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Psychiatry, Psychedelic Medicine, LSD for Anxiety, MDMA for Autism, Medical Ethics, Mental Health

Full auto-generated transcript below. Beware of typos & mistranslations!

Daniel Karlin 5:59

Yeah, absolutely, so Dan Carlin I'm a psychiatrist by by profession. And by training, I'm also board certified in addictions and clinical informatics, so triple boarded physician. I did my informatics training before medical school, which is a little unusual. So I've got a master's in clinical informatics and cognition and medicine, which caused me to engage with my medical training probably a little bit differently. One of the things that I'd studied in my, my very earliest research was how we how we teach medicine and how we practice medicine and how we think about medicine as we do it. So it set me in, in what would have probably been a somewhat critical viewpoint of, of my or at least a skeptical viewpoint of a lot of what we were learning and how we were taught it. And I think that is carried through my career today that I try to be very cognizant of things that we that we know, versus things that are just the way we've done things historically, versus things that we maybe think we know, but don't necessarily know super reliably and trying to categorize our knowledge and the information we encounter in the world in that way is has been as much of a theme through my career as anything. I trained tufts for residency for psychiatry, I went to undergrad and graduate school at Columbia here in New York, and went to medical school at University of Colorado, so have been all over the country along that path to where I am now.

Nick Jikomes 7:31

Yeah, I mean, it's really interesting when you think about science, but especially medicine, like obviously, it relies on science, and our knowledge is being updated all the time. And it's, you know, an explicitly science and knowledge driven profession. But it also relies on tradition, necessarily, right? Like you have to, you have to have ways that you do things, just so that you can, you can operate a medical practice. And because we don't know everything, right, you have to be able to act even even in the absence of knowing every single thing that might be wrong with someone or why or what to do about it. So there's this interesting, you know, sort of dynamic tension between sort of the science and knowledge side and the tradition side just doing things because that's the way that they've been done, you know, thinking about medical education. I'm curious, like, what were you skeptical about? Or like, what how does medical education work today? And what are the ways that maybe it's deficient? Or the things that's maybe not focusing on?

Daniel Karlin 8:31

Yeah, that's an excellent question. And I absolutely will second your point that so much of medicine, and the systems in which medicine is practice, so the health care system, but also even our political economic system, you know, everything sort of exists in these outer layers of of systems that many of the components of which are either political or non scientific or not studied in a rigorous way. So it's interesting to think in, in healthcare, about layers that are studied in so called Evidence based medicine, and we can talk about what that means, and maybe what it doesn't mean as well. While that sits inside of, say, a non evidence based for profit generating payer system that may modify the way that the actual medicine is practiced, specifically on medical education. I do think that there are some instances one specific example would be that the way that medical students and resident physicians are trained to think about diagnosis is this interesting process called differential diagnosis where we give them a bit of information and have them think about all the things that could contribute to knowing this one thing about a patient. And then as we give them more bits of information about the case, they narrow the differential until they're left with a few possible options. And then the question is, well, what would you do to narrow the options further so you might know which direction to go And while it's appealing to imagine that that's what's actually happening in clinical practice, what we know from essentially the study of cognition and medicine is that's almost never what's happening that when, when a clinician walks into a room, they have very quickly picked a leading hypothesis for what they're seeing. And they ask questions to confirm. And we hope to refute that hypothesis, because it's very easy to just ask questions that go down the road of confirming the thing I thought from the beginning. And so that's the difference between forward chain diagnostic logic and reverse chain diagnostic logic, we teach it one way, even as those folks who've studied it know that the reality is that what's happening in the room is very different. And you can find lots of examples like that in medical and resident education, I think another disservice that we do to medical students and residents is not teach them enough about the system in which they'll be providing care subsequently, the things that they'll be asked to do to make money to make a profession out of the, out of all the information they're gathering along the way. So it's, those are two somewhat isolated examples, but but you can find things like that almost everywhere you look.

Nick Jikomes 11:15

Yeah, I think there's an analogy with basic scientific research, in the sense that, you know, you're trained to do the thing. But you just have to learn by doing, what kind of system you're embedded in, what kind of structure you're embedded in. That, you know, like, what, like, when you learn to do scientific research, you really, more or less, just learn the scientific research part. And along the way, you know, you pick, you know, you learn to write grants and these things, but you don't really know until you become, you know, a PI somewhere, exactly what you're dealing with, in terms of, you know, running a lab from an administrative and financial standpoint, from, you know, what it takes to get grants and the the kind of pressure that will put on you and the amount of motivated reasoning and confirmation bias this will naturally give you and, you know, it sounds like it's similar in medicine. So there's, there's not not such an explicit focus on the education side to teach. You know, who will become physicians, what it's going to be like to work in a particular type of environment, especially when it's that you know, it's ultimately profit driven is gonna gonna naturally pull your thinking in a certain direction.

