Mushrooms changed the world in the 20th century, some say. Others say, psychedelics are older than humankind. But instead of synthesizing molecules and providing it people in a clandestine manner, what if, proper systematic drug discovery and development was done to make psychedelics better?
In this penultimate episode of PsychedeRx, we explore a few more stops before we part ways from this extraordinary project. As we all know, drug trials and molecule development require money and vision and fortitude. So, who exactly is driving the commercialization of psychedelics for responsible clinical use? We’ll hear from Doug Drysdale, CEO of Cybin. as well as Ian McDonald and Gideon Shapiro, CEO and VP of Discovery of Bright Minds Bio respectively. This is not just a hot stock tip, but rather a primer on what the future of the financial side of the psychedelic research and clinical industries. When we said we would cover all aspects of psychedelics in research, we meant it.
drug, molecule, psychedelic, gideon, dosing, receptor, patients, disease, lsd, treatments, treat, pharmaceutical industry, ketamine, mechanism, developed, great, psychiatry, medicine, schizophrenia, agonist
JoJo, Doug Drysdale, Ian McDonald, Arun Sridhar, Gideon Shapiro
So far, we’ve run the gamut of issues in matters that pertain to the use, misuse, reverence, recreational use, abuse, and the careful unlocking of psychedelic potential in the recent past. There’s some critical questions that require answering though, let me walk you through the conundrums that will ponder over the last two episodes. Question number one centres around the way psychologists are trained to work, what is currently being reimbursed or paid for? The current psychology practice deals with sessions under 16 minutes, repeated multiple times. Instead, the psychedelic assisted psychotherapy sessions, especially the drug dosing sessions, run six to eight hours long. Yes, it does depend on the molecule used to be at silicided, MDMA or ketamine, but irrespective of what the drug is, sessions are much longer than the current practice. What does this mean? It means the pace at which patients can be seen is going to be slower. So this puts pressure on the healthcare system. Question number two that requires thinking is while psilocybin can be isolated from mushrooms or DMT, from Ayahausca, the manner in which these sessions will be run and the duration of effect means that there will be chemists who will look for a better molecule, you don’t get it. Let me give you an example. Aspirin, as we know, is the most simple anti platelet molecule that acts to prevent clotting. It’s provided to patients with a heart attack due to a blockage of the coronary artery that supplies the heart. But just because aspirin is the cheapest anti platelet hasn’t deterred pharmaceutical companies from developing a better anti platelet molecule, one that targets multiple parts of the platelet aggregation molecular cascade. This has led to the development of more potent antiplatelet medications that can be ingested less frequently, and potentially are much better at reducing cardiovascular adverse events due to worsening of disease, so called mais, or major adverse cardiac events, in fact, and most recent antiplatelet medication that some of you might take is better than aspirin because it reduces the incidence of cardiac adverse events by more than 40%. Back in the day, can one simply have said, we’ll be fine. Let’s just keep taking aspirin. It’s cheap and readily available. Absolutely. One definitely could take that path. But if something is more potent, as efficacious, and potentially reduces the economic burden, wouldn’t it deserve a chance be a careful clinical studies? It’s easy to be idealistic. But please check your prescriptions if you’re taking an age old drug, or something more recent. Similarly, it’s only logical to imagine that psychedelic molecules will potentially get more potent, less systemic side effects and may induce shorter psychedelic journeys, thereby reducing psychotherapy session times. So how are people aiming to do that? What’s in it for investors and for scientists? Why do they care? Why should you care? This is psychedelics. scraps original podcast exploring the therapeutic use of psychedelic molecules. An enthralling story of an improbable drug class, as old as humankind itself, banished into exile get comes back, soaring like a phoenix from the ashes to save mankind’s affliction with mental health disorders.
Arun Sridhar 04:08
Let’s pause and reflect on a few things. For a second, let’s compare the half lives of various psychedelic molecules that we know of. LSD effects can last for up to 20 hours, but with what pharmacologists call as the elimination half life of three and a half hours. Psilocybin ingested orally can have a half life of about three hours, with the effect lasting for up to six hours. MDMA is another molecule that we explored that depending on the type of molecule, what chemists call as an enantiomer, can vary between three to seven hours with a duration of action of up to six hours. As a result, the psychotherapy sessions with these drugs by definition, last for a long period of time, depending on the property of the molecule The only exception to the duration is DMT, whose half Life is a mere 15 minutes or so, with the effects completely gone by 45 minutes, thereby earning the term businessmans lunch, as we alluded to in the earlier episodes. Yet, in the natural setting, I was asked ceremonies last longer due to the monoamine oxidase inhibitor that prevents the breakdown of DMT, thereby lasting longer in duration. So it is perfectly alright to imagine that in a group therapy session, as it might be done in a retreat, one would want the experience to last longer. But as these drugs are being explored for us via the healthcare systems, one cannot escape the situation where there will be a push for a more potent, shorter acting drug that might provide the same degree of efficacy or greater, and still does not carry the time liability that the existing molecules do. So more patients can be attended to. I can sense a bit of uneasiness in you as you listen. It’s a bit of a chicken and egg problem, you see. These substances occur in nature in a way that effects last longer. And so does other naturally occurring substances as well. By the way of the modern society invariably means, just like how MDMA was engineered, society will figure out a way to make psychedelic medicines mainstream. So it can only be done if it fits within the existing template to a certain extent. Let us explain this a bit more. We invited a few bright individuals to help us inform this line of thinking. Two of these individuals are CEOs of pharmaceutical startups in the psychedelic space. And the third is a lead chemist of one of these companies. First, I think it helps to understand the perspectives of these individuals. Much like the patients and the people that we have spoken to so far on the podcast, it is crucial to appreciate the outlook on the journeys before one makes a blanket judgement on pharmaceutical companies and startups. So let us suspend the bias for a few minutes, and listen to how they believe they can make psychedelic medicine field better for everyone. First, here is Gideon Shapiro, explaining his journey, we can promise you that Gideon is not your run of the mill, pedigree chemist, but he definitely has a story. For all the psychedelic evangelists who are listening. Gideon is someone who has a fantastic link to someone that the field celebrates. But rather than us telling it to you, let’s listen to it from Gideon himself
Gideon Shapiro 07:51
