Cybin Inc. (HELP) Earnings Call Transcript & Summary

Good morning, everyone, and welcome, and thank you for joining us today. It's my pleasure to be joined today by two eminent professors, Dr. David Nutt and Dr. John Krystal. Before I introduce John and David, let me quickly provide a short introduction to Cybin. Cybin is a mental health company, taking a derisked approach to new product development. We're doing that by leveraging decades of scientific research into classic psychedelics, such as psilocybin and DMT. Our goal is to retain the receptor binding profiles of psilocybin or psilocin and DMT while improving their pharmacokinetics. In other words, we're not looking to alter where or how these modules work in the brain, but rather to make how these molecules get in and out of the brain more efficient. And the purpose of this is to create highly efficacious molecules that have a fast onset; a short duration; low variability, making them more predictable; and improved bioavailability and brain penetration. Our lead asset, a generated psilocybin analog, or CYB003, has a pending IND with the FDA to start a Phase I/IIa repeat dose placebo-controlled study in major depressive disorder patients this summer. We expect preliminary PK data around the end of this year, and we're hopeful that this will validate the significant advantages over classic psilocybin that we've seen in our preclinical work. Our deuterated DMT CYB004 program has a Phase I DMT study underway in healthy smokers that we expect will provide us with meaningful dose ranging and dose optimization data to inform dosing of CYB004 before. Given these 50 healthy subjects are also smokers, we may also see some efficacy signals. And we expect the last subject in that study around the September, October timeframe. So we're excited to have four sponsored human trials underway this year, marking a significant transformation of Cybin into a multi-program clinical stage pharma company. Now let me introduce our panelists today. Dr. John Krystal is Professor of psychiatry, neuroscience and psychology and Chair of the department psychiatry at Yale University. Dr. Krystal is an expert in the areas of alcoholism, PTSD, schizophrenia and depression. Notably, his lab is known for discovering the rapid antidepressant effects of ketamine in patients with depression. He is also Chief of Psychiatry at Yale New Haven Hospital, Co-Director of the Yale Center for Clinical Investigation and Co-Chair of the Neuroscience Forum of the National Academies of Science, Engineering and Medicine. Welcome, John.

Thank you.

Dr. David Nutt is Professor of Neuropsychopharmacology at Imperial College in London, and since 2021, also Chief Research Officer of Awakn Life Sciences. As an expert in psychopharmacology, Dr. Nutt's research contributions include GABA and noradrenaline receptor function in anxiety disorders, serotonin function in depression, endorphin and dopamine function in addiction and the neuroscience and clinical utility of psychedelics. David has been President of the European Brain Council, British Association of Psychopharmacology and the European College of Neuropsychopharmacology. And he's Founder of the Charity Drug Science. Welcome, David.

Okay. Let's get into some of the questions. Perhaps we'll start by talking about the general psychedelic landscape. Maybe David, we'll start with you. Maybe you can walk us through the current mental health crisis and why you think psychedelic space therapeutics may be a revolutionary way to treat people suffering from some of these conditions. David, can you hear?

Yes. Sorry, Doug, you froze for a second. Did you ask me a question, sorry?

Yes, David. Sorry, I think the connection's a little bit on and off. So I was just starting -- we're talking about the psychedelic landscape. And maybe, David, you can walk through the current mental health crisis and why psychedelic-based therapeutics might be a pretty revolutionary way to treat some of these conditions.

Well, that's right. I mean I think psychedelics -- and I have to give John a credit here because in this context, he really is the pioneer because ketamine is a sort of psychedelic. And ketamine really was the drug that made us all begin to think there might be different ways of treating disorders like depression and addiction. And until -- it was thought that depression could only be remedied by drugs, which would take weeks to work. And of course, these are very well-known drugs like the SSRIs and tricyclic antidepressants. But it turns out that you can lift depression really quite quickly. And that, I think, is the biggest innovation in psychiatric research and clinical practice really since the 1950s when both antidepressants and antipsychotics were discovered by serendipity. So I think we're on the cusp of a new very exciting wave in terms of the treatment of many mental disorders. And is that needed? Well, that is very definitely needed because even before [Audio Gap] I just hope that the energy that the Western world put into fighting COVID will now transmit or be transferred into energy to help us develop, accelerate and speed through the development of these new treatments because they're very sorely needed.