Daniel Karlin 12:28

Yeah, and even if not profit driven, at least has to get Bahrain has to make more money than it spends to provide care. And I think what you're the maybe the zoomed out version of all of this is what what are the unwritten rules of the space in which you're operating? What are the untaught aspects surviving? So if if you're purely a provider, a doctor providing patient care, you know, patient care is the is the the economy is the currency of what you do. And it's you be seeing enough patients are you billing a billing enough is enough billing codes to make your practice profitable. On the far other end is, if you're doing research, the currency is papers and papers, get your grants and grants get you more grants. And a lot of folks, of course, live somewhere in the middle where they have a academic medical practice, and they see patients on with some of their time and have to seek funding for research with other parts of their time. Certainly, in both there can be strong, and this relates back to what I was saying before about how we teach diagnostic logic, there can be strong and center for confirmation bias. So if you've often this ties back to one of my core interests, which is measurement, how do we how do we measure things in science and medicine. But I often talk about the fact that we report caught financial conflicts of interest as these bad things that we're you know, you should be suspicious of me when I tell you that I get paid to do this, that or the other thing, but then to report things like papers written and grants funded about an idea, we ought to be equally if not more suspicious, and the things that I built the ideas that I built a career on that enabled me to continue to get funding, so that those are the things I'm most likely to go out and not refute. Because I start refuting my own ideas. How am I going to get funding to keep doing research?

Nick Jikomes 14:20

Yeah, no, I think I think that's super important. I definitely, I definitely, you know, when I was in the academic world, like for my PhD, you could see that very clearly like you, you know, you're, you're in a lab, you know, there's people running various labs, all of those labs, right? They need money to fund all of the research, you have to write a grant where you basically say, here's my idea, here's why it's relevant and important to human medicine or whatever. And I think this is the way it's, it's going to work. You know, you're very motivated to prove something like that is true. And once that wheel starts turning, right, you want to you want to keep it turning. And so there's just, you know, it's And there's nothing. Yeah, it's not like anyone is doing anything wrong. It's just that you're organically going to be motivated to go down certain paths and not disconfirm your original ideas, because there's always going to be this lingering risk that might shut off. What? What keeps everything going?

Daniel Karlin 15:19

Yeah, I think, well, we can obviously find examples of just flat out malfeasance in science and medicine. Of course, there are people who are dishonest or bad actors, for whatever reason. But those are almost less interesting to me, there's great folks out there who are actively working to find that and to root it out and to prevent it, and there's malfeasance everywhere. So that less interesting, but I think exactly what you say, which is that people respond to incentives in their environment. Often, it's hard to identify the incentives, if you trust that the meta structure that someone presents, the things that they're that they're finding, is the outside edge of analysis, right? So if you just look at findings in isolation from an individual research, study, find you may believe that you've learned something true about the world. But if you shift that meta structure out, you know, open the aperture as it were, you struggle to identify these incentives like you have, well, of course, you're incentivized to continue to find that your previous findings are generalizable and replicatable, and all these things. yet so often, when replication research, which is relatively hard to get funded, right, you're not saying I'm gonna go find something new about the world, you're saying, I'm gonna test to see if something we already believed to be true is actually true. And of course, in all of science and psychology is particularly suffered from this lately. There's this crisis of of replication, where other groups seeking to identify essentially replicated, same or similar experiments end up with very different findings, which usually suggest that something about the meta structure of the original research was set up in such a way that that's what generated the finding, rather than it being a generalizable finding about a larger population or applicable to other sites or their regions, or whatever it might be.

Nick Jikomes 17:09

Yeah, I remember I remember learning when I was in graduate school, they irrevocable, a replicable finding is, you know, across fields and across subfields is actually that, you know, when some result comes out, we find that something is true, we think about about the world. As that result gets replicated, the effect size tends to go down over time. Which, which sort of points to I think what we're talking about here is because people are incentivized to find these sorts of big, dramatic, sexy results. And even when they do replicate, they tend to very often turn out to be not not quite as striking as originally thought, as people do the same or sort of adjacent experiments over and over again.