I was a sort of a bit of a hippie and iconoclast at heart growing up, moved around a lot, as a kid actually lived here in England. And so my dad was a professor. So we dmoved around a lot. But I guess it started, you know, I studied chemistry in college and dad I went to UNC Chapel Hill there so that I started my training as a chemist, and loving molecules and how to make them and what do they do? And so then I decided to go to grad school and, and actually, you know, and then I had my own experience, of course, growing up, you know, we all smoked pot in those days, and also in college, I did take LSD experience at that point. So I knew what LSD could do, I was already open to you know, mind expansion. And then I, you know, that was that was like, you know, I did a lot of drugs or anything, it was just, I was more interested in experience. And then, and then I went to Berkeley, for graduate school, also in chemistry. And then that’s what we do, what we do is look at complicated molecules, but again, I did experience LSD, again, and that reinforced my understanding a little bit and it is it is life changing. You don’t you never forget an experience. Right, and it does open the mind. And so at that point, I also got curious, you know, very interested in molecules. LSD hadn’t be a very complicated molecule. Right. So I got interested also in it from, you know, the chemistry side. What this molecule, what is it? The era of alkaloids are incredibly complex, natural products. Um, so I started reading and then I picked up you know, in the hippocampus I picked up Albert Hofmann took LSD, my problem child, and I read it at that point for curiosity, and I was reading mobile McQueen, all the usual books to get insight into that and I was also starting to think more about the right side of the brain drawing, just getting into you know, that kind of side of the right side of the brain versus being you know, the PhD scientists at the other end So I read that it was fascinating. And then I actually decided to do my postdoc, to go to Switzerland. For I wanted to have another experience, I wanted to learn a new language, you have to think differently. And usually the Europeans come to America. So I didn’t always put that back away. I went to Switzerland to one of the most famous organic chemists in Zurich, at the institute called the Ha ha, to do my postdoc work on very complicated molecules again. And when I was there, guess what Albert Hoffman is giving a lecturer at the University of Zurich and I get to go and see them and give the give the talk and say all this stuff in his book, in person, and then I get to know that Swiss mentality as well like and understand what he wants, what bosses are, and then crazily enough as luck would have it. When it came time to seek a job. I didn’t go back to the States. I took a job then add Sandoz pharmaceuticals in Basel where our hospital discovered LSD and was just a phenomenal person. In fact, the number one seller when I was joining the company, was a compound called Hydergene, which is an ergot alkaloid derivative, which was the first drug is actually approved for Alzhiemer’s disease. So the first drug and they sold a lot of it, and nobody ever knew how much it works. But you know, that already, the pipeline of products of ergot alkaloids that he developed, was amazing. In fact, one of the big beta blockers, called pindolol is a derivative of psilocybin. So basically took part in suicide and patched it onto a beta blocker. And that was the great beta blocker blood pressure medicine but he used that fundamental insight into ergot, you know, early and did amazing things. But as it what would happen as Ian said, My technician once the guy had worked for Hofmann, I wound up in the same building and also inherited the ergot alkaloid collection to organise that he was sitting there rotting, because after Hoffman left fathers basically got out, we’ll all get scaled out. Because ergot alkaloids are very tough drugs. They have a lot of metabolites and adverse effects. So management never wanted to bury all that stuff in a basement, I organised the whole collection, I built the storeroom, or at two two kilo bottles of lysergic acid and built that facility. So but there were lots of stories of having to rush rush a technician hole in the lab, build something.
Did you catch that? Gideon Shapiro inherited the lab and the LSD collection from Hoffman. Once Hoffman retired, and he organised all of it. So while researching for the series, we heard from Stephen Kinzer that the CIA bought every single ampule of LSD that was ever made from Sandoz and Sandoz did not have anything left. So we asked how true this supposition was. And I guess you already guessed the answer.
Gideon Shapiro 13:10
No.I mean, I don’t know about the supply of LSD or you know that with the marketing product. But no, I mean, they have a storeroom they might have, they might have just destroyed or done something. But again, like all urban legends, I tend to be sceptical. So there were two kilos of lysergic acid sitting around probably somewhere, I don’t know. But and samples, you know, if so, and they decompose that one of the problems that ever got off the oxidize easily and just like psilocybin, when they talk about peeling back the mushroom and seeing colour. So these molecules are also tricky because there tend to be unstable as well.
Beneath the gossip in the urban legends, Gideon has given us some crucial nuggets to hold on to. Ergot alkaloids from which LSD was synthesised is very difficult to work with. They have lots of metabolites and side effects and dosing and testing can be super tricky. Then we heard that molecules like LSD and even psilocybin can oxidise easily and as a result, lose potency over time. Now let’s go back to Gideon and ask him how in his mind, psychedelics should be viewed via the lens of drug discovery scientists and companies. Here is Gideon Shapiro once again.
Gideon Shapiro 14:32
And now what we’re seeing is, you know, these applications are tremendous. And one of the reasons industry I think, is faster and it was really accelerated this is that the field that I lately worked in, NMDA. The first the biggest breakthrough in psychiatry in 50 years, I think was on the cover of Time Magazine, is the FDA approval of ketamine as the first major new treatment for MDD. Okay, and so what we know is that also that this basically, is a whole new paradigm shift in psychiatry, it used to be for almost all conditions, what do you do? get up in the morning, as I just did today, because my blood pressure medicine every day, you take your pill, right, and you stabilise whatever’s going on every day, and the same thing with Prozac, get up and take your Prozac every day. And that sort of dampens you down, right, and then brings it to some baseline level, this new medicine with ketamine, you take it one, you don’t take it every day, you take it on intermittent schedule. And so essentially, what this mechanism is, is you’re not dampening down a buzzing circuit that’s buzzing all the time, what you’re doing is you’re approaching the disease, as the neural circuit, the brain is the whole circuit, not just one neuron or whatever, you have multiple neurotransmitters functioning to each other, you have circuitry, let’s say the corticothalamic, circuitry, and striatal, which are electric, essentially electric loops in the brain, that that essentially are dysfunctional in neuropsychiatry at some level. So they’re out of sync, if you will, right, they have to, they’re too amped up. And what you’re able to do with these new therapies, which really started with electric shock, is by giving a single pole, right, you reset the circuit. So it’s like your circuit breaker goes off, right? And you go in the garage, and you put it back, you don’t sit there and hold your finger on it the whole time. And it did every day. Did you read that? Right? And so what ketamine is this new mechanism that you can actually try to approach these diseases at a circuit reset? level, it started with electroshock, right? Which sort of got this bad name, right from One Flew Over the Cuckoo’s Nest. But electroshock is actually a very great therapy that will take people who are really ruins and can be lifeprint formative, right, basically, you know, someone who came and talk, catatonic who can potentially cure for a certain period of time. And what what we like to look at and call these new medicines are chemical electroshock, essentially. So what you’re doing is you’re now able with a pill with the approval of provato by j&j about a year ago, which is Naval Academy, you’re able to reset the circuit, I mean, you come in, you can get a treatment. And then you won’t have to be treated again, until the circuit drifts back to dysfunction. So it’s not like a miracle cure. One thing that, you know, we’re sort of very disappointed about is this idea that with a new site development, you know, the first generation psychedelics And somehow, if you’ve got a disease, you come in, you have a trip one and you’re cured for life. Well, that’s true. Maybe if you don’t have a real serious disease, if you’ve got a life, you’re got a life event, right? You see religion, and you accept the new philosophy of life. But if you’ve got a if you’ve got a brain, it’s got a circuit dysfunction. It doesn’t get reset for life. Right? These things, you have a disease and fundamentally you drift in and out. Circuit function is function, right? And so what we’re all about here, the one nice thing is this sort of circuit reset to work from many different diseases. Everybody’s focused on depression, because that’s a multi billion dollar market, and the most patient but OCD, PTSD, all these a lot of these neuropsychiatric diseases just like they can be treated with the blunt SSRI for many of them, right to be treated. And the most important thing is this effect, the really, really, really tough case. So MDD where you’re suicidal SSRIs there’s no, there’s