Yes, I can't agree more. Maybe, David, you could just add, how are these -- how psychedelic is different from current treatments like SSRIs? I think we've lost David. Okay. Maybe John, we'll move over to you while David sorts out his connection. I mean you know the space well. What do you think are some of the most exciting and novel approaches that the industry is currently taking on the approach to mental health conditions with psychedelics?

Sure. Doug, maybe it would help if I just back up to cover a little bit of the end of what David was trying to communicate about the opportunity here about the unmet need and then talk about how some of the psychedelics might address that. And if David rejoins us, then he can pick that up. The STAR*D study showed us that our available medications are not as effective as we'd hoped they would be. First, many patients don't respond to them. Second, it can take -- in those people who are fortunate enough to remit during antidepressant treatment, it can take 2 months to get that remission on average. And then people who obtain a response have a high likelihood of relapsing over time. So the met need in mental illnesses like depression is tremendous. The situation in some ways is even more dire for disorders like PTSD and alcoholism. In PTSD, we just have two FDA-approved SSRIs as treatments in the United States. And for alcohol use disorders, we have two medications that are approved, but both medications have limited efficacy. So there are tremendous unmet needs for the disorders that we're talking about today. And psychedelics, and I'm going to use two different words, psychedelics and entactogens. Psychedelics for drugs like psilocybin that alter perception and entactogens for drugs like MDMA that do not. Both of these classes of medications are -- seem like they're showing very promising effects in clinical trials. In psychedelics, we have seen recently positive results for major depression and some encouraging results emerging from alcohol use disorder, other substance use disorders that are being studied, as you mentioned. And also these very interesting applications, which traditionally don't need any specific diagnosis, are significant life issues like end-of-life emotional distress. MDMA has been also shown promise as a treatment for PTSD. So the psychedelics are carrying the potential to treat disorders where we know there is substantial unmet need. But one of the exciting parts about these treatments is that they seem to work very rapidly, they can be dosed very infrequently in these clinical trials, and the results are overall quite encouraging. So I think this is a very exciting time.

So that's interesting. You mentioned the different classes of psychedelics there and entactogens. And maybe now that David's back. David, when you think about these different types of molecules, tryptamines versus, say, the phenethylamines or ergolines, do you believe that certain psychedelics are more effective than others or may be more suitable than others?

That's a really interesting question. I know it's a bit early to say, but they're clearly different. I mean that is -- so it's quite exciting, isn't it? We've got compounds that have really short half-lives and we've got -- like DMT and 5-MeO-DMT and then we've got compounds like LSD and [indiscernible], have enormously long half-lives. And what I find really quite fascinating is to work out what -- we've got all the options now. We just need to do the studies to find out which is best. And I mean, up until now, I think most people have assumed that at least a moderate duration of a psychedelic effect would be necessary to have a benefit. And that's why most of the work has been done with psilocybin because it gives a trip of sort of about 4 to 6 hours, which can be contained within a clinical session without having to keep people in overnight. But it's completely possible. And if it turns out to be true, then it will be even more revolutionary. That shorter-acting ones, like DMT might perhaps a kind of reset button in the brain and produce equally good effects. And let's remember that ketamine from John's work, ketamine, one of -- normally, the effect is given for about 1 to 2 hours. So they get antidepressant effects quite quickly there. And so that's the first variable, the kinetics. And of course, we can adjust those in several ways as Cybin is doing it, adjusting them with [ buterium ]. But we can also adjust them by being blockers and some of the companies working with the longer-acting drugs, particularly LSD are thinking about terminating the trip after, say, 5 hours by giving an antagonist, and we know there are plenty of these around. They're easy to come by. Many of them are in clinical practice. Stop the treatment with a drug like [indiscernible] restore them quickly. So that's that possibility. But then the other side of the coin is not just the kinetics. Well, what about the pharmacodynamics? I mean one thing is certain that many people who use these drugs sort of self-exploration of their mental states comment on their very -- they're quite different. And we've certainly found that in our experiments. People actually have subjectively somewhat different experiences, even though our brain imaging studies show that the brain changes are indistinguishable. So there's still the mystery there of what's going on at the subjective level, which may also turn out to be relatively important in terms of clinical outcome. And then on top of that, you cut the third variable, which is the -- to what extent they drive neuroplasticity. This is becoming an extremely interesting area of research now. It's clear that a number of these drugs can increase synaptogenesis, increase the branching of dendrite. But do they all do it to the same extent? And do they all do it for the same duration? So it's a complex tapestry we're working with it present. It's just very exciting that we've actually got so much work going on in this field.

