Bonus Episode: Psychedelic Research Inside an Academic Medical Center with Scott Thompson, PhD

Journal of Clinical Psychiatry

Publisher of peer-reviewed research discussed in this episode.

Dr. Scott Thompson – LinkedIn
https://www.linkedin.com/in/scott-thompson-241a1a15/

Harnessing Psilocybin (Hesselgrave et al., PNAS, 2021)
https://doi.org/10.1073/pnas.2022489118
Dr. Thompson’s mouse study showing psilocybin’s antidepressant-like effects persisted despite 5-HT2A receptor blockade.

Colorado Natural Medicine Program
https://dpo.colorado.gov/NaturalMedicine
State program for regulated psilocybin services discussed in this episode.

Definium Therapeutics
https://definiumtx.com
Developer of DT120, the LSD formulation with phase III results in MDD and GAD.

Scott Thompson, PhD, is professor of psychiatry at the University of Colorado School of Medicine, where he directs the Novel Therapeutics in the Brain and Behavior Innovation Center and leads the Psychedelic Public Policy Partnership. He trained at Cornell and Stanford, spent about a decade in Switzerland studying epilepsy, and later chaired the Department of Physiology at the University of Maryland. His lab’s 2021 mouse study found psilocybin’s antidepressant-like effects persisted when the receptor behind the hallucination was blocked.

Ben Everett, PhD, is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

This transcript has been auto-generated and may contain errors. Please refer to the original audio recording for full accuracy.

00:00 – Introduction: Is the Experience the Medicine?

Dr. Ben Everett: Hello, and welcome to the “JCP Podcast.” I’m your host, Dr. Ben Everett. On the podcast, we sit down with leading clinicians, researchers, and educators to explore the science shaping mental health care today with a focus on the insights that matter most in clinical practice.

Dr. Ben Everett: There’s a question or really a tension underneath almost every psychedelic trial that’s read out in the last few years, and it’s one the field hasn’t fully settled, is the experience the medicine?

Put another way, when a patient spends six or eight hours on psilocybin or LSD, is the trip itself what helps them, or is the trip something that comes along with a change happening at the synapse neurobiologically, neuroplasticity, that we might someday get without the long session at all? My guest today has spent more than 40 years studying the synapse. Dr. Scott Thompson is professor of psychiatry at the University of Colorado School of Medicine.

There he directs the Novel Therapeutics in the Brain and Behavior Innovation Center and leads the Psychedelic Public Policy Partnership. For most of his career, though, psychedelics weren’t part of the work. He trained at Cornell and Stanford and then spent about a decade in Switzerland studying epilepsy including time in Basel, the city where Albert Hofmann first made LSD. Later, he chaired the Department of Physiology at the University of Maryland. Then in 2021, his lab published a study in mice suggesting that psilocybin’s antidepressant-like effects held up even when the receptor behind the hallucination was blocked.

This conversation finishes where we started with Dr. Steven Berkowitz. We get into what it actually takes to run Schedule I research inside an academic medical center. We also cover Colorado’s experiment with legal psilocybin outside of the FDA framework. Then we look ahead at two phase III programs clinicians should know about.

One is Definium’s LSD formulation, DT120 OD, which now has reported positive phase III results in both major depression and generalized anxiety. The other is Atai Beckley’s intranasal 5-MeO-DMT, BPL-003, which is being studied for treatment-resistant depression.

We’re early in the story of how these compounds enter medicine or don’t. Much of what happens next will depend on people doing this work the right way and how carefully they do it.

With that, Dr. Thompson, welcome to the podcast.

Dr. Scott Thompson: Thank you very much for having me.

02:00 – From Basel and Zurich to Psilocybin and Synaptic Plasticity

Dr. Ben Everett: Great. Look, before we get into the research, I want to start with a little geography. So back in the mid-1980s, you did a postdoc at Biozentrum in Basel, Switzerland. Then you spent most of the next decade doing brain research at the Brain Research Institute in Zurich studying epilepsy and inhibitory synapses in the hippocampus, but not psychedelics.

Really nobody was doing psychedelics serious research in the 1980s. Basel, of course, is where Albert Hofmann famously first synthesized LSD at Sandoz. He had his famous bicycle ride home in April of 1943, now celebrated as Bicycle Day. And Zurich went on to become one of the early centers of modern human psilocybin research.

So in a sense, even though you weren’t doing the work, you were in the center of creativity around this type of work. And I wondered, has that history or that parallel ever registered with you?

Dr. Scott Thompson: Absolutely. I was certainly aware of it from the moment I set foot in Basel. It’s a beautiful city. Absolutely loved my ten years in Switzerland as a whole. Six months in Basel, then most of the time in Zurich, actually, which is a lovely city.

Dr. Ben Everett: Yeah, so what did pull you into psychedelics roughly, people don’t like being dated, so I apologize if you feel dated by.

Dr. Scott Thompson: No problem.

Dr. Ben Everett: 30 years in synaptic physiology, epilepsy, plasticity, certainly the idea of plasticity is very front and center with psychedelics. But before psilocybin showed up in your lab, was there a specific, result or something that really resonated with you that said, “I want to lean into this”?

Dr. Scott Thompson: Yeah so it’s been a long, complicated journey. No path that anybody could have foreseen from the beginning. But I certainly ended up where I am because of my interest in synaptic plasticity. I-in my years in Switzerland, I was very fortunate to be training side by side with Franz Vollenweider who had the ambition at that time to go on and study psychedelics.

And he and I shared many wonderful conversations and, unfortunately, I never got a chance to meet Albert Hofmann, but I know Franz was quite good friends with him and really had wonderful things to say about him, even in his latter years of life as a, a wonderful, warm, creative human being.

So in the 1980s, that was the heyday of synaptic plasticity. Long-term potentiation, long-term depression were some of the hottest topics in neuroscience, and I had a small part to play in that that ex-that exciting era. And I came to the psychedelics field through my interest in neuroplasticity.

And really, what launched us was an accidental finding on, SSRI action, the actions of drugs like Prozac. And we, accidentally stumbled on a neuroplastic response of brain synapses to to the application of either an SSRI elevating endogenous serotonin within slices of brain tissue or application of serotonin and pharmacological agonist and antagonist directly to brain slices.

In our– in that work that we were doing on SSRIs, we found an involvement of one of the many serotonin receptors that was not the 5-HT2A receptor, which is the one that is, of course underlying the subjective effects of classic psychedelic drugs. And in two thousand sixteen when Robin Carhart-Harris released his first really carefully controlled study of psilocybin for treating depression I got really excited thinking about the parallels between SSRI action and psychedelic drug action.

And we thought if serotonin receptors are involved in this neuroplastic response to Prozac maybe they would also be important for the antidepressant action of psychedelic drugs. And so we did a series of mice experiments published in two thousand twenty-one that showed in fact that that psilocybin in, in mice had both an antidepressant-like action in the behavior of the mice and also produced a a strengthening of excitatory communication between brain cells in, in, in parts of the brain that are important for the behaviors that are altered in depression.

And so we really thought this, this could be a, an important clue into how psilocybin produces its therapeutic response. Really I w-we argue it was amongst the first of the neuroplastic kind of responses to, to psilocybin that were reported.

Dr. Ben Everett: Yeah, it’s fascinating work. And it has certainly helped lay the ground for our foundational understanding of the, the biology. I think the neurobiology, but I guess I’m a scientist by training. I’m always intrigued in what the neurobiology actually shows. I think from a clinical sense, sometimes people might argue, does it really matter how it works if it works?

But I like to understand how things work myself, so.