been no medicine for that. So 30% of the depressed patients for whom there was nothing, right before now have a treatment that works for a lot of them with ketamine, essentially. So Academy word is a long story, but we’re trying to get to it. ketamine is now embraced by the pharmaceutical industry, the pharmaceutical industry has recognised that this paradigm shift isn’t going to stop this idea of treating someone with a neural circuit with the drug is out of the bag. And so now, what’s next? Right, ketamine is done. I’ve been working in that field now. For the next generation ketamine that safer because ketamine gotta go into the hospital. Right? You have hemodynamic side effects. They can quite severe so you have to be monitored. Right for hours. At least two hours. hours before the release, be safe to drive on your own to get your blood pressure, you have this huge spike in blood pressure potentially. Right? You have cognitive dysfunction for transient, but then they release you. And typically you might not have to come back one week, two weeks, one month, we don’t really know. Right? But what we know is, you have to come back. Right? So what we know is what would be experienced with ketamine that it’s not a lifetime cure, right? Even the people who do get treated, has to come back. And we don’t even know yet the times is early, you know, for the millions of people what kind of a schedule where they have to come back. So that that’s why the pharmaceutical industry is seeing this, and now psychedelics are the next. So this is the next big mechanism, which aids based in science, because it’s based on a receptor. Although it is magic, we know how it works. We know that the one of the five htt to a receptor is responsible for the effects so it’s right for drug engineering, essentially, that just just the kind of thing we do, we’re the first generation drug whether it’s a blood pressure medicine or a Staton. Right? The first one never win. Right? The ones who when they come, you know, Jen, what are you taking? I’m taking it but never heard of it? Well, that’s because the third generation of this drug is even safer. Right? So what’s the doctor gonna do give you something that’s less safe, or give you some safer world, they both work, you’re gonna get the safer drug. Right? So that is sort of, you know, where this is all movement. This is not a fad. This is a new revolution in in science and the pharma industry, to our surprise, you know, I think it’s getting on board accelerating rate of looking at, and it’s also a poll, right, they have their drugs are coming off market. So this combination of a totally new paradigm in neuro psychiatry, which means dead, you know, how many more dopamine blockers Can you make for schizophrenia, nobody had any new ideas, right. And now all of a sudden, there’s new ideas and science base that really works. It’s a revolution. And one drug is already on the market from with the related a different mechanism with the same approach correctly a circuit it is going to be embraced. And plus, and that on the other side, we have a poll from all these depressed patients who now you know, have nothing and they’re now seen as a new type of medicine.
Arun Sridhar 22:47
So Gideon Shapiro, is the Vice President of discovery at Bright Minds bio. And we also had a chance to speak to its CEO, Ian McDonald. But unlike Gideon, who so eloquently explained the scientific angle, Ian was an investment banker who decided that he wanted to make healthcare his primary focus in life. Let’s listen to Ian McDonald story. Yeah,
Ian McDonald 23:12
I got interested in this space in 2015. I read an article somewhere I can’t I can’t recall exactly where it was, but essentially saw the light saw that these drugs had exceptional promise in treating heart discrete neuropsychiatric disorders. With that went down the rabbit hole, read every single research paper, I get my hands on and started having conversations with those influential authors. It became apparent quite quickly that while these drugs we’re seeing today, drugs like psilocybin, LSD, MDMA are efficacious, they lack certain drug like characteristics necessary for them to be accepted by the big pharma industry. So with that, I developed a thesis of creating these next generation drugs assembled a team and away we went. One of those authors was Alan causa koski, who is a tremendous mind in the space and I’m proud to say one of our co founders at bright minds. He’s the Chief Scientific Officer. Another another of those authors was john McCorvy who’s responsible in my opinion for the most cutting edge science on the pharmacology side of psychedelics. He really understands what these drugs do in the body and how they act at a level probably greater than anyone in psychedelics today. So
Arun Sridhar 24:34
Ian assembled people are Gideon Shapiro, Alan Kozikowski, who is a well renowned name in drug discovery, and startups. And with these people, he started bright minds bio. So who invested in their company here as Gideon Shapiro, again, as to how they went about their investment theses?
Gideon Shapiro 24:56
Yeah. So the way we I think we’ve actually been quite successful with that. If you’ll from from the investments we received, because we received now now we’ve got pretty validation that we received investments on both sides. So we have all comers, we have those kinds of investors, who are, you know, wealthy people who, you know, are in the psychedelic cult, if you will, that are believers and really understand that, right? And, and, and want that and believe in that. But they do not understand. When you again, if you can explain it that we want to reach if you put it in terms of we want this medicine for everyone. And that is the goal, then that’s what are you gonna say? You’re gonna say no to that? You know, it’s like, you’re gonna say no to treating millions of people have brought diseases. So we’ve got, you know, as they say, we’re bringing everybody under the tent. And I think what’s more, what’s more revolutionary is not that group of people, the group of people already know, and you don’t have to convince, read the people who know the psychedelic medicine and experienced and change their lives. Right, the people we have to convince, and they’re not big money, generally, right? I mean, yes, they’re millions, maybe even hundreds of millions, but they’re not really to change a whole world, you don’t need Middle East. And that means you need big money. Hedge funds, VCs and you need pharma buy in, because the VCs are going to come if they don’t believe that pharma will eventually buy in. Right. So I think that’s the harder part. That To our surprise, is happening way faster than we thought. Even a year ago. I think the momentum here, this sort of paradigm shift is happening quite quickly. Right. And I think the good news is, it’s not a fad, right? It’s not like cannabis, where it’s a fad. And there are different things you can these are prescription drugs with a model to treat people, you know, as a classical drug. I think investors don’t have to worry, right? Because this is going to come and go and they have to ride the momentum play of getting in and getting out because this medicines here, day, and it’s not just cannabis, it’s not just THC, or, you know, or or die hydro. This is a multitude of drugs that affect the brain system, the fundamentals the menu. And so what was I like to think of it the way Merck the head of Merck, but one of the greatest of all time was named Roy Bachelet. Right, he basically ran Merck in the heyday. That’s what really the cholesterol drug, all that stuff came out of the 80s. When he was and he was a chemist, chemist used to run company. Right? Not not MBAs and lawyers. Right? That’s when we made real medicine, right at a different level. And what he said was, make the medicine and they will come. Right. So the idea is, yeah, just point in that direction, where I’m going to make a difference. I’ve got a medical target that I believe in. And even if you’re not quite sure, which is the case of the psychedelics now, where exactly right land is the goldmine, right? Because you know, it’s such a fundamental neurocircuitry that you’re affected, vital. There’s so many different mental processes. And the thing is, even though they’re different diseases, what we’re finding out and what’s already true, in fact, is that even with SSRIs, which is a blunt instrument, I mean, the main tip today, started with Prozac. It’s become a blunt instrument, because it’s safe and you give to everybody for every, every mental condition practically, except for schizophrenia. Right? You get a script. Oh, you’re feeling a little bit out here. Take Prozac. Oh, you got a little OCD, okay, take Prozac it works. It might work. It’s safe. You’ll never have sex again, but fine.