That's interesting, David. And maybe I'll ask you a follow-on question, David, there associated with that. And you talked about neuroplasticity, and we know that some of the effects of these -- some of these molecules like ketamine are quite short, and we see some of that in some neuro imaging and others are longer. Do you think there's any correlation between the length of the session, say, psilocybin being 4 or 6 hours or DMT being shorter? Any correlation between that and the durability of the effect? Would you know yet?

We don't know yet. I mean there is some evidence that from animal studies that ketamine doesn't produce as enduring persistence of synaptic -- synaptogenesis [indiscernible], probably because it's working not directly on the 2a receptor, and 2a receptor may have a particularly important role in synaptogenesis. But what we cannot say, we haven't got definitive studies comparing the different 2a agonists, the different serotonergic psychedelics with one another. And that is -- doing that is quite challenging because you have to think about variables like do you get the same level of receptor occupation as you would put it in a human brain and what is actually the -- what's the actual efficacy of each of these molecules at the receptor, which we know does vary. So I think it will turn out there are differences. But whether in the end, that looks translating to meaningful differences in clinical outcomes is still pretty unclear.

Okay. Thank you for that. John, maybe we go to you. We've talked a bit about here about psilocybin and ketamine, and I think those are some of the better known molecules. What are your thoughts on DMT, as David mentioned, sort of shorter-acting models, maybe some other cycle activity? Any insight from -- you can give us?

Sure. So DMT is really a wonderful tool for testing a hypothesis that was kind of alluded to by David, which is can we get -- if we induce the same general kind of reaction in the brain, even for a short period of time, will it induce the same kinds of neuroplasticity that you see with longer-acting psychedelic drugs like psilocybin or even LSD. And the -- this is really a fundamental question that while it's not resolved, it has really important implications for the development of psychedelics therapies. So DMT is a very short-acting psychedelic drug. And with its properties, if sustained, can -- by intravenous infusion or using the approach that you all are developing, which is the deuterating of the DMT molecule. If you could get a short acting psychedelic experience by administering DMT, it would change a bit the nature of how we think about psychedelic treatment. At the moment, because psychedelic treatment uses psilocybin predominantly, we think of long 6-hour sessions. And long 6-hour sessions, maybe in some ways optimal for producing the psychological effects of the drug and sustaining them for a period of time. But we're just not sure yet whether that psychological experience is essential for producing the therapeutic effects. If not, then a short-acting drug could capture all the benefits of a 6-hour treatment session, but in a way that is much more practical, safer, probably better tolerated by most people. And certainly much cheaper to administer and much easier to adopt in routine treatment settings. And so there's tremendous interest in the therapeutic potential of DMT. And there are some new recent data that's encouraging with DMT efficacy. There was a study of intravenous DMT that was just published in neuropsychopharmacology for my colleague, Cyril D'Souza, here at Yale. And so there's good reason to be interested in optimizing DMT. I would just add that many people are familiar with DMT as a psychedelic treatment even if they aren't familiar with DMT by itself, because DMT is a constituent of another substance called ayahuasca, which has long been used to treat -- used in addiction research and in mental health research. And in ayahuasca, the DMT molecule is stabilized by being co-administered. The ayahuasca includes a monoamine oxidase that protects DMT from degradation. Otherwise, oral DMT would be too unstable to be used as a drug.

And interesting that, that approach leads to a much, much longer experience, right? That's been the traditional approach to using DMT. Is the DMT experience for users, patients different from a psilocybin experience? Do we know that?

Well, I can only say what people tell me because I haven't used either of them. But from what I understand, the DMT is a relatively intense visual experience relative to, say, 5-MeO-DMT or psilocybin. But it's -- and it's clearly, when administered intravenously, a very short period of altered perception.

Okay. So we have different research groups, different companies developing both short-acting and long-acting psychedelics. We also have some companies involving psychological support or psychotherapy and others that are not. Maybe, John, we can start with you. What do you see the way forward there with this? And is the psychological support on psychotherapy, is that necessary?

