so on that clearly had potential effects. It just didn't receive the adequate scientific rigor. And I think that it's in keeping with advocacy for people suffering from agonizing mental illness, that we want to be sure we have safe and effective treatments that are adequately developed. And that means, you know, the foundational constructs of development are no different than any other medication. And when it comes to the whole issue of the psychedelic assisted psychotherapy, that is actually a hypothesis. But that hypothesis has become de facto a digure. It's become sort of just, as you said, it's kind of religious. It's a hypothetical belief. I think it's a hypothesis. Now, what is not a hypothesis is does particular eye psychotherapy help any patients with mental illness? Of course, it absolutely does. It is not a hypothesis that when you combine medications like antidepressants with CBT and depression, many patients do better than try to medallinal. That's not a hypothesis. But that's what we're talking about with the psychedelic assisted psychotherapy has a implicated mechanistic direction that what really is occurring is that the psychedelic through its pharmacodynamic effect is creating a biological change in brain that is then setting the fertile ground for the psychotherapy in its act as ingredients to go away and do the work. And again, that is an interesting paradigm. It is a very, it has a tremendous face validity to it. And it's compelling. But it is a hypothesis. And the reality is is we don't know if this is psychedelic assisted psychotherapy or whether this is psychotherapy slash psychoeducation slash support benefiting assisted psychedelic. Are whether this is a behavioral toxicity that you have to endure in order to get through to the other side with the neuroplasticity? Now, having said that, I'm a big champion of neuroplasticity and that a lot of these behavioral things are epiphenomenon that we would like to get rid of. Having said that, there is this very interesting thing which we've talked about before in a previous podcast, Andy, and that has to do with reconsolidation. There is an idea in animal models, which I think has a lot of validity, which is that you have a memory. It gets stored. If it's a horrible memory like PTSD, it starts deep, deep, deep into the atmolygd amygdala, never to come out, except it does come out, which is that if you're thinking of your memory and you can reactivate it, it becomes what you call labile. Because what happens is that the brain has a way of having a memory and then you actually can act on it. But you have to have that memory reactivated. You're thinking about it and then you can modify it, you know, change it, store it, you know, and guess what? Eliminate it. And so if you don't reconsolidate, the original memory is consolidated, then you have the memory later many times and you reconsolidate, restore, restore, restore. If you can disrupt the restoration and the refiling of that memory, maybe you don't have it. So it may be, and this is wild. Are you ready? I propose that it may be possible, if it's not your mechanism exists in humans, to forget your addiction, to forget your PTSD, to forget it. And so I mean, not that. So I don't want to throw it out the possibility that you could create some sort of open window that something is happening during a drug-induced event, which could then be exploited, you know, to actually cause some major changes therapeutically. We don't know any that. But I think we have to have an open mind about that. Right now, though, I think that I'm more impressed in this particular instance of patients coming to me and saying, oh my god, I went to Brazil and Africa and I had this incredible experience. It was a most amazing thing. I already talked to my dead mother and she forgave me and, you know, all this stuff. I'm better and better. I say, well, what are you doing in my office for treatment and resistant depression, then? Exactly. So I have have this incredible experience, but the dots are not connected to actually causing enduring changes in treatment resistant to pressure. So I'm a little bit skeptical that those experiences, which are quite dramatic obviously, clearly, whether those are the therapeutic ones. Well, it does appear that there's some degree of enduring benefit, but the question is always how long, you know, of course with ECT and with ketamine, that benefit may only last, you know, weeks with psychedelics that might last months, but eventually it may wear off. Okay, guys, I'm going to put you both on the spot. I'm going to put you both on the spot. I'm going to start with Roger. Actually, let me start with Steve and then I'll go to Roger. Steve, is the psychedelic trip necessary for the therapeutic effects of psychedelics? You can't wiggle out, Steve. No, or hell no. Okay, Roger, what do you think? Yeah, I think that I'm going to land in in in in in camp stall on this one. I think that's still a test white pauses. I haven't seen any evidence whatsoever that the psychedelic trip is relevant to the therapeutic outcome. Well, I think what's happened is you put your finger on this, Roger. I think that we're learning more and more our drugs do a lot more than we think they do. And you use the analogy of the guy looking for his keys in the middle of the night in the parking lot, right? And let's say his car is over here, but the he's searching way over on the other side of the parking lot. His friend says to him, what are you doing over here? Your car's over there. Shouldn't your keys be in the case? Yeah, but the lights better over here under the street light. So we know, for instance, that our traditional reuptake inhibiting antidepressants are increasing monoamines. But guess what? They also, some of them you mentioned can be sigma one agonists, which is emerging as an antidepressant mechanism. Steve, I don't know if you know this. You may not remember it because you've written so much. You wrote an article a few years ago