So Gideon just casually slid in some very interesting nuggets in that last answer. He said that if you were to use the molecular mechanisms of these psychedelic drugs, and if they can affect various disease conditions beyond psychiatric disorders, and treat a broad variety of conditions, who wouldn’t want a piece of that pie? Well, why do you say that, as explained in Episode Five of this series, where we spoke of psychedelic pharmacology and how they’re close to 17, different serotonin receptor subtypes, one can make selective modulators of these receptors and thereby help to modify various disease conditions because not every single tonin receptor influences a psychedelic experience. Bright Minds bio has finished its latest round of financing, and is exploring serotonin receptor modulators for conditions like neuropsychiatric disorders, including depression and PTSD. But also excited Tory conditions like epilepsy, metabolic disorder with neural underpinnings like binge eating disorder, chronic pain and opioid use disorder. So we will pause here with the Bright Minds bio story and turn our attention to another company that is garnering some attention in the space. seibon Inc is another company among the ones that we researched that has a fantastic team of researchers, and one that has a different chemistry approach to psychedelic drug discovery. While many others focus on synthesising newer molecules like like five methoxy DMT, without killing Sonoran Desert toads, or synthesise DMT, Simon is taking an entirely different approach. Let’s hear about it from Doug Drysdale CEO of Simon.
Doug Drysdale 31:06
I’m Doug Drysdale. I’m the CEO of Cybin. At Cybin, what we’re looking to do is we’re looking to revolutionise the way that we treat mental health disorders such as addiction, and depression. And there’s a real opportunity here to completely transform how we do that. When you look at some studies that we’ve seen out of Johns Hopkins, and NYU using psychedelics in these conditions, we’ve seen patients that have many months of remission after just one or two treatments. And that’s clearly radically different than the way we treat depression and addiction today. I think what also is quite unique about what we’re doing is that we know an awful lot about these molecules. We know a lot about psilocybin and LSD and MDMA and DMT. Because these molecules have been discovered for decades. The challenge is that many of those molecules have issues of their own that make them therapeutically difficult. psilocybin has very low bioavailability. MDMA has a very long half life. And DMT has a very short half life and and almost no oral bioavailability. So collectively, they’re not ideal from a therapeutic point of view. So what we’re doing at Sabin is we’re using medicinal chemistry. And we’re using drug delivery systems to address each of those challenges of those markings and make them more therapeutically useful and more scalable and accessible by patients.
Arun Sridhar 32:30
So beyond the usual facade, the drug discovery executed as provided by our press releases, we probe dug a bit more, a dog was very excited to share the information beyond the usual template pitch that he provides to investors and others here has done and we are extremely thankful to him for sharing this information.
Doug Drysdale 32:51
Now, this is a very good question and still lost that we don’t know, a lot there hasn’t been studied in very large studies, but in some smaller academic studies, was set aside and stay out of Johns Hopkins, where they looked at psilocybin in both depression with MDD and TRD. And also in addiction solution, smoking cessation, it did for their benefit, there’s been a number of meta analysis where we’ve followed up with patients, and a good number of them around 80% or so saw a continued benefit for many months, five to six months, in some cases, depending on the study they can look at. So clearly, there’s some durability. What we don’t know, of course, is exactly how long that durability lasts, and in which it does it differ between different patient types, different indications, different dosages of these treatments. So that’s work that we will need to do once we get to market for sure. And as part of our continuing development. Our clinical studies are aimed at single dose single use, partly for simplicity of design, and partly for the ease of getting through the regulatory process. But it’s certainly of interest to us to determine what their ongoing dosing might be. The indication out of those studies I mentioned, john hopkins meant maybe is that patients need to take these two three times a year. But that’s in my mind, that’s still a dramatic improvement. On the chronic use of SSRIs, which we’ve seen in meta analysis are really no better than placebo in treating moderate depression load on to
Cybin’s approach is in a way to drive better compliance, which raises an interesting question for a population that does not want to take chronic dosing.
Doug Drysdale 34:37
I agree. In fact, I’d take that a step further to say that we may need to rethink how we treat mental illness mental disorders completely. So we used to go into the doctor taking getting a prescription and taking a pill every day. But this this requires a different kind of investment, personal investment. It means going to a clinic and spending sometimes, maybe multiple ours, investing in your own mental health, and and all of the supporting therapy that may go with that, as we’ve seen that the integration of the findings from these sessions into a therapy regime improves, improves the outcomes. So but that’s not the way we do things today. So that impacts training impacts education, impacts infrastructure. So we will have to rethink a little bit, how we approach mental health treatment. In the context of these these medications. We looked at some of the treatments that are being developed today, in this space, and you have MDMA being developed for PTSD, that has, I think, 70 hours of therapy around it. And we’ve seen it as an oral version of psilocybin that’s been being developed that has a very robust therapy programme around that, and very long acting image six or eight hours. And you take just those two examples, and you try to project forward how those might scale. And it’s hard to see, frankly, it’s hard to see how we scale that. We know that just from talking to physicians and nurses, around spravato esketamine. For for depression, that just the REM standard requires patients to be observed for two hours after treatment is a big hurdle. They don’t want to spare a nurse to babysit a patient for two hours, they don’t want to give up a room for two hours. So these very long acting treatments, we see as facing a real challenge in terms of scale, I’m certain that the most severe, most resistant patients will benefit and we’ll get them but we’re looking at this from a much more holistic perspective. So right at the bench, we’re focused on shorter acting, often faster acting treatments. So for example, we have a deuterated tryptamine programme. And with that, we’re taking very short acting tryptamines. So take something like I’ll give you an example, say let’s have like DMT, or derivatives of DMT, that have a very short duration, maybe 15 or 20 minutes, and but a very high spike. So they come with lots of side effects as well. Well, we’re able to do through deuteration is selectively replaced the hydrogen atoms on the molecule. It has the effect of increasing the molecular weight of the molecule, but also slowing the breakdown through oxidation and demethylation for that molecule in the bloodstream. And so you end up them being able to reduce that high spike the plasma spike, extending the half life and having a smooth PK curve and kinetic curve, that then we can tail it around an hour and a half or something more that fits more within a regular treatment paradigm. You combine that with with inhalation delivery, as we’re doing, you then get a very rapid onset of action pretty close to IV, so the patient’s not waiting around, and tremendous controls. And then we can control both the intensity and the duration of treatment. And when you can get to that stage and we hope we can get to that’s when we’re heading into phase one, before the end of this year with our first of these, then you’ve got treatments that are far more scalable, then I think the infrastructure and the reimbursement is a lot in detail the hurdles are far lower.