Dr. Scott Thompson: I think right now with the the incredible energy and activity around the discovery of novel compounds chemically related to classic psychedelics and also various efforts to to let’s say, harness classical psychedelics to make them more viable in our commercial medical legal environment.

And so i-i-in order to advance those efforts, it’s absolutely critical that we understand how these drugs work, what receptors are important, what are they doing to the brain. If you wanna test a novel compound at early stage investigations, you have to have that as a background. Otherwise you, it makes no sense to invest the millions and millions of dollars that it takes to move that compound through the clinical development pipeline.

07:30 – Psychedelic Research and Policy at CU Anschutz

Dr. Ben Everett: I certainly agree. All right look, before we really dive in, I just wanna orient a quick note for our listeners. So this episode actually completes a two-part conversation that began a few weeks ago with Dr. Steven Berkowitz, and he suggested Dr. Thompson might be a better person to take us deeper into CU’s psychedelic research program. So with that, let’s really– I wanna talk about the CU program ’cause I think it is really a foundational example of what I think psychedelic research programs should look like.

It’s multidisciplinary. You’ve got from different backgrounds, from different specialties all coming together at look at psychedelics. So maybe if we can start with a 30,000-foot view, you direct the novel therapeutics within CU’s Brain and Behavior Innovation Center. So can you orient our listeners to what’s happening in psychedelic research within your department and then the Psychedelic Research Consortium more broadly?

Dr. Scott Thompson: Yes. So I’m a professor of psychiatry here at CU Anschutz, the University of Colorado School of Medicine. And, our, department has a Brain and Behavior Innovation Center, as you mentioned, and I direct one of the, pillars of that, center, which is for, advancing novel therapeutics. And right now, the hottest thing going in psychiatric drug development is certainly, in the psychedelic drug space.

I was very fortunate to arrive here in Colorado just a few short months before the voters, passed the Natural Medicines Initiative, which, decriminalized possession and growing of psilocybin for personal use, for people over twenty-one in two thousand twenty-two.

And found myself very much involved, with a group here, centered on this campus called the Psychedelic, Public Policy Partnership, PPPP. And were, able use our expertise to help the state draft the regulations that led to the implementation of what we now call regulated psilocybin services here in Colorado, very similar to the similar program that happened in Oregon as well.

So that was a big effort, out of the CU Anschutz campus. We also have a, clinical trial that we have just completed here in the Department of Psychiatry, looking at one of the symptoms that I study in my mouse experiments, and trying to move that, towards humans as well, and that is the symptom of anhedonia.

And so this is a, an RCT that was led by Dr. Andy Novick here in the Department of Psychiatry a blinded placebo-controlled study of psilocybin, looking specifically at anhedonia as an endpoint. And I should say that Andy found very positive results. Psilocybin had a far superior performance against anhedonia compared to the the inactive control substance.

And so that’s been really exciting for me as a mouse guy to be involved in a human trial this, at this late stage in my career. I’ve cured a lot of mice and it’s really nice to be able to do something in the… for humans as well. And what motivated that study is really trying to get to an objective endpoint.

10:30 – Functional Unblinding and the Search for Objective Endpoints

Dr. Scott Thompson: One of the biggest limitations we have in all forms of drug development in psychiatry is that we don’t have good measures. We don’t have good objective outcomes. At the end of the day, most of our clinical trial data is based on asking people how do you feel now?” Obviously, we want people to feel better.

That is the ultimate goal. But of course the gold standard in any form of drug development is a placebo-controlled trial where the subject ideally does not have any idea whether they… and the investigators don’t have any idea whether the subject has been given a placebo, an inert compound, or an active substance.

And then the prediction, of course, the hypothesis is that only people who got the active substance will feel better. Unfortunately for the psychedelic drugs what the field has long recognized is that’s, that sort of gold standard clinical trial is virtually impossible because it’s impossible to come up with an inert compound that mimics in any way the subjective effects of a psychedelic.

And that means that almost every subject and almost every clinician involved in the performance of the clinical trial is pretty certain who got the placebo and who got the psilocybin. And so if you’re a subject suffering from depression, and many of these trials are done on people, suffering from treatment-resistant depression, which means they have been depressed for a long time, they have failed to get better with, conventional, antidepressant drug compounds and they’re desperate to feel better.

And you’re pretty sure you got the psilocybin. You’ve read Michael Pollan’s book, you’ve seen the Netflix special. You read the newspaper every other day. You see a positive article about the power of psychedelics to change mental health treatments. And you’re just gonna naturally want to feel better, and you will feel better.

And I don’t mean anything pe-pejorative about that. It is an innate human response. And conversely, if you went into this trial thinking, “Oh, my gosh, this is it. I’m gonna get psilocybin. This is finally gonna be the thing that makes me feel better.” And you get your treatment, and you realize right away that you are not having any subjective effects.

You’re not having anything that resembles a response to a psychedelic drug. Y-you’re… Again, an innate human response is to be really disappointed that you’re in the placebo group. There’s a famous New Yorker cartoon, if anybody is familiar with that one. And that confound the, the, the unavoidable fact that people know whether or not they got psilocybin just makes it really hard to rely on a subjective endpoint like how do you feel now?

And so this has really motivated a search of a lot of people for harder biological endpoints. And so the, the– one of the motivations for initiating this clinical trial looking at anhedonia as an endpoint is that we know a lot about the brain circuitry that underlies the response of both mice and people to things that are rewarding.

So maybe I should mention that anhedonia is one of the two cardinal symptoms of depression, depressed mood, obviously, but also the inability to respond in a way that feels pleasurable to things that ought to be pleasurable. If you are suffering from de– major depressive disorder you c– do not get the normal pleasure of a good meal, of time spent with your family a good movie, a good book.

All the things that give us pleasure in life f-feel unpleasurable to people suffering from anhedonia. And it’s also of the two symptoms, it’s one of the one– it’s the one that responds least to conventional antidepressant therapy. So there’s first of all a real need for better treatment.

But also I think the idea is that anhedonia can lead us to a much more objective measure. And the, the hope is that here at CU Anschutz that we will go on to, to take these positive anhedonia results and begin to look using modern functional imaging techniques to see whether we can detect a change in brain function that corresponds to the improvement in the reward function that people report.

If so, this would be a, an objective measure. That would be great. It’s not one that obviously can be used for treatment purposes and regular clinical practice but it will give us finally, I think, a way to surmount this, this problem of clinical trial design. Most clinical trials measure whether people thought they got the placebo or the psilocybin.

And in trial after trial, what is observed is that about eighty-five percent of people’s guesses are right, both on the clinical staff side and also on the subject side. So it is a real problem.

15:00 – Facilitator Support, Placebo Response, and Predictive Biomarkers

Dr. Scott Thompson: The other aspect the issues of clinical trial design is that because the response to psychedelics is so intense it would be unethical to not have a support, network built around the delivery of psilocybin in a clinical trial environment.

And the field has evolved to a sort of a three-step, process. There’s an initial preparatory session where where we explain to the subjects what’s, what they’re about to experience, how it’s gonna feel, how long it’s gonna last what they should do if they should lose control of their thoughts during the process, if they should start to have panic attacks.

We help them to understand what they’re about to experience. Then there’s the dosing day in which that same, person, we call them facilitators, sits with the subject while they’re experiencing their psychedelic journey. And is this there to provide support. If they should have a panic attack, we’re there to help them to get control of their feelings and thoughts.

It is not in any way a direct psychological, intervention in the way that the Lykos MAPS MDMA trials were. People who are experiencing psilocybin are generally have their attention focused inwards. They’re not really in a communicative state. They are mostly focusing on inner experience.