called the sigma enigma, talking about this. I realize, you know, that you've written so much as hard to keep track. But also, guess what? They also bind to the truck B receptor we've been talking about. They may have direct neuroplastic effects, but they have low, very low affinity. So it could be they don't work as robustly or as quickly as the psychedelics, which have high affinity. So the fact that psychedelics may have more than one mechanism, and some of the mechanisms may be therapeutic, and some may not. And Steve mentioned ketamine. We know that ketamine causes robust association. But yet there are other drugs in development, and certainly dextramatorphin is one. This is a pharmacokinetic issue. If you bind the NMDA receptor too tightly, you get toxicity of dissociation. But if you bind just enough, you can still be an antidepressant. So maybe here we just have assumed this trip is necessary, because it comes along as part of the package of the other things that these drugs are doing. So I kind of, I'm with you guys. I think that the trip may not be necessary. I do think, as you said, Roger, I think this is a very nuanced and balanced approach that therapy may be very helpful in addition to whatever these drugs are doing on their own. But I was in Japan a month ago talking to some of our colleagues in Japan. They are deathly afraid of psychedelic trips. They don't like to lose control. This is partly an Asian cultural phenomenon. And so they're more likely to take a medicine if they don't have to have therapy and a psychedelic trip on top of it. So what if we have a menu of options where if you want to get the psychedelic trip and the associated therapy great, but you can also get this class of medicines as a pure antidepressant that is having these neuroplastic effects and still be effective. And then your personality isn't wired to have the other part. You know, the issue, I think we should bring up now, not only your agonist, different than antagonist, as we've just talked. So are the way you give drugs, whether it's an agonist or an antagonist. So for example, if you slam a drug and you get a completely receptor occupancy very quickly and then it come off of it very quickly, that can be an entirely different effect than if you kind of slowly go up because there's obviously hallucinogenic effects of ketamine. There's anesthetic effects and there are dissociative effects. And then there are sub dissociative sub anesthetic effects. And some of those are related not only to the plasma level, but to how rapidly and how long you stay there. I mean, after all, think about it, you've got deemphetamine or methamphetamine, which if you slam it and smoke it and put it through the surface area of the lung and put a sludge hammer into the brain over two seconds, it causes a glorious output of dopamine and a horrible depression and all that. Same drug can be used in six-year-olds for ADHD. You know, but it doesn't do that because you're using much lower doses and has different mechanisms. So the DMT is the psychedelics, the psilocybin, could be very much different depending on how we administer them. That's true. And so we have to be sensitive to that. And I think that what it's beginning to look like is that slamming these drugs into somebody is not a good idea. That maybe you get some of the better effects and you can dissociate some of the bad and the good effects by giving them slowly and more enduringly and for a really longer period of time. Yeah, so well good. And you know, maybe our colleagues joining us may be wondering, well, they've heard or maybe they've read or what have you that there is evidence that you need the psychedelic trip for it to work. And so are we just ideologues or have our own opinion or how does it help us together? I think that the challenge that we have with the published and available literature that has looked at that is the issue with called blinding integrity in all these studies, more than 90% of people know with a very high level of confidence that they're on the treatment they're allocated to. So you have with called the expectancy effects and so on. So and that's going to bias the outcome. So you don't know if that's the trip or that's just expectancy and bias. And this is not an academic point. This is very serious. And you know, I remember when ketamine first came into psychiatry as a treatment for depression, there was a view which has now been provably untrue that you needed to dissociate for ketamine or S ketamine to work. That has proven to be untrue and you don't need to do that. And an example with some colleagues have said, me not necessarily be the same example, but I think there is some similarity to this next example when I give, I know when I was a medical student and I was starting in, you know, in early residency in psychiatry left medical school. So in other words, this wasn't a million years ago, although it was a lot of time ago. And I remember that on the ward, like it happened an hour ago, and some of the colleagues joined us, we'll remember this. I was told to dose the antipsychotic in my patients. To a dose they got EPS. They got an acrophysia. And that was actually, and I remember having discussions and nurses rounds in the nursing rounds, we were talking you know, you know, the patient's not benefiting. They have schizophrenia. Oh, well, did you did they having any acrophysia? No, it will push the dose up. You had to push the dose up to get an acrophysia. And again, this wasn't like a thousand years ago. And that was based on a very similar idea, in my view, where the thought was okay, you needed to serve and don't be an occupancy to be in anti-psychotic. And that don't be an occupancy was overlapping with acrophysia. So that's going to be our phenomenal logic characteristic that's going to guide our dosing. Well, turn on. It's all wrong. It's all right. It's incredibly wrong. So, and that left people with unnecessary drug-induced movement disorders and TD and so on. And