Arun Sridhar 38:08
So now let us explore one of the ways in which one can address the issues of ensuring that a smaller dose of the drug is delivered for a quicker effect and potentially lowering of untoward effects. Oral administration means that the drug is absorbed from the gut, and from the intestines where absorption takes place. The drug is then shunted through a special circulation that exists between the intestines and the liver. This circulation is called as the portal circulation, no prize for guessing why it’s called portal circulation. As it ports the nutrients absorbed into the blood in the intestines to the liver to enable storage and processing in the liver. So drugs taken via the oral route will undergo what the pharmacologist will refer to as first pass metabolism. And the mere nature of this pathway is that only a fraction of what is ingested is available for action. Instead, if the drug is taken via the nose as an inhalational mechanism, it prompts immediate diffusion of the drug through the lung into the blood, which goes to the left side of the heart and pumped into systemic circulation, including the brain. So you can see how the inhalational route can be beneficial. medicinal chemists will spend many days two months two years tweaking the properties of the drug to ensure that the drug can be dissolved for the right type of administration route. Let’s hear again from Doug Drysdale, CEO of Cybin.
Doug Drysdale 39:56
Yes, of course, and you know, each of those is a different different delivery route. has its challenges. What I mentioned was inhalation actually not not nasal. But inhalation is a platform that we’re using it’s a, we’re actually using a pre existing pre approved platform that we’re putting the molecules into, and other delivery mechanisms and routes to will, we will look at IV and I am and various others as well, and decide which of those to take forward depending on the results that we see. But I think very interesting, very interesting results so far. And if we can provide that rapid onset and find control that I think we’re really onto something
is Cybin focus strictly on mental health disorders. What else are they looking at?
Doug Drysdale 40:41
Yeah, these these molecules are unusual, and that they seem to have shown some benefit in many different indications. So our lead programme, which is a sublingual film version of psilocybin, where we hope to see that faster onset of action, hopefully, a shorter duration, as well, we’re targeting major depressive disorder there. There was a great study out of Johns Hopkins, in November, last year and published in JAMA psychiatry, which showed a 71% effect size to 71% of patients had a greater than 50% reduction in their depressive symptoms in their study of four weeks in major depressive disorder. So that was very encouraging, and obviously very supportive of the work within, for the leader programmes, the tryptamines and phenethylamines, we’re looking at a range of treatment resistant psychiatric disorders. So there could be, it could be treatment resistant depression, could be suicidal ideation, you can imagine that an inhalation delivery for a patient in a suicidal state would could be very useful in the ER on a venue like that, and potentially OCD. So we will decide on the exact indication and the order of those indications as we go on through development. And then we have a further programme that we’re targeting addiction. And again, I think that these we’ve seen some good data in smoking cessation, we’ve seen some good data and alcohol use disorder, it’s very likely that these treatments could work in opioid use disorder. So if that’s the case, then we’d like you to pursue all of those indications, it’s just we have to determine which order we do that in what the clinical pathway is, what the animal models are, etc. So a little bit of work to do there. But over the next several months, we’ll be disclosing the precise indications and the order that we’re coming to plan to come to market with.
Oh, and one more thing, the inhalational route and the sublingual or medicine placed under the tongue, have similar drug uptake and less first pass metabolism route. Because just like something that is inhaled, goes into the lungs and into the left side of the heart to be pumped into systemic circulation. The sublingual route ensures that the drug is absorbed into the small capillaries under the tongue, and goes right into the heart through the veins, and pumped into circulation, bypassing the gut, in a situation where the drug will be taken orally. Cybin is doing more in the innovation space, bridging the technology and biology. But we’ll come to that in a bit.
Arun Sridhar 43:12
Now, back to Bright Minds bio, we left that conversation at a place where we said they are exploring and exploiting a range of molecular tweaking of chemicals to understand how their molecule affects the various serotonin receptor subtypes. So every receptor like a key can be turned on or off. So turning it on triggers a cascade of molecular events, which is understood for some, but not so much for the others. And this is called a stimulation or with a fancy word that the pharmacologist use, called as agonism. In contrast, a drug molecule can jam the receptor and prevent the lock from being open. And if you equate that to a villain in the movie, you can call it as an antagonist. So bright minds bio is exploiting the chemistry to better understand the serotonin receptor chemistry to either stimulate or block the receptors. While many companies in the past have tried to build serotonin receptor modulators, for example, ones that was alluded to by Jo Neill in Episode Five for migraines, or schizophrenia treatments. They’ve been unsuccessful because a lot of the serotonin receptor pharmacology has taken a while to be uncovered. And in the last decade, since 2010, almost all major pharmaceutical companies that used to do such work and such type of chemistry, have pulled out of neuropsychiatric research. The reason provided by many include lack of good translational models and high degree of risk Between preclinical research and clinical efficacy. So having tools like the psychedelic compounds, and understanding how the psychedelic molecules that are fairly simple in structure, compared to some of those heavy organic molecules with multiple cyclic aromatic rings, has been a great starting point, and is currently driving a lot of interest from both scientists and investors. While psychedelic effects are a result of five htt, to a receptor agonism or stimulation, bright minds bio is also looking at the five ht to see receptor for conditions like the non opioid pain relief, seizure disorder, binge eating disorders, and even Alzheimer’s. The first preclinical study in an animal model of binge eating disorder was published recently, by Bright Minds bio collaborated with an investigator at University of Texas Southwestern in Dallas. And in addition to looking at the 5HT2C receptor, they’re also looking at targeting of the five htt to a, through selective mechanisms for developing the next generation molecules for PTSD and depression. In addition, bright minds bio is also looking at the combination of stimulating both the 5HT2A and 5HT2C combination actions on 5HT2A and 5HT2C is being explored for pain treatment. For anybody taking a prescription pain medications, you might know the status of addiction that the opioids have left us with. So bright minds bio is exploring a combination of 5HT2A and 5HT2C modulation for non opioid pain relief. Here is Gideon Shapiro, Vice President of bright minds bio, explaining how and why they started working on serotonin receptor modulators and drug discovery with a dash of philosophy and storytelling.