They come back for a third visit, which we call the integration session. They talk about what they experienced and how they’re gonna take that and move forward with their lives. So the point is that there is a lot of human interaction that the subjects undergo in these clinical trials. And that also has an effect, right? The the people that are trained to serve patients, they have a deep-felt need to make people feel better. And it just, it, you– the patients respond to that. They recognize it, and they respond to that even though we try to dial down the interactions as best we can.

So that’s another confound to doing these, psychedelic drug trials.

Dr. Ben Everett: Yeah, I think– so thanks for that very thoughtful and intentional answer. I think there’s several things I want to unpack from that. Certainly the functional unblinding has been a, a big issue, but it’s, like you say, it’s impossible to really address in a way that at least the FDA has been happy with so far. I like to look at other therapeutic areas. I’ve been fortunate to do drug development in a number of different therapeutic areas, and the idea of a placebo effect, even a nocebo effect is very marked across therapeutic areas. And I think it is because you have patients, you’re going into a clinical trial because there is something going on with your body that we don’t have a good enough option for right now. Otherwise, I don’t think many people would probably go into a randomized double-blind placebo-controlled trial. And the idea of hope and just the informed consent process, the amount of counseling, even if it’s for, a cardiology drug, the amount of counseling that goes into, “This is what we know about the drug.

These are the side effects you could expect to to have.” And we typically see placebo effects, even pretty marked ones a-across the board. I’m working in like rare neuromuscular disorders now and, have patients who get placebo who are best objective measures. They still show a pretty marked improvement.

But, to that point, I think beyond subjective into objective criteria is so important. If the more objective we can find things, even if it’s just for the clinical trial purpose that will not extrapolate to the regular clinic, I think is so important for understanding and frankly, being able to prove to regulators, yes, this is more than just, somebody having a psychedelic experience, in a dark room by themselves.

Dr. Scott Thompson: So I’m, yeah back to see what we’re doing at CU Anschutz here. There is a team led by my wife, Dr. Tracy Bale, and also our chair Dr. Neill Epperson looking at extracellular vesicles as a drug agnostic predictor of res- treatment response and and placebo response.

And the hope is that we will have then a, a blood-based biomarker for who is likely to show a placebo response and who is likely to show a drug response so that we can go in and design these clinical trials in a more effective way.

Dr. Ben Everett: And that’s great too because, years ago, back in the mid-2000s, I think the FDA put out a white paper inviting, drug sponsors or people doing INDs, investigational new drug applications. If we can have a biomarker that can somehow predict response or, predict or monitor treatment, like it’s all the better.

And we haven’t been that good really across all of medicine in necessarily coming up with biomarkers beyond, our kind of traditional ones. We’ve got, millimeters of mercury for blood pressure and A1C and these things for diabetes. But yeah, it’s, it gets much harder in psychiatry when, like you say, it’s, a, a lot of our questionnaires are built more around, how are you feeling now compared to previously?

20:00 – Building Safety Into Colorado’s Regulated Psilocybin Services

Dr. Ben Everett: Look, I want to turn to the Colorado’s National Medicine Health Act, which you brought up a minute ago. So i- if you can just talk a little bit more about the way Colorado’s law was done. I like that Colorado reached out to, a number of clinicians and scientists, experts in the area to help guide the regulation pathway. A little bit different from what Oregon did. But can you just explain to us a little bit about how it’s going so far? As a scientist, not as a healthcare practitioner, but, I was a little worried concerned might be too strong a word, about, it’s not a medical model.

How do we make sure we understand, history, physical comorbidities, what other medications a patient might be on? So just curious for your take on, how it’s going so far, and I think you’ve got a, a paper on this that might be relevant.

Dr. Scott Thompson: Yeah. As I mentioned in two thousand twenty-two, they decriminalized psilocybin immediately and they set about writing the regulations that would govern this regulated psilocybin delivery pathway. I have to give a lot of credit to the state of Colorado and its regulatory leaders.

They did it in an iterative way. They took a lot of comments from the community. They would draft legislation. They would listen to the comments. They would modify the regulations and listen again. And it took a full two years. And I think, a group associated with us at CU Anschutz here was very involved particularly from the point of view of safety.

The the voter initiative actually said that nobody should be denied access to regulated psilocybin services. And so that creates a bit of a problem. Of course, before they were called psychedelics, they were called psychotomimetics because the subjective effects of psychedelics in some ways, resemble the hallucinatory psychotic response of people suffering from schizophrenia.

And there, there has been a long-standing fear in psychiatry that psychedelics can promote the the appearance of schizophrenia-like disorders in people that are susceptible to them. If you talk to psychiatrists, they will tell you a lot of their schizophrenic and psychotic patients will track their first, psychotic episode to the use of psychedelics in their twenties.

So of course, it’s a little bit difficult to disentangle because that’s also when people are experimenting with psychedelics and also when they tend to have their first psychotic break anyway. And it’s like pizza and birthday parties and chicken pox outbreaks a little bit difficult to disentangle.

So we had a lot of interest in making sure that that there would be a very detailed screening process in place when people came into the Colorado Regulated Services, that they would be asked questions about their family medical history. Do you… Have you ever received a diagnosis of schizophrenia?

Has any in your– anybody in your family been diagnosed with schizophrenia? Because we know there’s a strong heritability — condition there. And really, we encourage people to not only ask that kind of a question, but also ask do you have, an Uncle Charlie who lives up in the woods and and, hasn’t had any contact with human beings for the last two months,” right?

It’s just warning flags. And I have to say that that the people that are administering this, these psilocybin services in Colorado here, the facilitators are incredibly thoughtful, caring people, and they’ve taken this, this understanding that we need to take care of our subjects to heart.

And I believe that they really do take this screening process seriously. It’s also mandated by state law that they do this, so they have an obligation to do it as well. Another thing that we recognized is that for some people coming into the regulated pathway, they’re gonna bring with them conditions that require some, some real experience in clinical care.

If you are a subject who’s coming to psilocybin with a history of sexual assault or domestic violence or any of these kind of conditions, it’s really important that the facilitator you’re working with has clinical experience in how to treat with these conditions. We always talk about psychedelics as opening up a, a window of neuroplasticity.

But of course, neuroplasticity has no valence. And we hope that and when the window is open, that good things will fly in and be encoded in your brain. But the chance that bad things happen too an insensitive therapist who doesn’t know how to handle somebody with those kinds of conditions and experiences could lead to actually harming the patient so we also built that into the process.

24:30 – Real-World Outcomes From Colorado and Oregon Psilocybin Clients

Dr. Scott Thompson: If you are dealing with these conditions then the facilitator should be a clinically trained person. So in the end of the day that the, the regulations were passed I forget, I think it was March of… I don’t know. I won’t say it ’cause I don’t remember when they finally came online. And I worked with a close colleague Niko Skievaski, at a company called Althea.

They’re providing back office support services for healing centers and facilitators in Colorado and Oregon helping them to stay in compliance with with the state regulations a-and other sort of services like that. And Niko agreed to help create a system where we could collect data on the experiences of people that have gone through the regulated pathway here in Colorado.

And earlier this year, I received from Niko this amazing spreadsheet full of data. We have responses from, I believe it’s two thousand three hundred and sixty-three people in Colorado and Oregon who have gone through the regulated pathway. And I spent a delightful several months f-forging my way through this spreadsheet pulling out all kinds of interesting correlations and really looking at outcomes and safety issues.

But also things like motivation. What, what drives people to to seek regulated psilocybin services. Now, as, as somebody with an interest in mental health, I assumed that would be the major issue. And so one of the first surprises we came across was that the majority of people are actually rep-reporting that they’re seeking psilocybin services not for mental health, but for personal growth, for spirituality, for improving quality of life just general wellbeing desires rather than mental health.