Daniel Karlin 17:56

I think that's, that's exactly right. And it can be something as simple as how much of social psychology or psychology research is done on college campuses, where the recruitment population is college students at that particular university, and you recruit, you know, 40, or 50, or however, and randomize them and, and then run whatever the experiment is find some finding, and say, Okay, well, this is true about people in general. But the, the selection bias happened way upstream of the research itself, the inclusion exclusion criteria could be very robust. But if the population from which you're picking is just psychology students at an undergraduate, particular undergraduate campus, you know, that this is exactly an example of, within that narrowly defined meta structure. This may be a true finding, but the generalizability is hampered just because of the population from which that sample was selected.

Nick Jikomes 18:52

And, you know, when you think about some of these things, you know, how the structure in which we do things can can bias us and when you think about things like medical education, how do you think these things have affected the field of psychiatry generally, especially, you know, in terms of how we think about treating things, so treating treating symptoms, rather than treating causes, and, you know, putting people on medications, that will be revenue generating over and over and over again over many years, and things like that, you know, because, you know, some of the some of the stuff we'll get into is sort of where is psychiatry today? And and where did it come from and where is it going? But, you know, what, what are some of the, I guess, what would you say some of the major problems are today in terms of how effective our psychiatric treatments are or aren't and where does that come from? And how do you think about

Daniel Karlin 19:43

it? Excellent question, and right up sort of right up my alley in terms of what I spend a lot of time thinking about what I'm not working on the core aspects of drug and device development, psychiatry has allowed itself I think and contributed to itself becoming less than it, it could be. And it's done that in the service of this sort of neuroscientific occation of psychiatry. But the reality is that neuroscience and psychiatry are still living very far from one another. And, and that's okay. And we need to be making efforts to bring the two together, but recognizing in the in the interim, that fundamentally, the practice of clinical psychiatry largely deals with some signs and symptoms, right, the phenomenology of disease and things like the DSM, while we need standardized ways of defining disorders or diseases in psychiatry. roughhewn combinations of signs and symptoms just aren't aren't going to do the trick. And they don't really bring us toward a set of disease definitions that will have biological meaningfulness. And so you look at things like GA, D, and MDD, right, which we would think of as being pretty different diagnoses, right? Once an anxiety disorder, the others have a mood disorder and affective illness, yet, the construct overlap between the disease definitions for JT and MDD in the DSM is 80%. So that means that, in theory, 80%, of folks diagnosed with one also could be diagnosed with the other, and we see that their code diagnosed often. So we've got in there a few factors here. So this is going to take a minute of some history of psychiatry, but So fundamentally, we have a biologically imprecise set of disease definitions against which drugs have been tested, and in some cases have been demonstrated to work enough to be approved by regulatory bodies, and then are prescribed for these conditions. But unsurprisingly, what we repeatedly see is that drugs that are very narrow and precise mechanisms of action are not shown to work. Because of course, if you take a group of say people with GID, or MDD, acknowledging they have a range of biologically diverse underpinnings of their disorder. And these disorders are, of course, the result of complex interplay between the biology of the person they're there in utero in early childhood experiences, their adult experience, their current living environment, the stresses in their life on a day to day and year to year basis. And so very precise mechanism drugs, well, why would we expect them to work against something that is likely a multitude of fundamentally rare diseases, and drugs that do work against anything often seem to work against a bunch of things, you think about the second generation antipsychotics that started with indication for things like schizophrenia then wandered into bipolar disorder, and of course, they're now adjunct antidepressants as well. So, psychiatry, so taking that, you know, as as a starting point, and then we look at okay, so what's the role of psychiatry been in the world, since it's the start of the start of the 1900s when psychiatrists becoming a thing, and, and psychiatry initially, think back to Freud, and you know, who's doing the talking cure for neurological illness curing neurological disease with his voice, and people like Kraepelin, who are doing very fine grain phenomenology in mental hospitals. And what's happened is that along the path to hear one, when a disease gets more of a biological underpinning, so think, epilepsy, epilepsy used to be treated in mental institutions, it was seen as a as a psychiatric disorder. As neurology advanced and EEG signals for epilepsy were discovered, it became a neurological illness. Now there's some accidental tails that come along with moving a cluster of diseases into a new specialty, which is that we know that there are what we used to call psychogenic seizures or non epileptic seizures. Now, neurologists have to own non epileptic seizures, even though those are very likely more psychiatric disorders, some sort of conversion disorder. And so that trend over time has been reduced and changed. What psychiatry takes care of in interesting ways. Every specialty has diagnoses that the specialist in that field, like functional, abdominal pain acknowledged are a complex interaction between brain and body, which most diseases probably are, that maybe would better be treated by addressing someone's stressors and their mood and their anxieties. But this gets into a whole nother line of reasoning, which is defense mechanisms and how we defend against uncomfortable feelings. Certainly, some people defend against uncomfortable feelings by experiencing them somewhere in their body. So then when you confront that defense by saying, Well, maybe you should go see the psychiatrist. Oh, are you telling me this is all in my head? And that's the defense doubling down on itself by saying, Well, if you don't accept this as In my body, I just see someone else, right, because when you confront a defense directly like that, it, it pushes back strongly to protect to protect itself. And it's protective function for the person. Psychiatry moves forward through time. And in the modern payer environment, we've disposed of our most precise, and at times curative intervention, which was psychotherapy. And really, I'm talking about dynamic or depth psychotherapy. And given that providers with less training, who get paid less, because they, they're expected to be able to make a living on the payment rates from third party payers for psychotherapy, while psychiatry is very much moved in the direction, this is all we're talking third party payer supported it's a different deal with you can afford to pay some privately and you can, you know, their providers who just do that and provide psychotherapy as psychiatrists, you know, whatever else. But from a payer perspective, if you're a psychiatrist is going to take insurance as your primary payment mechanism via network and all of this, likely what you're doing is short med management visits, because that generates the sort of salary you were told to expect, based on the training you received and the time you spent getting there. And so psychiatry is more or less relegated itself in the payer environment to prescribing and psychotherapy has been shifted over to Masters level psychotherapist who says some of them are incredibly competent, and they united in no way do I want to. Sometimes it sounds like it's sort of inter provider rivalry, but I'm really just trying to describe the reality of the practice environment. And because those folks likely have, they can go get a lot more training, but in order to practice, they have less training to get get out the door. And psycho therapies like cognitive behavioral therapy, are meant to be a solution to that, how do you take someone with less training less experience and give them something that's more likely to be effective. But of course, cognitive behavioral therapy is not historically what psychotherapy depth psychotherapy was, and is, you know, by all it's called evidence based, because it's easier to study, it's easier to show results that look a lot more like drug results, which has symptom reduction at four and eight weeks. But maybe that's not the point of psychotherapy is symptom reduction at four and eight weeks, maybe, maybe symptoms get worse on the way to getting truly better.