Gideon Shapiro 47:14
we almost like to say – we like to take the magic out of the magic mushrooms, right? So try to basically, you know, demystify. Yes, it is a mystical experience. But, you know, science, its job is to somewhat demystify as much as possible and bring it to the level, you know, of the graspable. So that’s the balance, we’re in the field of trying to balance that, that element of the mushroom hunters of the world, and the end is basically the cult of psychedelic versus the establishment, right, but rejected in all these years, and to come somewhere in the middle, and also the fringe groups to work on it. And then bring the science and sort of bridge the gap between those elements and let everybody understand it’s not this or the other. It’s not, oh, you’re the establishment, you know, we’re against that we don’t we even investors, though, we don’t want to invest in that we’re investing in, you know, changing the world. So well, you got to choose the world in the framework of the legal framework, as you know, to really help if you really want to help people, then if they’re your goal, you set your goal, if your goal is to help people, then the question is not always, is this magic? Or is this my is my special field? But how do I do that? How do I bring magic, or the magic of this medicine? So that reaches millions of people, not just, you know, 100 people, and that’s what sort of we’re trying to do. And we’re in a very lucky position, because, you know, that level of making medicine for the masses, legally, right is the domain of the pharmaceutical industry, you cannot achieve the goal. That goal without the biotech industry. So to accelerate this, you want buying as fast as you can. I mean, we’re not trying to become Amazon and take over the world. We’re trying to make this happen fast. And get it into all of the applications. It’s gonna take, you know, the entire pharmaceutical industry report, as you see what they do. I mean, I never cease to be amazed. They new great product come up, look at the vaccines. I mean, it’s just amazing, you know, the power when the pharmaceutical industry get behind something. So that’s, that’s our goal.
And what is different about the approach that bright minds bio is taking compared to other companies. Instead of re engineering an existing molecule, they’re looking at modulators with a fresh view with a world class team and scientific philosophy. Here again, is Gideon Shapiro,
Arun Sridhar 49:55
The psychedelic field itself, specifically, We tend to look at more broadly as the 5HT view. And so out. So in the past, nobody worked on 5HT2A because hell, it was psychedelic. So the whole pharmaceutical industry has been working on 5HT compounds and 5HT2, but the whole goal has been it’s sort of not to make psychedelic, so you were screening that away. So basically, nobody knows how to do it because you didn’t want to do it. And the field at the time was really interested in this other subtype called 5HT2C. So, 5HT2C. It’s been a mainstream target in the pharmaceutical industry for other neuropsychiatric disorders. Right. And so Alan, we’re so lucky, because our co founder, was working on the neuro psychiatry applications of this with brian ross, he is a few before it was the superstar actually discovered that it within the five htt class, you essentially have three flavours A, B, and C. And Brian, actually was one of the founders who discovered that five ht to be agonist have cardiotoxicity. Right. And that has been a major achievement and is a problem with the current psychedelic compounds in the pharmaceutical industry. Even they won’t touch it, if you have any five attb agonist activity, many drugs have been removed from the market. So, you know, that was he made that fundamental discovery. And so that was the drivers in the past where no 5HT2B and low five ht to a but if you had five minutes, etc. What can you treat? Well, initially, the people at Roche knew were interested in neuro psychiatry in the late 90s. And then the field moved to, okay we can use these metabolic diseases became hot, obesity became a hot area. And then other company called arena and other companies were focused on developing that for obesity, metabolic disease. So the 5HT2C, Alan and he basically was Brian Roth focused on neuro psychiatry. And they realised that, you know, the real excitement could be in schizophrenia. So let’s investigate and see what these things do and delve more into neuro psychiatry. So they did that and designed and Alan designed beautifully selective, potent compounds next generation to the market approved drug which was called Lorcaserine. Lorcaserine was the only drug It was developed by arena. It’s called belviq. And they wanted to market it and they marked it for us. So we were really lucky and are very lucky this efficient because Alan’s work, he invented a new class of compounds that are verify vctc selective that the excitement for us is now I think, clear now with the wave going to neuro psychiatry, their their effects on obesity, were actually very marginal where it got approved. And so actually, in 2020, the drug got pulled from the market because long these long term post marketing studies showed a slight increase in cancer risk for this first generation drug called as Lorcaserine. So they did two things. It shut down all the research in neuro psychiatry, all these people will try to move and do Clinical Investigation, for drug addiction for nicotine abuse, all these potential indications for this 5HT2C have stopped. And so the people are basically begging to know there’s a huge need for a new market and drug that has all this potential. And so the patent was that, Alan’s work was novel, this new class of molecules have patented and bright mind has been in real life and it’s also an issued patent. So I think we’re one of the only the only psychedelics company that hasn’t issued granting global patents and IP which is essential for you to partner with the pharmaceutical industry. So there are some interesting ways to look at this. And as someone who worked in the pharmaceutical industry, let me tell you how the value creation works. In the case of pharmaceutical entities, companies or startups spend a lot of time synthesising the right molecule and performing tests prior to human clinical trials. Once they enter the clinical trials, or when they are about to, they filed for patents on the chemical that enable them to capture value and exclusivity with regard to how they synthesise a particular molecule. And patent claims are eventually granted for steps in synthesis. In certain cases, patent applications may not be filed until much later when the molecule is in later stage of development. The reason for this is because as an investigational molecule, pharmaceutical development is a long game that spans multiple years. So filing for intellectual property, and getting patent claims granted, is a balance of when one potentially hits commercialization, and what benefits the timing of the filing made to the patent office is going to be. So in very simple words, you would want to file the patent as late as possible such that you have many years of exclusivity left when you commercialise the drug molecule. But unlike traditional pharmaceutical, drug discovery, psychedelics, and companies in the space like Cybin, Bright Minds, Bio, compass pathways, and others like ATAI Life Sciences, and mindmed, etc, are filing early. It is interesting that each one of these companies have picked a different starting point. For example, Simon has deuterated silos and as a starting point, with a goal to modify the physical chemical properties of the investigational molecule that they are developing for depression. Others have taken DMT or five methoxy DMT. As a starting point, companies like Bright Minds bio have taken a completely different approach to discovery of new molecules. And here as Gideon Shapiro, again,
If you don’t have patent protection, you got it, you’ve got no partnership possible. So we’ve got a great, a great, we’re so lucky, we’re in a great position where there’s no drug on the market is a huge on medical medical needs. There’s a body of literature that really showing that in neuro psychiatry, and even in neurology, they’re tremendous application, we have IP, so we were developing ourselves, but we’re sure they’re gonna be partners that are very interested. The mechanism is is really bonafide Big Pharma recognised. So we just, we just want to run forward with that. And we’ve got a great asset to start with, in the pipeline that’s in the psychedelic family writ large, because it’s just a five htt, two, agonist, compound, and then, and then we build out our pipeline and psychedelic the same approach, making it selective, again, removing the toxic effects, which is five HGTV, which nobody has done. So the real secret story is, you cannot dose get today’s psychedelic, like silicides and let their LSD because, you know, if you need to dose that more than once every six months, I think now you can dose it twice in the current clinical protocol. We know from our experience, that different patients are going to need different reset frequencies of dosing. different diseases are going to need different doses, different regimens, right? So you really need something that’s safe. So and if you have something to say even those less frequently, what are you going to take something that could basically kill you shouldn’t give me cargo, the Hobby Lobby or something that’s safe and work. Safety is key. I mean, for anything, I mean, the FDA, number one is do no harm. Be safe. Number two is efficacy. So a little evidence is important. This class of news, like regular psychedelics, it’s great, great breakthrough. But, you know, we see just the beginning.