That said, there was plenty of evidence of mental health issues in our subject base. People reported lots of depression, anxiety. I think two-thirds of the people were actually under the care of a mental health professional at the time of they were seeking psilocybin services.

It’s not gonna be a surprise to anybody listening to this podcast that mental health issues are incredibly common in the community we we– What we observed was that the, the typical dose of psilocybin that people are getting through the regulated pathway is something like twenty-eight milligrams which is actually very comparable to the standard clinical trial dose of twenty-five milligrams.

That’s great. And then we were also able to look at at mental health outcomes. And so what we found was that for both depression and anxiety, that there was a s- statistically significant and robust decrease in depression as measured with the PHQ-nine and also anxiety as measured with the GAD-seven to standard psychiatric instruments used in clinical research.

And those– again, those events those improvements persisted for a full two weeks after the treatment period. And also, not surprisingly corresponding to that improvement in mental health conditions, there was an improvement in their well-being as reported with the WHO five questionnaire.

So that’s really great. We found a couple of interesting correlations that basically people who got doses of psilocybin less than thirty milligrams displayed the same improvement in symptoms as people who got doses more than thirty-five. And so that’s pretty interesting.

It suggests that that there may be a ceiling level of psilocybin that you need and there’s no reason to go to higher doses. You may be familiar with the expression of the heroic dose, and somehow this manly model that more is better does not seem to apply here.

28:00 – Dose Thresholds, MEQ-30 Scores, and the Evidence on Microdosing

Dr. Ben Everett: Yeah, that was Terence McKenna who heroically, termed the or coined the phrase heroic dose and it was, five grams of dried psilocybin mushrooms cubensis mushrooms. But, I think the standard sort of 25 milligram synthetic dose is supposed to be pretty equivalent to that, that five gram heroic dose.

Dr. Scott Thompson: We also noticed that we tracked people’s MEQ-30 scores on a standard instrument for measuring the intensity of the subjective effects. And what we noticed was that people’s, again, self-reported MEQ-30 scores plateaued at around thirty milligrams. And then we did not see any s-statistically significant increase in MEQ-30s at doses higher than thirty milligrams.

So that’s also a, a bit surprising, I think. Lastly, we did a correlation between MEQ-30 scores and improvements in depression and anxiety ratings on an individual level basis. And again, the hypothesis that most of us would have is that the, the more the, the higher the MEQ-30, the greater the improvements in mental health.

And that did not seem to be borne out in the data. Again our correlation coefficients were relatively low. And so there, there seemed to be, be… a relatively weak correlation. And so that suggests to me that maybe that there’s a threshold you need.

You have a threshold dose of psilocybin producing a, a certain level of MEQ-30 scores. And if you get to that level then you’re gonna be fine. You’re gonna– That display improvements. And that there’s no further benefits to be seen if you get a higher dose or report a higher MEQ-30 score.

So it’s not a sort of a standard dose response kind of curve, but maybe more of a threshold level that you need to cross to re-experience mental health benefits.

Dr. Ben Everett: Frankly, that might be the best data that has been released, at least to my knowledge now, on sort of the idea of the microdose, which is all the rage in Silicon Valley and communities as well. It comes up at every, conference I go to where there’s a section on psychedelics.

People are really interested in microdoses and I haven’t seen any data that says it’s really beneficial, but, I think that’s maybe more placebo effect. If you think it’s helpful.

Dr. Scott Thompson: So this is a little different than microdosing. This is a just single one milligram dose would be the lowest dose that we quantified. But I do have opinions on microdosing as well. There are now two excellent clinical studies that have been done with microdosed psychedelics in a placebo-controlled sort of manner.

And both of them have failed to show any difference between microdosed psychedelics and placebo. One of my favorite studies from Szigeti et al. Shows in fact that that some people benefit and some people don’t. It’s not psilocybin versus placebo, but it’s in fact who thought they got psilocybin versus who thought they got placebo.

Everybody who thought they got psilocybin, regardless of whether it was in fact placebo or psilocybin, reported feeling better. Everybody who thought they got the placebo, regardless of whether it was placebo or psilocybin, thought they did not get any better. There’s strong evidence now that microdosing is primarily a placebo effect.

As I said before, the placebo effect is real. The goal is to feel better, feel more creative, feel more relaxed, and if microdosing psychedelics is the thing that helps you get there, then by all means go for it. The only thing I would encourage people to be aware of is that in Colorado and Oregon and a few other states, psilocybin is legal.

LSD is not legal anywhere, so if you’re going to microdose something to avoid putting yourself in legal peril, I would recommend microdosing psilocybin.

Dr. Ben Everett: I’ll say I am aware of one small study of ADHD, I believe it was in Switzerland, somewhere in Europe, adults with ADHD, and it was double-blind, randomized, placebo-controlled. I can’t remember if it reached statistical significance, but it, by and large, there was a treatment difference, and I have some anecdotal N of 1 evidence on that.

And I’d say, know, you don’t always need your Adderall.

Dr. Scott Thompson: Yeah. There’s also a study that, what you might call a mini dose rather than a microdose. And again, I think the threshold is around three milligrams of psilocybin. Right at the point where people begin to be aware that they’ve taken a, a psychedelic compound.

32:00 – Running Schedule I Research: Regulation, Funding, and INDs

Dr. Ben Everett: Yeah. Look, let’s move on a little bit. So one of the things that’s really interesting from a research perspective, and frankly very difficult to do research, is that these are all Schedule 1 drugs. Psilocybin, LSD, MDMA, none of them are FDA-approved. So all of this happens within a Schedule 1 framework, which frankly is much, much more difficult than I think a lot of people might realize. So can you walk us through what is required to even attempt to do Schedule 1 research?

Dr. Scott Thompson: Well, from my perspective, what’s required is a good collaborator who’s willing to take on a task. And I wanna give a shout-out to my colleague Andy Novick, who did all the hard work. It was about two years’ worth of back and forth with the FDA with the DEA, with the university, with all the regulatory authorities.

And look, I think that the bottom line here is we all care very deeply about safety and we need to make sure that everything we do is… has the patient’s safety and the subject’s safety at the forefront. And so I don’t want to demonize that or diminish that in any way.

But it’s a lot of back and forth. One of the frustrations I would have is it’s everybody reinventing the wheel every time you study an– the same drug, but at a new site or with a different endpoint you have to go back to the very beginning and work your way down this long trail.

There’s a lot of things that are, again, done in the name of safety that might be done more efficiently, I would say. It takes a willingness to face that challenge to go forward with any of these clinical trials. I’m not sure that there’s anything we can really do about it.

They are dangerous drugs. They have cardiovascular effects. They have the interaction with potential psychosis risk. All these things need to be taken into account. And we as taxpayers and citizens and the FDA is our first line of defense, we need to make sure that people are not gonna be harmed by receiving these powerful compounds.

Dr. Ben Everett: Absolutely. And then funding is another issue. Certainly NIH funding has become more and more difficult more recently, and I’ll just leave it there. But, who have you found can fund this Schedule 1 work? Are you looking at NIH foundations, philanthropic, sources is working with a drug sponsor helpful for getting funding for these, or is it a little bit of everything?

Dr. Scott Thompson: I think it’s very sad that in fact, most of the work that has been done to date has been done almost entirely with philanthropic or commercial funds. There are so many things that we don’t know that maybe don’t have a direct effect on the pay line of some company’s, balance sheet.

But are in the public interest that we need to know. We talked about mechanism earlier. I, I think up until very recently, the NIH has been very reluctant to get into the psychedelic drug d-discovery– the psychedelic drug action space. I think they saw this as a domain where commercial interests could do all the work.