Well, I think that there are two questions related to that. And the first one is how does integrating or embedding psychedelic administration in the context of psychotherapy support make the experience safer and more tolerable for people. And the second -- and I think there's no question that with psychedelic drugs, people often have profound experiences and benefit from a period of time to -- in therapy to make sense of the experience that they've gone through and integrate that experience in their life. I think one of the questions is how essential are these sessions that prepare people for the drug experience and support people afterwards? How essential are they for seeing the therapeutic effect? And are there something specific that you need to do to prepare people or to help them integrate it? Or is it a more general kind of support -- is there a more general kind of support reasonably effective? And that's really where we don't have good answers to the question because you could have a very short-acting psychedelic like DMT and embedded in relatively intensive forms of psychotherapy as has been used for longer-acting psychedelic drugs like psilocybin. And so the person would still be engaged in this process of self-exploration and integration that seems to be so helpful in terms of safety and tolerability, but also helpful for leading to the full realization of the therapeutic benefits of the drug, at least from what we can tell so far. However, we don't have a good test of the idea that just the drug by itself without the psychotherapy can produce the same degree of benefit. And this is where the ketamine experience is really interesting because we didn't conceive of ketamine as an antidepressant that worked through changing insight. It began as a neurobiological intervention. And so it didn't begin as integrated in these kinds of psychotherapies. And yet, it is a profoundly effective antidepressant medications. It's possible like the recent DMT study published in neuropsychopharm that it's not necessary to have that intensive psychotherapy to have the effect. So it was just something I think that needs a lot of careful study before we draw strong conclusions.

Right. So David, maybe for you, just move on from that thought. Some of the questions we get around the psychotherapy is, how do we practically integrate that within the current health system, within the clinic system that we have, the infrastructure we have? How do we make that scalable? Is it practical? What are the hurdles?

Well, the hurdles generally are personnel, which usually then translates into training and cost. But at time, I'm more optimistic. I get a slightly different view to some people because I think that, certainly, the majority of psychiatrists are good psychotherapists. Everything we do in psychiatry involves -- every patient interaction involves developing rapport with our patients. And the better that rapport, the better they do. And psychedelics, I think many psychiatrists will say psychedelic as being a way of even magnifying their ability to perform that psychotherapeutic role with patients. Now that's in the ideal situation. And I accept completely the quality of clinical care, particularly in state-run systems is generally not as good as it should be and psychiatrists don't have as much one-to-one time with their patients and as much -- and patients don't get the need continuation of care that they would really like. But if we can provide that, I think we'll empower psychiatrists, and they will provide the backbone of this therapy. We don't necessarily need to employ hundreds of thousands of psychologists or other therapies to do this. However, it may be that the need outgrows even the psychiatric community, in which case there will be a value. One of the ways you get around the cost is to start thinking about group therapy. And of course, that's traditionally how these drugs have been used in indigenous culture. So John has already spoken about ayahuasca. But ayahuasca has been around for thousands of years, but it's almost always done in group setting. So that means 1 or 2 leaders or guides or shamans can provide care and support and therapy in a way for maybe 5 to 10 people. So that's one way of reducing costs. The other thing we've discovered is that -- and this may just be something to do with the fact is we're in the early stages of this kind of new phase, a new era, but the patients themselves are quite keen to form support groups which provide care over the long term. And that may be good for two reasons. I mean, one is because we do know that social support is a hugely powerful factor in keeping people well in protecting people against stresses of life and maintaining their social integration, social communications, optimizing human performance. And so that's one aspect of it. But when people get well, it may help them stay well. But also, they are beginning to see -- the patients becoming kind of mini therapist themselves because they're actually more in tuned with other people's experiences. Depress people get very locked into a very internalized, a very self preoccupied, often very hostile way of thinking. And if you break them out of that, then they can become more open, more receptive, more supportive of others. So we may find that our patients actually begin to do quite a lot of the work for themselves in the long term.

Interesting. Interesting. It does sound like we've got a bit of work to do to optimize the psychological support part of the process. Maybe, David, as we think about more -- now on the scope of kind of clinical development and the -- that these treatments are being moved towards being approved therapeutic. What are some of the therapeutic goals we should be thinking about say for depression? And are they different -- should those goals be different from those current treatments?