Did you hear that? Did you listen very carefully. The way that some of these companies are thinking at this point is to develop these molecules and have two options. One to commercialise it themselves, which has its own risks in execution, and requires that they build out an entire manufacturing supply chain and sales infrastructure from scratch, or partner with existing pharmaceutical companies into partnerships or acquisitions. And the most amazing thing is none of the major pharmaceutical companies that have existing commercialization mechanisms have invested in psychedelic research. So it opens up an interesting possibility, when is the right time to jump? And what will the right value for acquisition or partnerships be without overpaying. So this will be a great cat and mouse game to watch out for in the near future. Another interesting area that companies like Bright Minds bio are tapping into is what is referred to as bias signalling. Let me explain this with an example of a classic receptor, the receptor that binds to native neurotransmitters like adrenaline. Agents like adrenaline bind to a certain class of molecular locks called receptors, which share some structural similarities to serotonin receptors. As explained in Episode Five, the episode where we spoke to Dr. Brian Roth from the University of North Carolina in Chapel Hill. Imagine the adrenaline molecule binding to the receptor. If you remember Brian Roth back in Episode Five, and Gideon just earlier in this episode, described the drug binding to the receptor as the key sliding into the lock. So when the key opens the lock, it triggers the motion of a number of levers and cogwheels. That is equivalent to the molecular cascades. But the beauty of these molecular cascades is that you have one to prevent overstimulation and acts as a turn off switch. And another one that favours activation of the proteins downstream of the receptor to elicit the function of the receptor like increased heart rate when adrenalin binds to its receptor in traditional molecules like adrenaline, this is a failsafe mechanism, where overstimulation is prevented. But in certain disease conditions, the same protective mechanisms can become counterproductive and cause disease. In the last two decades, there’s been an explosion of specialised chemistry to perform biassed signalling. One to favour the switch off mechanism are one to keep the molecular process going.
I mean, it’s the US in the end, pharmacology and chemistry go hand in hand, you spend the circle and that’s life. So the pharmacology is is the key driver, all we can do is we have ideas, but we don’t know what’s going to work. We need to make molecule test them. And the pharmacology is the key. And that’s what he was saying what are we are fortunate and having? You need the world leading you need the world leading understanding of the pharmacology of the second messenger system. It’s very complicated, like you said, You have different signalling pathways. So first the molecule binds the receptor. And then the signalling pathways now that have been worked out, like you said, in terms of how do they couple How do they create a signal? Whether it’s arrestin, right, which then basically turns the system down versus g the G proteins we simulate. And so the prevailing theory is, right now what you want typically why agonists are bad drugs, I mean a pharmaceutical person say Oh, you don’t develop an agonist because when you give an agonist and you give it once you give it twice the system desensitised and then it doesn’t work anymore. And that’s called tacky falaqa. Right. So the key to having an agonist work is either it’s not a full agonist, it has a partial signal, or what’s really the revolution now that everybody’s talking about is bias signal. So if you can tease out the desensitisation pathway from the activation pathway, and be selective, that you’re just activating your heads down regulating and turning the system down over the long term. So you need the science to run that acids, you need the molecular what’s happened now the revolution is just in the last few years do we have the molecular biology tools to clone these receptors and express them with the signalling molecule to tease this apart. And so that’s where you need cutting edge pharmacology that that’s been working in the field for long I mean, brian ross is, is the granddaddy of this field who Alan did his initial work with five H’s PC. So that whole programme they developed together. And now you know, we’ve got you know, the fan with a pedigree is, you know, john, trained with Brian. And so we have the guy who actually did all the work as a grad student, postdoc, you know, running the as a technology that gives us you know, the leg up, because that’s absolutely critical. And just to, you know, to put it in perspective, all historically, you have to redo everything. Because before people just did binding, they didn’t know, is this a blocker? Is this an activator? So all of the chemistry actually has to be redone. We are we doing? You know, the work from 20 years on silicides and an analogue to set a baseline because you get the point is nobody wanted an agonist and all the old literature, you wouldn’t even find the 5HT2B activity is pretty recent, this 5HT2B story really came out in the 2000 timeframe, you know, people have been working 50 years. So, you know, we’re going back to Albert Hoffman, and, and Shulgin did his work and, you know, it’s been a fringe area where, you know, it’s anecdotal data and we’re having to apply you know, the rigour of this modern signalling pharmacology to understand when we make a molecular chemical change, what is it to quantitative we had as an effective signal. And tease that out. At some level, it’s complicated at some level of engineering, once you have the athlete system, it’s almost like you know, an artificial intelligence, you crank out the data, you refine it, you do it again, until you get a drug. So the process is, is kind of boring and brutal, but you need the tools, right? And you need to. And we’re lucky because nobody wanted to do it. So we sort of lucky because we have the starting base, we have probably more knowledge and in the essay on psychedelics, and how to make it selective and anybody in the world.
Arun Sridhar 1:05:42
So this is chemical mimicry at its finest, if it works. So how do Bright Minds bio work on such concepts? What are the underpinnings to exploiting this in various disease conditions?