Nick Jikomes 27:18

And what, you know, one interesting question that comes to mind is how, how should we think about something like patient autonomy, when it comes to thinking about the whole diagnostic and treatment process? Because on the one hand, you know, naturally, naively, intuitively, you want complete patient autonomy, right? You want to have your choice of doctors, you want to be able to choose the doctor you're comfortable with, you want to be able to go to whoever you want. That's, you know, that's definitely my inclination as a potential patient. I think it's everyone's natural inclination. But on the other hand, you know, just just like in any other sort of sector, we could talk about when, when the customer, the patient, in this case, has the choice between multiple providers, multiple physicians, you know, this sort of insidious loop that that can take, take hold as if, you know, if I don't like the answer that my physician gives me, I can simply go to another one until I get the drug and the prescription I want or the treatment I want, I might not like, I might not like a diagnosis, even if it's accurate, just because I don't like it. And you know, I can think of many examples my own life. And I think this is probably pretty obvious to everyone, you know, a lot of people out there who have some pill they take or some treatment they're getting, they sought it out, they either got it on the first shot with the first position, or they simply went to someone else when they didn't get what they wanted the first time.

Daniel Karlin 28:44

You're touching on something that's incredibly important and societal, even as much as it's medical. And there's so many different angles to look at this from. One is the ethics of medicine, where there are four values that can align or can be in competition, beneficence, non maleficence. Justice and autonomy. And we, in American medicine tend to privilege autonomy over almost everything. So if you think about end of life care decisions, or as you say, the ability to sort of get the treatment that you that you think is the right one for you versus the one that the first doctor recommends. And intuitively, autonomy makes a just a ton of sense, right? People should have the right to bodily autonomy to choose for themselves. But at the same time, that presupposes that, particularly in psychiatry, that what someone wants for themselves is necessarily what's best for them so that the best beneficence and autonomy can come into tension with one another, or that someone what someone wants for themselves necessarily represents what's best for everybody is a generalizable concept. So there is autonomy coming into tension with with justice and you can think of examples where what someone wants. So someone goes into an ER and says they have back pain and wants opioids, and that may be harmful to them. So So those two values, non maleficence, and autonomy come into tension. So there are all kinds of examples where what the request for services doesn't necessarily match what the provider of whoever the patient is seeing thinks is best for them. And so how do you resolve that tension, it's a really tricky thing. And then overlay on that. And the example I like to use is anxiety, depression. So thing neurotic illness, pain disorders, and addictive disorders. Some people clearly live in one piece of that pie or another one part of that Venn diagram, however you want to think of it or another, but a lot of folks sit on an intersection between either two, or all three parts of that. And, for example, if you're someone who sits somewhere in the middle of that you go, see a psychiatrist is your first stop. Well, they'll take probably an orientation toward how do we deal with your neurotic illness? You know, what are the medicines and the potential psycho therapies we can do for that, to make your pain or your your addictive, drive less relevant and less, less important to you unless needed. If you go to a pain clinic, they'll start with the pain and give you pain treatments. And if you go to an addiction clinic, they'll start with with the addiction and maybe give you a drug to reduce, you know, an opioid partial agonist like suboxone to make it. So you use fewer drugs. And so what a weird thing, that the person is sitting at the intersection of these likely disturbing and functionally impairing experiences of life is the one picking what the right treatment is. So it's it's both understandable that we privilege autonomy. And really tricky mean, another example is informed consent. So we, we, and again, not saying this isn't important, but there are aspects of informed consent, particularly an overemphasis on the risks of an intervention, that increase the likelihood of having that risk, so that the no