Well, no, I think they should be the same because if we start looking at different outcomes and the regulators are going to start getting fixed, I mean we're still using a HAM-D 50 years after it was developed, even though it's not a great tool because we've always done it and regulators want to make sure that any new intervention does at least perform as well as old interventions, even on a less than ideal scale. So we will have to use similar kinds of ratings. I think there are two things I would say to this. The first is we've been talking about the very fast onset, but we haven't captured it in many of the trials. I mean in our trials, the first -- our first ratings were at 1 week, even though you know that people were getting better within a day. So I think there's definitely work to be done there to get a more fine brain analysis at the time scale of the responses. And then the other aspect that we've been surprised by -- and this came out of our trial -- recent trial head-to-head of two doses of psilocybin versus the standard SSRI, a very good SSRIs Escitalopram. We discovered that actually -- although overall short changes in our primary measure, the self-rated score of depression didn't differentiate between these two treatments at 6 weeks. Remission rates were very much better with the psilocybin, sometimes 2, depending on the scale up to 3x better. Now remission has been the holy grail of all treatment in psychiatry. Get people to a state where they're no longer ill, whether they -- so they can go back to work and they can function as the rest of society. So I think if we can keep on demonstrating these powerful impacts on remission, the regulators will be extremely receptive because that is not just the goal for patients, but it also has a huge economic value to society. If people are back in the workplace, then they are not a burden on the taxpayer or the health funder.

No, I think that's exactly right. And when we've spoken to payers here in the U.S. and especially payer provider models, they're quite excited about that potential for durable effects that last many weeks or months because of the impact of depression, say, on other comorbidities and how depression drives severity, well, other diseases and mortality, frankly. And so the overall cost of the health system will be dramatically impacted.

And there's another angle here, Doug, which is that the other thing we started to look at the other side of the coin. So as psychiatrist, we tend to focus on depression as being a negative state of mind, and we want to get rid of depression. But we've also begun now to look at the opposite, as I say, the other side of the coin, which is well-being and how well people feel. And there are validated rating scale. The one we've used is an English scale -- sorry, British scale. It's the Warwick-Edinburgh Wellbeing scale. And psychedelic or psilocybin, at least, does remarkably well to improve well-being much, much better than Escitalopram. And it may be that well-being is what protects you against future episodes of depression because you're actually in a better frame of mind to cope with the stresses and strains of life.

So definitely lots of potential here to really change how we treat depression. But clearly, many companies are still in fairly early stages of development. And John, as we think about some of the hurdles that lie ahead, what kind of hurdles do you think the companies are going to have to overcome that maybe we haven't thought about yet to get these treatments to the approval stage?

Well, I think, David addressed the number that already, but I'll return to some of the points that I think he made and just emphasize them. The first is that if we want indications for that capture, the essence of what we think is unique about the therapeutic effects of psychedelic drugs, we need to make sure that the studies are designed in order to prove that those effects occur. So if you want to make a case for a rapid onset, for example, you have to make sure that you have the rapid effects. If you want to make a case about overall quality of life, you have to make sure that quality of life measures are used, et cetera, et cetera. I think that, that, in some respects, many of the earlier hurdles that one would have needed to overcome in order to get serious consideration for approval have been dealt with in the approval of S-ketamine. And that is, is it reasonable to think about administering a drug that alters perception in the context of routine treatment of patients with various problems, with various disorders and are there ways to both document and increase the safety of patients participating in these trials. And these sorts of -- one of the things that David hasn't mentioned but -- is the interplay of the regulatory agencies like the drug enforcement agency that's involved in scheduling the drug and the FDA in the United States that would be involved in approving the drug. Because right now, both MDMA and psilocybin and our boats, what are called Schedule 1, which means there are legal drugs and you obviously can't prescribe them or -- and the paths to obtaining access to the drugs are really quite constrained and limited to very highly regulated research studies. So there are those kinds of regulatory hurdles to overcome. But I think that my belief and others' belief is that the data will trump anxiety. The data will carry the day, and demonstrating safety and effectiveness will enable these drugs to overcome those regulatory hurdles.

Makes sense. David, anything you want to add on this subjects of hurdles to getting approval?