I think that shortchanges science and shortchanges the interest of the taxpayers in this country. We need to know more. Up until very recently, the NIH was very reluctant to lead here. And I think that there’s one of the few positive things to say about science in the last year or so is that the NIH, the FDA, the DEA seem to be stepping up their efforts and really finally taking a, an a major role in advancing the science of psychedelics.

So I applaud that.

Dr. Ben Everett: That’s excellent. All right, so let’s get specific about the difference between running an investigator-initiated trial versus participating in an industry-sponsored study. So what changes when your institution rather than the company holds the IND for the research program you’re doing?

Dr. Scott Thompson: Getting the IND, the investigational new drug stamp of approval from the DEA and the FDA is really one of the biggest hurdles that needs to be cleared. And part of that is a very rigorous examination– description of and examination of the research protocol. Exactly how are you gonna do what you’re gonna do?

What measures are you gonna look at to ensure the safety of the subjects in the trial? Those things. And one of the advantages of doing a sponsored trial by industry is that there’s a standardized protocol that they’ve already worked out. They will have will provide that to the investigators that will allow them to get through the faster.

It’s already been pre-cleared it’s already been run by the authorities and approved in many ways. And so everybody is doing the same thing. And essentially for all purposes, one approval for all.

36:30 – Safety Signals: Psychosis, Suicidality, and Adverse Event Follow-Up

Dr. Scott Thompson: So it’s fantastic we have real evidence of benefits from the regulated delivery of psilocybin here in Colorado and Oregon.

One of the biggest issues and one of the biggest motivations for collecting this data is that almost everything we think we know about psilocybin comes from clinical trial, studies. And clinical trials of course, are incredibly rigorous about their inclusion and exclusion criteria.

Who do we allow in as subjects? Who do we to ex-exclude, keep out as subjects? And so the criteria for a psychedelic clinical trial usually excludes people with family history of psychosis people with various cardiovascular risk factors all kinds of things like that. And here in Colorado we are, required to accept all comers into this regulated psilocybin pathway.

And it was really important to know how psilocybin does in the real world where anybody can be can receive psilocybin compared to a clinical trial where only the most narrowly winnowed fraction of people who might benefit are allowed in. And we– the state required that facilitators and healing centers report adverse events during the dosing session and also after the dosing session.

I have to say that the data was collected in a little bit of a, a way that’s less rigorous than it would be for a clinical trial adverse events collection process. And we examined what we had. It was a little bit incomplete, it was a little bit fuzzy, as I said and a little bit lacking in f- a, a, a lot lacking in follow-up.

And so really what we’re looking at, I think are safety smoke signals rather than actual the kind of hard data that one would really like to see. But on the whole, things looked good. There were a, a, a few people that came in who had reported previous histories of psychosis or family histories of psychosis previous use of antipsychotic drugs, for example.

And there was no evidence in the adverse data that we collected or in other indicators that there was any worsening of their condition or a revealing of a latent condition. So that’s reassuring, again, with the caveat that we only followed these people out for two weeks. Adverse events during the dosing session and afterwards were exactly what we had seen in rigorous clinical trials.

Nausea, headaches a little bit of sleeplessness perhaps. These kinds of things again, very mild, very transient. Most of them day of or day after, but not persisting in any We didn’t see any evidence of of reported persistent hallucinatory responses, things like that. And lastly, one of the, one of the, the biggest issues of concern, of course is suicidality.

Anytime you’re dealing with people who are depressed there is concern that that they will become suicidal or their suicidal thinking will be accentuated in some way. Of course, rigorously studied in clinical trials. And we have a lot of data that, that speaks to suicidality here. The good news first we didn’t see any particular evidence of increased suicidality.

Most of the people who reported suicidality at baseline reported no change or a decrease afterwards. There were a handful of people, though, that reported no suicidal thinking beforehand that had a low level of suicidal thinking after their psilocybin response. So that’s extremely concerning.

Again, one of the biggest flaws we have is that that we don’t have a lot of follow-up. So for example one of the things that we were very interested in is the use of the emergency medical service system. So a lot of the opponents of psilocybin services said in the run-up to the initiative that, “Oh, this is gonna create an incredible burden for our emergency medical providers, and that it’s gonna drive up your taxes.”

We found very little evidence that EMS was called. One person reported an EMS call. One facilitator reported an EMS call. It turned out the patient was experiencing kidney stones while under the influence of psilocybin, which is the worst kind of trip I could possibly imagine. There was– And then there was one other incident where the subject reported that they were having a heart attack, or the facilitator reporting that the subject thought they were having a heart attack.

They were put in an ambulance. They were sent to the hospital. But again, we have no follow-up. We don’t know, was it really a heart attack? Was it a, a feeling of chest pain because of an extreme anxiety response? We just don’t have any way to know. We don’t have any follow-up from the hospital where the ambulance delivered the patient.

We don’t have any way of tracking that subject through their hospital system to know what became of them. And so one of the strongest recommendations that comes out of our work is that the state should be doing a better job of follow-up and tracking adverse events.

We need to s- to strengthen this system.

Dr. Ben Everett: I’d say especially when it’s a serious adverse event like a, a probable, or I should say possible or probable heart attack. And not to diminish that event might have happened, but also in the context of psychedelics, there are often somatic manifestations that patients have that, can just be related to them processing their journey and going through some kind of, psychological I don’t want to say reset, but just a process.

These things happen even when people do breathwork, you hear about these types of things. Yeah. But it seems like some yeah, additional follow-up, especially if there is a possible or probable serious adverse effect would be a good amendment to the to the legislation. I am curious if you’re able to look at the data, ’cause you mentioned the low level some patients have a lower level of suicidality after their event. It would be curious to know for me if that’s like within twenty-four to forty-eight, maybe seventy-two hours afterwards versus a week to two weeks. Because, the flood of serotonin that happens while the patient is dosed and in this non-ordinary state of consciousness can come very often with some depressed feelings the next day just because your body needs to reset after this flood of serotonin.

Dr. Scott Thompson: Yeah, there’s physiological responses for sure. There’s also psychological responses. You could have experienced under the influence of of the psilocybin some, confrontations with issues that you have from your past your childhood, your parents your current situation.

All kinds of things can come up under the influence of psychedelics and they could, be an uncovering of something, extremely, neg-negative emotions in those subjects that could cause this kind of a feeling of increased suicidality afterwards. Again we need better data.

We need better follow-up.

43:00 – Blocking the 5-HT2A Receptor: Is the Trip Necessary?

Dr. Ben Everett: See, this is why it’s so great that we have real scientists and clinician scientists thinking about these problems and working hand-in-hand with regulators to make sure they’re addressed appropriately ’cause safety is paramount. Look, I’d like to shift a little bit now into this idea of, is the experience the medicine?

This is always a fascinating conversation at conferences. Know where my hypothesis is on this, as well as a number of the names you mentioned already have talked about this, Robin Carhart-Harris famously, among others. But, your lab actually published a paper in PNAS showing that in mice, the antidepressant-like behavior and synaptic effects of psilocybin persisted even after the 5-HT2A receptor was blocked with ketanserin. So in other words, you took away the signal that we would associate with the trip in the animal, and the therapeutic signal was still there. So can you walk us through that study? I remember when it was published, I read it with great interest.

Dr. Scott Thompson: Yeah, so this, that, that study came out of c-came out of the point that I made earlier that, that we had, we’d come from studying the action of SSRIs and looking at serotonin-dependent effects on synaptic plasticity, neuroplasticity. And in that work what we found was that SSRI responses, neuroplastic responses were independent of 2A receptors and involved, in fact, the 1B receptor.

And so then when we started to think about psychedelics, we started to think about them as essentially a, a supercharged version of an SSRI the, the analogy I like to use is your grandmother’s Subaru, right? Your grandmother can get in her, nineteen ninety-two baby blue Subaru, and she can drive across downtown and she’ll get to the other side, but it’ll take her a long time because she’ll be five or ten miles under the speed limit.

She’ll stop when the light goes yellow and she will drive very cautiously and carefully. But she will get to the other side even if it takes her a long time. If you put her grandson in that same car he will get across town much more quickly because he’ll be driving much faster. He won’t be stopping for yellow lights.

And it’s the same Subaru but but the grandson will get to the other side more quickly. And so that was our working hypothesis at the outset, is that, that psil- psilocybin and other psychedelics do what SSRIs do. They just do it more potently and more quickly. And so we went into it with the hypothesis that it– well, if the 2A receptor is not necessary for the action of SSRIs, and there’s no reason to think that it is people do not experience any psychedelic subjective effects even if they swallow a whole jar of Prozac.

And so I think everybody can agree that SSRIs work in a way that is independent of 2A receptors. And so if psychedelics share any of that mechanistic action then you might think there might be at least something that they do that would also be independent of 2A receptors. And so as you mentioned in that study, we found that you could com– you could block the 2A receptors and retain both behavioral therapeutic-like response in mice to psilocybin and also the physiological, biological strengthening of synaptic transmission in a way that was independent of 2A receptors.

Now that’s goes against the dogma in the field. Of course, anybody who’s ever taken a psychedelic will tell you that it is one of the most powerful and unique and meaningful and spiritual experiences that they’ve ever had in their life. And that feeling is almost certainly due to the ability of psychedelics to activate the 2A receptor.

If my, my good friend Franz Vollenweider was the first to show that if you gave that same drug ketanserin to people that were taking LSD or psilocybin, you could completely block the subjective effects. So we know beyond a shadow of a doubt that subjective effects are mediated by 2A receptors.

And so the, the short answer is we still don’t know the answer to the question in human beings. There is a clinical trial that’s been going on and my understanding that the results are about to be revealed looking at the ability of of atypical antipsychotics, which have a strong 2A receptor antagonistic, potency whether they block the subjective and therapeutic actions of psilocybin in depression.

47:30 – Cost, Access, and Shorter-Acting Psychedelics

Dr. Scott Thompson: So stay tuned for that. I will hesitate my bet until we, till we have those data. But it’s at least a, it’s at least an arguable hypothesis. And there’s some benefits to thinking that wouldn’t it be great if we could dispense with the 2A receptor? I think one of the issues on which psychedelic medicine is going to potentially founder in the coming years is the incredible expense that’s involved with treating people with psychedelics directly r- arising from the subjective effects.

You need to have two people sitting with you for eight hours day while you’re taking your psychedelic. That means you’re also losing a whole day of work while you’re undergoing your psychedelic therapy. And then these are costs that fall on the subject.

Ultimately, if these drugs get FDA approved, they’ll they’ll fall on the healthcare providers and the insurers and ultimately the taxpayers. And so this is a real issue of, I would say, access and equity. Not everybody is gonna be able to afford what it costs to receive an FDA-approved psychedelic.

Not everybody can afford to go through Colorado’s, regulated, psilocybin services even. And so there are real challenges here. And if we could dispense with the trip, we have the potential to lower the burden and increase access. So stay tuned for that. There’s some really exciting, work going on in the commercial drug development space as well.

People are working on, whether, psychedelic compounds that have a shorter duration of action would also induce, therapeutic benefits. And so there’s some work with DMT and other analogous compounds. Some early-stage work that I’ve seen, from the, company GH Research, shows that an inhaled form of DMT, produces a trip that lasts for eleven minutes, but produces therapeutic benefits that seem, pretty comparable to those seen with a full day of psilocybin dosing.

Again, early days for these kind of compounds, but imagine that you could drop your kid off at school go in, get your DMT therapy, and be back in time to pick them up at lunchtime. This is a hope and correlating with that is gonna be a lower cost effect.

Dr. Ben Everett: Yeah, you really hit on a couple of key things there. And we’ve had guests on to really try and get to some of the economics and just how difficult these are to do. E-even in a clinical research mechanism, and this is a lot of the work that I was leading at Lykos, was just trying to get people to think about, and the payers in particular, to think about, w-what kind of burden this might place on, on, on the healthcare system when you’ve got to have two, licensed therapists or healthcare practitioners in the room, and we already have a shortage of licensed healthcare mental health therapists and people who might be willing to do the work. And then there’s also this idea that not everybody is good at this work, which you indicated earlier. We would spend a lot of time ensuring that the people that we had in the room with dosed patients were the right people that could hold the space, not really try to direct the therapy, but were really there to hold space help ensure that the patient was in a safe place, and then when appropriate, or if appropriate, direct the patient back inward, and maybe, this is about you.

50:30 – Receptor Promiscuity and Non-Hallucinogenic Compounds

Dr. Ben Everett: So it’s– I think it’s fascinating. Yeah, and then I know your lab has been working on some of these non-hallucinogenic psychedelics. Can you speak a little bit about some of the work that y’all are doing in particular?

Dr. Scott Thompson: We’ve looked at a, a couple of non-hallucinogenic a particular non-hallucinogenic psychedelic compound in mice for what that’s worth. And it’s important to note that these drugs are very promiscuous drugs. They activate a lot of different receptors. And you’ll often see written that psilocybin is a potent two-A receptor agonist which it is, but it’s also an agonist at about thirteen other serotonin receptors.

And so we know that the two-A receptor is necessary for the subjective effects, but we don’t know what psilocybin is doing at all those other twelve serotonin receptors and which one of those might be critical or contribute to a beneficial response. I don’t wanna imply that the, the subjective effects are not in some way beneficial.

They are. Certainly I guess the most responsible thing I could say is that the combination is the most effective. A synergistic maybe let’s simplify it as a biological mechanism, a strengthening of synaptic communication together with a psychological mechanism, facing the challenges of your your upbringing and your experiences going through them to get past them those kinds of things.

They’re bound to be synergistic. If you are more neuroplastic and you are dealing with issues that you’ve been avoiding the two things are gonna combine to, to leave you feeling better after the experience, one of the pieces of evidence that is often held out as evidence that the two-A receptor is necessary is that a correlation between therapeutic benefits and the intensity of the subjective effects.

As I mentioned, we didn’t see a strong correlation in the Colorado regulated psilocybin pathway, but it’s been pointed out from various clinical trials from people. But what I wanted to remind people of a pharmacological bent is that it’s proportional two-A receptor agonist activity is really proportional to how much of the psilocin, the active compound of psilocybin, how much of that psilocin actually got into the brain.

And so when you have a stronger subjective effect, yeah, that means you got more two-A receptor two-A receptors activated, but it also means that all thirteen other of those serotonin receptors were also more strongly activated. And so a correlation is not causation, and certainly in this case, that’s a, a flawed argument.

Dr. Ben Everett: I think you mentioned atypicals and this study going on with atypicals and I can’t remember if you said psilocybin or LSD. But yeah, the a-atypicals are also pretty promiscuous, not just at serotonin, but at different dopamine receptors, histamine receptors, alpha receptors. And so sometimes it can be difficult to tease out in a very clear scientific way, right?

You do your, your one-way ANOVA versus your multi-ANOVA type of analysis variance types of a-arguments. But yeah, at the end of the day, it’s very difficult to say. And also, both things can be true, like you said. Some people might enjoy the psychedelic effect and still get some meaningful benefit beyond that from activating other receptors.