Gideon Shapiro 1:05:56
So that’s a great question. And I’ll try to make it simple. It looks complicated, but it’s actually not that complicated. Number one, the drug profile you want for any of these diseases, is fairly comparable. So number one, you need as with aggelos, for Merck said, you need a great drug. That’s number one. So you need to have something that’s safe at the basically binds to the receptor, and otherwise is going to be a safe drug to dose. And then the question is, that drug could be then the question, which, which indication do you develop and as you know, from Big Pharma, you develop many indications. And the trick is taking as a small company, if you’re doing it picking the right entry. indication, that gives you for the investor the most value, the shortest timeline to build on the way to think about we think about five hgtc initially, is it controlled impulsivity, right, and so impulse behaviours, like addictive behaviours, OCD behaviours, even the obesity, binge eating is essentially how it works is on the impulse on the eating impulse control. So all of these things we put into the bucket impulse control, both even the opioid disorders, etc. So that’s one way to look at that group of disorders and which one you pick. That’s the strategic plan that’s based on market Who’s your partner, whatever. What’s happened in the mean, what what happened, what Alan worked on, right was, was the application initially in schizophrenia in psychiatry. So Pfizer was trying to develop a drug called AB Catherine. That was one of the other big pharma project in schizophrenia. They did some big trial. Right on the animal models, it works. So in terms of what it does schizophrenia, is all about dopamine. So it’s not the five attc directly Intel five hgtc impact the dopaminergic system, which typically you want to dampen, for schizophrenia. So these compounds actually came out and were discovered to be effective in the classical animal models of dopamine release dopaminergic behaviours, catalepsy, etc. So that was a way back when Alan was doing the work where there was a big focus. But that’s maybe too overblown. So there are other agitation syndromes that we thought of done are quite full blown schizophrenia, which is a very hard disease, even if you got a drug that works to show an endpoint because the trials are so hard. Right even you’ve got a drug that works in schizophrenia, proving it clinically is tough. And and Pfizer’s results are on the edge. Okay, and then that field stop. So that’s sort of a, you know, something that you could do if partners are interested, and we’re sort of thinking about that, that still needs to be fleshed out. The big thing that’s happened really recently, is the one you mentioned in neurology, on epilepsy, and specifically, paediatric epilepsy. And the big difference here is that that’s very opportunistic. It’s just come out since chloramine, was approved since Appala, for dravet syndrome, even though it’s cardiotoxic. So it works. So well. This shows me the need that this mechanism of ceratin is quite amazing, right, that the serotonergic mechanism which typically you don’t think about for seizures, is working five HD mechanism. So that basically broke the door open and all of a sudden, there was this opportunity and in the meantime, there’s been a small trial with more Catherine right, which is specific for vibhushan be a better drug right, but still got removed from the mark. But it’s now being re investigated. Because the potential is huge. And it would be a better drug even though it’s got its own safety issues. Right. And so it’s just, it’s just obvious. I mean, it’s not rocket science, oh, they did it, we’ve got the same flavour and a better drug. And it’s the same mechanism. You know, I’m not saying we’re geniuses, in this case, this is just oh, there’s a, there’s a huge indication of unmet medical need. Everybody in the industry loves orphan diseases. That’s the focus of everyone, you have the multi billion dollar companies, you know, with 10 patient market. So, I mean, it’s just a no brainer that if it could work in there. And so we have data. Now, the exciting thing is, we’ve got the old that the interesting thing is in this epilepsy field, almost none of the animal models work. The traditional road models do not work for paediatric epilepsy, especially genetic ones that are inherited mutations. It’s notorious. And so in fact, the only thing that works is this genetically modified exact mutant of the ion channel in the zebrafish, which you can actually run an assay. And, and that is the model. So I mean, basically, that’s what we have now is a benchmark for efficacy to compare our compounds versus workouts or and essentially, these things work. And now it’s basically, you know, using basically the mechanistic analogy to say, yes, the seeds can treat this, there is a development path. The beauty is it’s a very nice development path. It’s very, very attractive for a small company, to be doing that kind of indication. So if you look at that, opportunistically, even though it’s only recently emerging, it’s really moving fast. That’s just, you know, it just fell in our in our laps, essentially.
Arun Sridhar 1:11:51
So with all of this help design safer molecules, I think one of the one of the interesting questions, it’s not so reported, everybody knows about part of the valve philosophy. But you know, there are acute hemodynamic effects. Right. And the point is, the dirty secret is the psychedelic, you get your heart rate, your your stuff, your blood pressure goes up, right. And so I’m not sure how much or whatever. And that’s not, you know, well captured in the databases in the literature. But there what what we do know is that for this class of drug, not all of you want to be selective, right? What you want is this, this electric, this sort of reset, doesn’t need a long trip time. Essentially, it’s a pole. So the idea that you don’t need a long trip, right, you need a reset. And where you want that reset to be is as fast as possible. So you can go into the doctor’s or the or the therapists office and be released not in six hours or be held overnight. But you want to go in and be released, like ketamine would be ideal, and sort of a two to four hour. That’s now an accepted practice that’s industrialised. So one thing that we need, as drug engineers is to engineer the molecule. And that’s what Ian was saying this next generation so that it’s convenient for dosing. Not only that it’s safe, but also that the trip time, or the experience is a manageable experience, on a timeframe basis, and on a doctor’s office basis, and eventually, potentially even at home. So I hope you’ve had a flavour of what and how these companies like Cybin and Bright Minds Bio are developing. But there are significant challenges. These drugs currently are not like traditional drugs, ingested once daily over multiple days, two years. The ones under development needs to and will go through all the processes needed for regulatory approval and clinical testing. But even with the existing molecules, combining psychotherapy and drug therapy is challenging the psychologist and the existing practices in psychiatry. So this is only going to compound over time and foreign investor. It is an interesting conundrum. Where and how should they invest? Do they go for new drug discovery, or novel discovery systems like the sublingual or the inhalational dosing? or forget all of this and focused on investing in wellness centres? How do they decide that? Who decides that? And given that most of the effects mediated by psychedelics are subjective, and psychotherapy acts as a guide through the journey? How can one clearly understand the effects more carefully, so more selective and better molecules can be developed and understood? How can technological innovations help the area of psychedelic medicine? How do we go from subjective To objective endpoints to understand psychedelic drug action. Well, the interesting parts are definitely coming. You just have to wait for the next episode for that one. You’ve been listening to PsychedeRx. PsychedeRx is a SKRAPS original podcast, produced and narrated by Arun Sridhar and JoJo Platt. SKRAPS is a volunteer run organisation created by our Arun Sridhar and JoJo Platt to disseminate factual stories of science, scientists and innovators as a service to the world. Select research for this podcast series was performed by Sharena Rice. The producers thanks Clara Burtenshaw for her invaluable input. Multimedia services was provided by Dr. Romeo Racz. The scripts were written and edited by Arun Sridhar and JoJo Platt. Financial support to cover the production costs was from Cybin Inc. and a kind donor, BB. Recordings were done at Caprino Studios in the UK, and Slightly Red studio in San Francisco. SwaminathanThirugnanasambandam performed the mixing and mastering. All recordings including interviews or properties of the producers, and should not be reproduced without permission to show notes, transcripts and useful links pertaining to the episode are located at the podcast website www.PsychedeRx.com