the other part is to you guys know this is that the trip is a big part of the safety concern. It's a big part of the wrap around the support, the expense, the access. This has huge implications. And finally, some people, it doesn't seem to be very common, but some people are susceptible to what's called HPPD. Hallucinogen, most perceptive, persisting perceptual disorder. Flashbacks for our audience. Yeah, lessbacks. Yeah. So, so if we don't need to have this and that's good. And then one final point, I think people have made a good argument around the issue of just equity getting into these studies. Because right now people who have had predisposition to psychosis or mania are not allowed in because well, you get a trip. It's not good for your underlying mental illness. But if you don't need the trip and they're being excluded on that. And of course, the fact that the trip is really what led to these drugs being scheduled one to begin with. Now, I think two, this is not merely an academic discussion we're having guys because if somebody who's been involved with drug development now for 30 years, you know, it seems to me that if we can parse out these different mechanisms, it may lead to more sophisticated and targeted drug development where I can get what's now being developed or second generation psychedelics that target these other mechanisms without causing the trip. So it could be this will lead to more sophisticated drug development with less times. Could be, but you know, I also see the possibility that this bifurcates. And you go down the direction of some sort of politically motivated legalization of these things in which case, they will be administered, you know, like medical marijuana. They just are able to get it. It'll go into the lore of clinical practice and in the psychotherapeutic practice and people will claim what they claim. It won't be FDA approved, then it will probably be in the area of anecdotes. And then the other one will be to say if there's any science at the residual, now that we're in of our podcast, if there's any science here, that, you know, we'll be able to actually dissociate the hallucinatory experience from the therapeutic experience and have drugs with safety and efficacy by FDA standards. And then that will go forward. I think Australia is already moving even. in Oregon, there are places in this world where you can get these drugs, and you can take a mushroom, you can lick a toad, whatever you want to do to get your DMT, and it's just legal, and so you go to a therapist with your toad and have a nice day, I don't know. But I mean, I'm getting facetious, but the issue is that it could get out of control very rapidly. You're talking about classics like adults, I'm talking about going beyond that, I'm talking about developing drugs that don't have those drugs. Oh yeah, that's the other bifurcation, I think that classics will go down the road. Yeah, exactly. I hope it doesn't bifurcate. Right. Well, that's a good point. I mean, the gene is out of the bottle to some degree. You know guys, I mentioned earlier before we started recording, I was at a meeting recently with some of our colleagues, and Alan Young was speaking about the history of psychedelics, and I didn't realize, I was wondering why these things were put on the shelf, schedule one, no legitimate scientific research, and all of a sudden recently they started coming back in a big way. And apparently, a colleague of ours, who's a bit on the stubborn side, David Nutt almost single-handedly forced people to reevaluate and start being able to study these drugs again. So it is really fascinating how these things are ebb and flow with the political and other wins. David is an amazing character, we should probably have him on a podcast. We should. We should. He, as you know, he was one of the government's top experts on marijuana, and he said more people died of horseback riding accidents than marijuana, and he got promptly fired by the Tories. He didn't like that because they liked horseback riding, and they didn't want to say nasty about it. And they wanted to regulate marijuana. So he's sometimes on the wrong side of the politics, but he's the most provocative smart guy ever. That's right. Yeah, but you know, I think that, and I agree, I think that it would be great to have David come on. And, you know, we already have a history of success. Catamene, of course, has also had a somewhat romantic history, but look, it's saved lives and own people with the pressure to reduce the suicide. Dextamathorthia still has, in some parts, the world is restricted, out of concern, blood abuse liability, and so on, yet it is now an effective and safe antidepressant helping many people. So, the message is, can we, in fact, develop these treatments using adequate well-controlled studies, safety, safety, safety, and let's see, we get the right dosing, the right intervals, the right patients, and let's see if they could work. So I think it's still a wide open conversation for serotonin psychedelics, but the comment made earlier, I just happened to really believe that we have to make sure this is guided by thoughtful drug development and not emotional or ideological development. Roger, it's very hard to top what you just said. I think you've just summed up really what we're trying to do here in a beautiful nutshell. And I think that, while it's fun for us to sit here who are kind of psychopharm geeks to do mental self-gratification, there is another term mental, something else that I'm not going to use. Mental self-gratification here to talk about these receptors and these activities and all of this. But the bottom line is what you're alluding to is the proof, oh well, I should use our friend, Lester Trum, taught me that the original version of the saying was the proof is in the tasting of the pudding, not the proof is in the pudding, but ultimately, either these drugs are going to work or they're not. And then we're going to have to figure out how to employ them in our practices, and there may be certain logistical issues and regulatory issues, and we're going to have maybe certain trained people and monitor all these other things. But isn't that the truth with ascadamine, which now requires certain kinds of special considerations? So I think if a drug works, we're going to figure out how to use it. In the history of psychiatry, if nothing else, we've used pretty toxic interventions, we've used some pretty dramatic things like ECT. But ultimately, if they work, they endure, and we'll figure out how to use them. And especially if they work differently, or if they work as you said, on a different set of patients, more patients, or if they work on a different set of symptoms or a different kind of outcome as we talked about, if they help people to feel differently, to feel more like themselves, to feel more engaged, then we got something. We got to talk about the tale, I think. Yeah, so I'll put it in, and I think that, as you said, I think that we're talking about sub-populations. I don't think these are going to be the dinosaurite for psychiatry, but look, nobody needs to be convinced that we have a large number of people who have difficulty treating mental illness, whether it be PTSD or depression, bipolar, OCD, the list goes on and on. So we have a large number of people who are suffering, unfortunately, the conventional approaches haven't helped, but those conventional approaches help other people, and we need options. And so I think we absolutely have to study this and look at this, and that's the promise I think of ecstasy, which we didn't talk too much about, but also the promise I think of Sarah turned to herself. They're really helping some of these more difficult treatments. And guess what? This is nothing more than the history of psychopharmacology recapitulated where a failed antihistamine became a tranquilizer for schizophrenia, where an antihiburculous drug worked for depression and so forth and so on. So these anecdotal observations can really revolutionize our field, so keep our minds open. A drug that was developed to treat post-lumbar puncture headaches became an emphetamine to treat ADHD. That is the history of emphetamine, actually, too. So guys, this has been great, I could continue this conversation, in some ways guys, we've known each other 25 years or so we've been having this conversation in some form or other for over 20 years, but we've run out of time for this one, and I think we need to give each other the commitment that we will continue this conversation, and hopefully our audience has got something out of it. If nothing else, we've talked about some really intriguing theories about what could be going on with these medicines, how they may work, various kinds of molecular bases, if you will. But ultimately, the science hopefully will win out, and I think Roger's point is so well taken. We really need to take some of the emotion out of this. We can all have our opinions, that's fine, but we really need to expose these treatments to scientific rigor and figure out if they can help people how to do that. All right guys, we're going to have to wrap up, so Steve, I'm going to give you a couple of final thoughts, and then Roger, I want to come to you. Well, I couldn't be more pleased, you know, this is a real brain trust here on this call with Roger and you Andy, and so I think we brought up a lot of interesting things, the audience should feel they're on the cutting edge, because this is where psychiatry is today, so it's been a delightful time, thank you very much. Roger? Yeah, look Andy, great, obviously this is always fun, professionally, it's more secondary, personally this is always fun to be with both yourself and Steve, and it's invigorating, it's hopeful, and I think that, you know, for me, how I see it is, I think that this new frontier, I think it is a new frontier, it is really exciting for patients, and I think that to the best we can, let's just shepherd this, let's just shepherd this in a way that's careful, because if we do have a serotonin psychedelic that is really going to help some patients, let's not spoil the broth, and let's do the best we can to shepherd it properly, it's an exciting time, and I've learned in my careers in an academic and as a clinician, that we don't have a surplus of hope, and we need more hope, and I do think, in fact, these are very, it's a very hopeful, a new set of treatment considerations and developments, it's been fun to have this conversation. Yeah, I agree, and I think for our audience, you know, we realize that clinical care is difficult, and sometimes it can be quite frustrating, and I think one of the things about this science we've been talking about that's exciting for me, it's an reinvigorated me, I mean, I sometimes joke, I feel like I'm falling in love with my wife again, you know, I fell in love with psychopharmacology over 30 years ago, and I'm falling in love again, as I'm learning now about these actions that truck B receptors, for instance, and BPNF, and neuroplasticity, oh my God, but it is really part of the excitement, I think, and part of the things that gives us hope is clinicians that, and some optimism maybe, that we can have new treatments, and we can help more people in better ways. So if nothing else, I hope this podcast has been somewhat uplifting, and hopeful. So I want to thank everybody for listening to another edition of the Psychopharmacology podcast, and for more information about our various offerings at NEI, our educational and other events, you can go to our website, NEIGlobal.com, thanks so much, we've got a couple more podcasts in this series that we're really looking forward to. Thanks a lot, guys. Thank you for joining us for another episode of the NEI podcast, please let us know what you'd like to hear more about by leaving a review. Don't miss another episode, subscribe today. For more information about NEI and our premier educational content, please visit NEIGlobal.com.