53:30 – The Role of Psychotherapy in Psychedelic Treatment

Dr. Ben Everett: Look, I’d like to turn to therapy and the idea of therapy during or in combination with a psychedelic experience. And this has been a hot button i-issue that’s come up, and I know there are different thoughts on this. Compass, famously started with therapy and then pivoted away from therapy. And frankly, also as part of the FDA’s comments and comments from advisors at the Lykos advisory committee meeting, I think it actually scared some of the some of the drug development companies maybe away from psychotherapy. So I just, how do you think psychotherapy fits with this?

I know that there is like Barbara Rothbaum’s got some interesting data coming out on using prolonged exposure in dosed patients with MDMA and PTSD. There are others looking at like CBT in, literally in combination with a dosed patient. So I’m just curious how you think of psychotherapy in this, space.

And, is just taking the drug and having the experience enough, or are the post-dose integration sessions, know, a-as equally important, more important, maybe not as important, but, are they important, period?

Dr. Scott Thompson: So it’s a really important question, and I have many thoughts on that. They are thoughts. They are not, We don’t have the data that we need to really answer this question thoroughly, so this is more intuition. And I think my thinking is in line with most people in the field. There’s something about– something biological about the opening up of a neuroplasticity.

The possibility that you can learn something is increased by the presence of psilocybin. But then the question is what does… And again, neuroplasticity is just a, a framework. And then what is being encoded by that neuroplasticity is really where the, the therapeutic aspects come into play, I think.

Certainly in all the clinical trials and in all the healing centers, we direct people to focus their attention inward, to let their thoughts take them where they will. And I think that, that brings people to places of challenge and helps them to overcome challenges. And chicken and egg, really.

And I think the answer is synergy for sure. We know that talk therapy alone works. Having gone through talk therapy, I can tell you it works. I feel I’m a better person for it. I can also tell you it took a lot of years and a lot of blood, sweat, and tears. And so maybe if we go back to Grandma Subaru analogy then maybe talk therapy is like grandma riding her bicycle across town, right?

You can also make it across town, but it’s gonna take a long time. And there seems to be something magical, biological about psychedelics that, that help to speed that journey. So synergistic. Now, we don’t have any data to show that and here’s a place where I think the federal government’s response has been a little bit of a, a mixed message.

The, the FDA has held out very strongly that we should know more about the importance of psychotherapy. Is it is it dependent on a particular type of psychotherapy? Is it dependent on a particular amount of psychotherapy? Or is it all about the drug, right? And that’s been a challenge for commercial developers notably MAPS Lykos and now Compass has dealt with it, as you said, by just trying to dial down the psychotherapy to, to the bare minimum.

It’s a place where we don’t have data. Nobody has done a trial where they compare the efficacy of psilocybin plus very intensive psychotherapy versus minimal psychotherapy where you might be able to tease that kind of effect out. This would be a place where I think the, the NIH could really be sponsoring some good scientific research there that would fall out of the, needs of a commercial drug development, but would tell us a lot about the, the science behind behind these effects.

Dr. Ben Everett: Yeah. I think that’s so true. And yeah, my own journey with psychotherapy mirrors yours. Yeah, it’s– it, I think anything that we could find that would maybe accelerate the therapeutic process, and that’s one of the things that came out again anecdotally just talking to therapists who participated in our study, was a lot of them would say things like, “Yeah, I felt like I was able to do…”

And this is in the integration sessions, let’s say after week one. Yeah, it was, typically it would take a year to get this far with a patient with PTSD. And then some disorders like PTSD make it– the disease itself and the patho- pathophysiology in the brain frankly just makes the evidence-based therapies just very difficult for a lot of patients. And again, it comes back to a- to access because not everybody has access to a good, therapist. And so I think there’s so many different things that we can potentially address with psychedelics here in the coming years, and I’m very excited for that. So.

Dr. Scott Thompson: Yeah.

Dr. Ben Everett: Well, look.

Dr. Scott Thompson: There’s some really interesting clinical trials going on outside of the depression space. I’m sorry, I’m depression-centric, and so I always go there. But there’s a lot of fantastic work going on with PTSD now, where we have evidence-based psychotherapeutic approaches, CBT and some of these other things.

And there’s people doing very careful clinical trials now to look and see whether psilocybin can catalyze and accelerate some of the benefits that we know happen with things like CBT. Stay tuned for those results.

Dr. Ben Everett: Yeah, I think it’s fascinating, and that was actually exactly our thought on the process at Lykos, and I would frequently say, we feel like the drug is a catalyst to the therapeutic process, and having the right skilled people who understand trauma-based approaches to care and, are just the most incredible empathetic humans, that was really a very important part of the whole process. But from an FDA standpoint, then it’s okay, how do you tease out? This is sort of the multifactorial approach. What’s actually getting the benefit? Is it the drug? Is it the therapy? Is it a combination of the two? And again, that’s difficult to prove in a rigorous trial type of manner.

59:30 – Definium’s DT120: Phase III Data, Payer Realities, and Dose Selection

Dr. Ben Everett: So well, look, I’d like to spend the last little bit of our time together talking about a couple of programs that are maybe on the ascendancy. So I- I’ve had many guests on. We’ve talked about ketamine and esketamine. We’ve talked about Compass and psilocybin a good bit. But I’d really like to focus in on Definium and then Beckley Atai’s program with GH looking at 5-MeO-DMT. So if we can talk a little bit about DT120 first and I should say DT120 OD because they’ve gone to that formulation, OD meaning or- what, orally dis- disintegrating tablet. But DT120 is LSD, right? And they’re looking at this form of lysergide or LSD in both MDD, so not treatment-resistant MDD, like what Johnson & Johnson looked at with esketamine’s Spravato. So they’re looking at MDD and GAD. It’s been a very busy year for the program. They’ve now reported three separate positive Phase III readouts EMERGE, which was an MDD, VOYAGE and PANORAMA, which were in GAD. I believe they have one more in MDD that needs to read out. So at a high level, can you walk us through what’s going on at Definium?

Dr. Scott Thompson: Yeah, I think the results that Definium has shown with their their compounds are incredibly exciting. They’re very positive. They are in line with analogous trials with psilocybin. And given what we know of the pharmacology of LSD psilocybin there’s enough overlap it makes sense to me that both would be effective.

How that’s gonna play out in a commercial mar-market, I have no idea. Beyond my skill set, but the results are not surprising to me. And I think they’ve done an excellent job running very careful, rigorous clinical trials. It’s a I’m glad that they’ve taken, their compound also into the study of depression.

It’s been one of the curious things for me that, On this side we have, MDMA that’s for PTSD, we have psilocybin for depression, and we have LSD over here for anxiety never the three of them should cross. So I’m very glad that they’ve shown good results for MDD as well.

Dr. Ben Everett: I’m curious on your thoughts on MDD versus TRD and LSD.

Dr. Scott Thompson: My, my understanding i-is that’s really more of a question about market share getting into the marketplace. How are patients gonna think about this? How are payers gonna think about this? I don’t think it’s so much about the neurobiology. And I think the reality is that the payers are always gonna say you should try these this Prozac for pennies a pill and its cousins before we go on to administering a psychedelic in a day-long three-session sort of paradigm,” right?

The numbers that are being thrown around for for Compass when they release their psilocybin product are three visits at twenty thousand dollars a pop over a year. No payer is gonna look at that and say, “Yeah, we can just– we can skip over Prozac and go straight to a psychedelic compound.”