It is important we educate regulators that they are different. I mean, it's still -- that's one thing. I mean it is -- sometimes it's quite challenging because when you have 50 years of a model, which is it takes something to happen, it's -- a lot of the mindset in regulators is sort of directed at that approach. And I think there might be probably unconscious resistance to the idea that things could happen quickly, not quickly. So that's the first thing. And then, of course, there is -- I think John's point about the DEA, a lot of people believe that these drugs were correctly banned. They believe they are dangerous drugs. They believe they're addictive drugs. They -- in fact, they're not. I mean people need to understand that the banning was, to a large extent, a political decision rather than a health decision. But of course, that's something that hasn't been very explicitly discussed. And my own personal belief is that the banning of these drugs in the 1960s and '70s has -- well, it's led to 50 years of censorship of research. I think that's the worse censorship of research in the history the world. There are clinical opportunities that have been denied by essentially taking these drugs out even of medical research, is that right? But a lot of people think that must -- there must have been a reason for that. And there's some of skepticism. And I say that also translates into our patients. And one of the things we perhaps didn't touch on earlier is the necessity of preparing patients who may be cautious and anxious about these drugs because of what they've been told at school or elsewhere, preparing them to experience something which is generally very different to what they've ever experienced before and to make sure that they don't get so anxious about that. That they don't get the whole benefits.

I think you're right. We've seen it ourselves in our interactions with physicians and with regulators that this misinformation from the war on drugs is pervasive. We've had one regulator that questioned us about the addictive nature of psilocybin, which, of course, is not habit-forming. So even within the regulatory bodies, there's a misunderstanding. I'll just add something to the comments on DEA scheduling and, of course, as many pharma companies are overcoming those scheduling hurdles with many drugs, but it really does add to cost and time line when we think about that every part of the supply chain needs to have a license. So whether it's chemical synthesis, whether it's doing analytical chemistry, whether it's a vivarium or a clinical unit, every one of those bodies, those facilities have had a license, it has to have a safe, it has to have electronic marks, it has to have cameras. It really adds a lot of cost and time to the whole process. So certainly, rescheduling or rethinking the scheduling would help with speeding up research, for sure. Okay. Maybe just maybe finally then, John, we've -- Cybin has presented some of the attributes that we believe provide advances over classical psilocybin and classical DMT, primarily modifying the pharmacokinetic profiles and just beginning to turn these molecules into sort of second-generation therapies. What are your thoughts on the sort of next-generation psychedelic therapies? And are there any you think are particularly interesting?

So maybe I could just -- I'll start with your own compounds and what I think they bring and then I can talk more broadly about what broadly other companies are trying to explore. So the idea of getting more precise drug exposure in individuals is really -- has its own merit because variability in drug exposures are often contributing to side effects when the drug levels are too high or lack of efficacy when the drug levels are too low. And it's much earlier days with psilocybin than it is with ketamine, but it's really clear with ketamine that if you're as much as little, I should say, as 50% low in your dose exposure, ketamine that it's going to be much less likely that you'll see efficacy. And it's clear that if you double the dose of ketamine that you get more side effects but not more efficacy, at least in the trials that have been done so far. So these safety efficacy trade-offs are greatly affected by the ability to precisely dose the drug and achieve predictable levels in the brain. So that's just one simple part. Then there's the question of duration. And the issue of duration, we've talked about already, but shortening the duration of the psychedelic effects of psilocybin would make it easier to use in the clinical setting and likely make it more tolerable. Increasing -- paradoxically, increasing the duration of DMT's stability in the blood and therefore in the brain would similarly make it easier to use clinically and perhaps even make it possible to be dosed orally as opposed to needing a sustained intravenous infusion. So these are important ways of improving upon the existing molecules of potentially important ways to increase the value of psilocybin and DMT. I would add that broadly in the field, there are efforts to try to produce the therapeutic effects of psychedelics without reducing the psychedelic effects that is an interesting hypothesis that remains to be demonstrated in people. There are interest in reducing the abuse liability of drugs like MDMA, which do have more abuse liability or the abuse liability of ketamine, which has associated with significant recreational use as well. So improving the safety, improving the efficacy, improving the duration of efficacy, increasing the precision of exposures, all of these are basically ways to try to take the exciting observations and make them even more practical or useful and safer. So I think that's what I see as the horizon across the entire spectrum of development in this space.