Just it’s not gonna happen, and it doesn’t really matter what the biology says or not, right? You might, as a psychiatrist, think that my patient is gonna really benefit from a psychedelic but a payer is not gonna see them the same way as you do.

Dr. Ben Everett: It’s not even $20 because I looked this up when I was at Lykos, and the, some of the things that we were thinking through, the, what we call the, the WAD, the wholesale… Or I’m sorry, the WAC, the wholesale acquisition cost for the SSRIs is about 60– Oh, excuse me, about $6, not 60, $6 for a 30-day supply. So yeah, there are gonna be some real, I think we’re gonna need real good real-world evidence and some good health outcomes research health economic models, and those things to follow patients in the real world to see, i-i-if it’s different. And I think the durability data is gonna be really important also.

Dr. Scott Thompson: I can imagine a future the path is you’re gonna go on, two SSRIs two doses. So maybe it takes you four months, five months and then you’ll be cleared to get either Spravato or psilocybin or, lysergide or any of these other compounds, right? I think we can streamline the path because let’s acknowledge the difficulty, right? You’ve– your loved one is depressed. You finally convince them to go for help. They get seen by a doctor. They get a diagnosis of depression, and then they’re given a dose of Prozac, and they’re sent back and say, “Come back in six weeks and tell me how you feel.”

And you come back, and I’m not better, doc.” And, “Okay, then we’re gonna double your dose and come back in another six weeks.” And then, “I’m still not better.” And that, that’s an unbearable burden for patients. And we need to dial that down as much as we can within the confines of the American medical system.

Dr. Ben Everett: Yeah, and it’s challenging to think about how to do this in a more maybe equitable and faster way because when you’ve got a patient suffering the whole time and sometimes it’s just okay we didn’t get you on the right dose first and it’s this journey of, you have to fail.

Okay it’s, two adequately dosed and what it’s adequately dosed and the length of time, so two adequate trials is typically what we look at in psychiatry. Yeah, but that’s just difficult for a lot of patients to do, and then you can say in the backdrop of people changing insurances over 18, every 18 months and it’s difficult to document from payer to payer.

And so there’s a lot that I think could be improved upon here. If maybe one more question on the Definium program. So in their early dose-ranging studies, they found that it was the 100 milligram dose that, that really showed the clinical benefit, and these are early, phase II PK/PD studies generally.

But the 50 milligram dose didn’t really do anything. They decided to include a 50 milligram arm as well as a 100 milligram arm and a placebo arm in some of their secondary trials for MDD and GAD. I’m just curious if you have any insight on what’s the purpose of throwing a 50 milligram, dose in if your own dose escalation work showed it didn’t really do anything?

Is it trying to be an active placebo where they… And you might not know. I’m just curious.

Dr. Scott Thompson: I think anybody that’s in the pharmaceutical drug development space likes to think that their novel compound is gonna display a, a nice dose-response relationship. And so the, the… then the question is, what is the right d-dose to get the, the response that you need? And so I would give them credit for exploring the dose space as carefully as they have.

The what they haven’t reported yet is the relationship between those doses and the subjective effects that they produce in the patients, right? Again, if we think the subjective effects are necessary and beneficial does that account for why one dose would be effective and the other one would not?

Or in fact, if on average, are people’s subjective experiences the same then maybe then you would choose to go with the lower dose. I give them credit for doing a thorough job and doing it carefully.

Dr. Ben Everett: I agree, actually. So even though my setup was maybe not that friendly about it. No I think it’s always good when we have options, right? I think options for patients and providers are really good. So maybe someone, based on data that we get later, maybe someone is maybe not as good a candidate for the 100 milligram dose.

There can be some hesitancy ’cause even in our trials at Lykos, we started the first day was a lower dose of MDMA, and then doses two and three, the patients were invited but did not have to escalate the dose. So I think it’s really important also.

Dr. Scott Thompson: I recall sitting here today the data that Definium attained was very comparable to the Compass dose response data as well there. They did one ten and twenty-five, to the best of my recollection.

Dr. Ben Everett: I think that’s.

Dr. Scott Thompson: They showed that both twenty-five and ten were superior to one, but they did not report a difference between twenty-five and ten.

And I think that’s where Definium ended up as well. I don’t remember very well.

01:07:00 – Beckley Atai’s 5-MeO-DMT and Other Short-Acting Compounds

Dr. Ben Everett: That’s good background for me ’cause I don’t have a lot of insight into the inner workings of those programs. All right look, let’s switch over to, Beckley Atai or Beckley Psytech and Atai Life Sciences. I think most of us in this space just say Beckley Atai. But they’re looking at this intranasal form of 5-MeO-DMT, which is, famously the frog toxin DMT. It’s intranasal. And DMT, very interestingly especially this formulation of the 5-methoxy-DMT, is very rapid. It’s about a five-minute experience typically. So I’m just curious your thoughts on this program and anything you can tell us about it right now.

Dr. Scott Thompson: Yeah, I think the excitement here is that these DMT compounds offer a way to shorten the psychedelic experience, a way that may lower the barriers that we talked about earlier, economic and time intensity. The challenge the flip side of that coin, though, is that these, drugs come on very fast.

They produce very rapid and very intense subjective effects. The downside of that promise is that, they may be too intense for a lot of people to bear who might benefit from a psychedelic experience. And so I think we’re really gonna have to see more how this plays out once we get closer and closer to real-world populations.

Many of these, DMT companies, GH Research and Atai Beckley have been working on ways to, lower the slope of the onset of the effects, and prolong a little bit the decay of the effects in a way that may make them more tolerable, less terrifying for people that are taking them.

There’s a lot of excitement, a lot of promise there, and there’s a lot more that we need to see, I think.

Dr. Ben Everett: A- and I’ll note that the 5-MeO-DMT also has very strong serotonin 1A receptor activity. And so maybe we get a little bit more lens into, the pharmacology aspect of it, at least from this drug.

Dr. Scott Thompson: I should– Yeah, we should also mention perhaps the the Delix compound Zalsupindole, if I can say that correctly which is another short-acting, fast-acting non-psychedelic compound. They have also shown some very early-stage results, open label trials looks incredibly promising. One of the exciting things about their compound to me is that it has almost no appreciable 2A receptor activation.

Again, really exciting things happening all over this space right now.

01:09:30 – Clinical Takeaways

Dr. Ben Everett: Look, you’ve been very gracious with your time this afternoon. I appreciate that. If there’s one thing you want a, a clinician who’s practicing right now to take away from today’s episode, maybe what would it be?

Dr. Scott Thompson: I think keep an open mind to the promise of these compounds. Again, with psilocybin, we have a good awareness and understanding of the safety profile right now. And I think with proper guardrails and an abundance of caution I think that the promise is starting to outweigh the risks that we had feared at the outset of this journey.

And so keep an open mind. Wait for the data, look for the data and start to imagine this as a form of medicine like every other medicine in your toolkit that can produce benefits. A little more scary, a little more problematic but nevertheless when the goal is to make people feel better this may be the best option that we have.

Dr. Ben Everett: Dr. Thompson, with that, I’ll just say this has been a fantastic conversation. I’ve really appreciated it. We started in Switzerland, we finished in Colorado. We talked about operational realities, mice, academic research, the question of the, is the experience necessary, which is a very hot button philosophical topic.

And really, I just want to thanks for your time again and your expertise in this area. Congrats on all the work y’all are doing in Colorado. I really appreciate you coming on today.

Dr. Scott Thompson: Thank you very much, Ben, for having me and giving me this opportunity to have this important conversation. And thank you to the journal for supporting this podcast as a way of getting the good word out there.

Dr. Ben Everett: Absolutely. This has been the JCP podcast, insightful, evidence-based, human-centered.