It's interesting, John, what you were saying about dosing because we realized as we have been developing CYB004, our deuterated DMT asset, there's still a lot to learn about dosing DMT. DMT is broken down so quickly in the body that maintaining someone in the psychedelic state through an infusion -- it can be somewhat challenging. And so there's a need for perhaps a bolus followed by an infusion. And then, of course, we have to understand, well, how much is the bolus and then how long do we infuse for, what rate do we infuse at. And so there's still a lot to learn, and Cybin just acquired a Phase I dosing study in the Netherlands that has 50 volunteers. So we hope that by the end of this year, we'll have a lot more information about dosing -- dose optimization and dose dynamics. So that's a very interesting point. Well, that's the last question from me, John and David. And thank you both so very much for all those very insightful thoughts into what is very clearly filled with tremendous potential, and we think a real opportunity to create a paradigm shift in how we treat mental health. So with that, perhaps, we'll open up for some questions from the audience. I think we have a little bit of time. Leah, do we have any questions for John and David? And maybe also, we'll have Amir join us as well, our Chief Scientific officer.

Thanks, Doug. Yes, we have a number of questions, so we'll try to get to as many as we can in the time that we have. But first off, first question, should we view psilocybin, DMT and LSD as being optimized in their natural or synthetic forms? How important is it to reduce inter and intra-patient variability of PK and PD when dosing psychoactive compound?

Well, I'll kick off because John -- I'll just repeat what John was saying. We're in the very embryonic stages of this research, and it's -- there's still so many questions left to answer. We don't know what the dosing is. But the good thing is we do actually have a tool. We can explore receptor occupation. So we can do what's called target engagement studies. And because there are -- there's a tracer that is actually quite sensitive to psychedelics, it's called [ CYN36 ]. And a number of sites, John has it, and we have in Imperial. So we can actually titrate the dosing to the level of our receptor occupation that -- and potentially we'll give a readout. And the group in Copenhagen have already begun to do that. And it does look -- we've now got a good relationship from their data between plasma concentrations of psilocybin and the receptor occupations. So we can make some kind of estimates even just from plasma concentrations. But that binding, I don't believe has been done with any of the other psychedelics yet. And I guess at some point, it will because it could be quite informative.

Great. Thank you.

John, any thoughts from you on PK/PD?

Yes, I would agree. One of the questions -- one of the things we don't really know is whether the secondary targets for the psychedelic drugs are contributing to the therapeutic effects of the drug. And that makes it difficult to characterize all of the actions of psychedelic drugs into -- to develop models that predict the multi-target occupancy and dosing. But I think we have to start where we are, and where we are is the thinking that the stimulating the serotonin 2a receptor is really the critical step in the action of the psychedelic drugs in common, and so I would agree with what David said.

All right. Thank you, John. Leah, do we have more questions from the audience?

We certainly do. Next question, can you discuss the importance of assisted psychotherapy. Does the intensity of the experience and variability of perception impact the importance of psychotherapy?

Well, that's a good question. I think I want to -- I'll just say one thing about this because it's still really early days. I mean the -- there is some evidence that the bigger the effect -- the bigger the subjective effect, the better the outcome. But I want to say one other thing because this is something of the game I find regulators, and I find my colleagues also get completely wrong. People -- really, knowledgeable psychopharmacologists have said to me, " Well, of course, these people are getting better from psilocybin because they're having a fun trip." But they're not. Our experience is that depressed people have what we call challenging trips. They're not lying around having fun. They're not floating down the river looking at marmalade skies as per the Beatles. No, they're not. They're actually struggling with memories of trauma and damage to their lives imposed by others and also problems that they've created and other people through their behavior. These trips are challenging and difficult. And one thing is certainly, for sure, that helping people make sense of that. And also, again, deal with some of the memories that they brought up is I think quite important. I think whether we do it routinely or not, we need to have psychotherapy present for people that do have a difficult trip and want to talk about it afterwards.

I just want to underscore that, which is that -- and this is something that we've learned in the United States from ketamine clinics, which is that ketamine or psilocybin or any drug is an intervention, but an intervention isn't necessarily a treatment. A treatment takes care of the whole patient and addresses whatever the patient needs. And for many people, after an extreme experience like exposure to a drug like ketamine or psilocybin, having the space to both get a sense -- get a handle on what came up during the session and to manage that and to make that a part of their lives, that's often critical.

If I can just add a very simplistic take on the psychotherapy bit. I mean, we know in some ways, this is not very different from, let's say, SSRIs. We know that SSRIs work on their own. We know they work better with CBT, for example. And CBT works on its own as well. So something quite similar could very well be seen with psychedelics as well.

Yes. And so this question about synergy is an interesting one because it gets back to the issue of neuroplasticity that David talked about earlier. And certainly, this has been an issue with ketamine as well, which is you can do the treatment by -- you can just give ketamine and get people responders. But there's evidence that if you combine ketamine with CBT that you get more pronounced and longer lasting efficacy from ketamine. So that the distinction between effective treatment and optimal treatment is a bit about what we're talking about at the moment, I think.

Yes, makes sense. Next question, Leah.

When you look at the psychedelic molecules, what do you think is the key bottleneck for such molecules to be used as actual treatments? It could be a factor of things, but is it formulation, dosing? Is it regulatory hurdles? Is it efficacy safety trade-off, reimbursement, social stigma, perception or anything else entirely?

I'll just say in multiple choice tests like the psychiatry boards, in psychiatry, the answer is always E, all of the above.

Exactly. Exactly.

But maybe there -- yes, I mean, maybe -- I'll just chip in one thing here because we've touched on a lot of these questions. But I still think we've still got to win over quite a lot of the public. A lot of the public are I think kind of still a bit bemused by this. Why are these drugs coming back after all these years? Didn't we put them to bed? And so there's quite a lot of public education to be done. And of course, that extends into educating politicians as well because it's very easy to ban. It's very easy to block the development of the drug. It's very hard to undo that. So I think it's really important we have a public education program going alongside the research program. And that should also include other doctors as well.

All right. Maybe we have time for just one more question, Leah?

Sure. This is for both and Dr. Nutt and Dr. Krystal. Can you comment on the preclinical data generated to date for CYB003 and speak to the potential therapeutic attributes of 003 as compared to psilocybin?

I think John is better able to answer that than me because I'm not close to that data.

Yes. So I mean, I think it's just reiterating what I said earlier, which is if you can shorten the duration of the exposure to psilocybin and increase the consistency of the exposure, both of those are positive attributes. And I think to really answer the clinical part of that question about dosing and efficacy and safety and tolerability, I mean, we'll need more clinical experience with the drug.

And if I can just add to that...

Maybe we have -- go ahead, Amir.

We've done all that's required in terms of a preclinical package that the FDA would need before you go into the clinic in humans. So we completed all of that. We've also compared CYB003 with psilocybin as it occurs naturally, and we know it has a number of potential therapeutic advantages. Low PK variability, as has been mentioned previously, it means more consistent dosing, more predictable dosing, improved safety. A fast onset of action means the patient spends less time in the clinic. Less time actually anticipating the psychedelic effects, something that we label. And anticipate anxiety, we see that more in anxiety. But with the psychedelic experience, there is some anticipation. There's some trepidations. So faster onset kind of reduces that. The shorter duration of effect means less downtime that the patient has in the clinic. There's less of resource requirements in terms of clinic and staff. Other one interesting thing with CYB003 is it rapidly redistributes to the brain that we've seen in preclinical studies. So it means the drug spends less time in the [indiscernible], especially in the gut, and potentially less GI side effects like nausea, maybe lower or smaller doses required, which again means better tolerability. It also means CYB003 becomes more commercially viable as a medicine. Except one thing we didn't...

I think there's one thing...

Sorry, I didn't touch on it earlier on, but there are other -- there are differences in the physiological effects of these drugs, which are not understood, and that psilocybin intends to put blood pressure more than LSD, and LSD has a bit of heart rate. And we don't understand why there are these differential effects. I don't know much about DMT in either of those things, but it's quite likely that there are physiological differences, which could be relevant for some patient groups.

I think that's a good point. And we're excited about moving into the clinic with CYB003. And we're hopeful by the end of this year, we'll have to answer some of those questions as we see some of the PK and the safety data being generated from the early cohorts. So more on that in the next few months. So thanks for joining us, Amir. David and John, a real pleasure. Thanks for spending so much time with us today. Wonderful responses, and wish we had time to go through the many other questions that are coming in. But maybe we'll do another one of these and take a chance to answer some of those. Thank you both very much for joining us, and thank you to everyone that joined online. Thank you.

Thank you, everybody.