SIBO effect is alive and well, right that you can, if you if you hit what the bad things about this medicine are going to be too hard, someone's more likely to experience them, you know, you weren't someone about sexual dysfunction enough, you can definitely get them to have some sexual dysfunction. And on the other side of that, if, if a medicine is prescribed with good trust and rapport between the person prescribing it, and the person taking it, the medicines more likely to work? Well. We know so. So there's clear tension with the right and responsibility for a person to know the risks of something they're undertaking medically, but also the risk that they don't sustain enough benefit or that they're even potentially harmed by knowing, knowing those things. And I don't think we have good resolution to this or clear answers. But the will offering that there is a real, at least starting point solution in the dyad between a physician and a patient is to discuss these things. And if there's of course, now there's the tension with time and the room and billing and all that and all those things, but just start from the perspective of what are your goals for yourself? How can I help you reach those goals, and to make it to make it as much as possible about the person and what they really need, versus what they're their primary request for services.

Nick Jikomes 33:28

You know, one of the things we'll talk about too, is sort of the Mental Health trajectory in the US and the Western world, broadly speaking. I mean, I think most of the world broadly speaking, you know, a lot of things are on the rise. So mental health, by many different measures has been on decline for quite some time. So, you know, we can cite various statistics to anchor us but you know, anxiety and depression, generally up into the right for most groups, some more than others, things like ADHD up into the right autism, I mean, you know, we got on the list, you know, more people are being diagnosed with things more people are taking, not just a psychiatric medication, but often combinations of them very often, chronically for long periods of time. You know, costs are ballooning, et cetera, et cetera. But just on the piece of sort of our mental health trajectory, how do you start to think about the, the apparent conundrum of you know, on the one hand, things are good, right? Like we have more technology and fancier technology than ever, we have more medical and biological knowledge than ever. Our lives are easier by many measures, and they were for our ancestors in the deep past, certainly, the more comfortable at least. And yet, you know, people are sadder and more anxious and less able to focus. And there's a million different things we could talk about the tie into this and many different sort of levels where the discussion could sit out. But why are we on this mental health trajectory and what does that have to do with the way that we can ducked Western medicine today?

Daniel Karlin 35:04

Well, you certainly acknowledged one part of this, which is maybe maybe we're just detecting this better and we're giving people permission to be unwell in whatever way they are and ask for, hopefully to ask for help with that. And that helped may come in the form of medicines that may help. That's almost Well, interesting from a health systems perspective and and a service delivery perspective, I think from a philosophical, or even from a true psychological angle is a little less the interesting question which is, so let's, let's assume that we do, as you say, probably live in about the safest world humans have ever lived in. We have some blips COVID, obviously, was not a period of radically increasing safety or anything like that, and wars and things will, will put us into a regressive periods where more people are dying younger. The generally speaking, we probably the safest it's ever been, and more likely to have access to food and water and things that, you know, hundreds of years ago, or even 100 150 years ago, we're less likely, of course, there places in the country in the world where that's not true. There are places in the country where that's not necessarily true. And there's not access to, to say, clean water in certain places. But why are we so anxious? And why are we so depressed? And there's an angle on that which you mentioned, access to technology. So for even with folks who have their basic needs met, and are able to get food, water and shelter? And are generally you think, living in what should be relative comfort versus most of human history? Why are we so anxious and so depressed? And I think part of that is that we're constantly confronted with messages of danger, and risk. And it's all around us, right? Partly, I think, because that sells that captured, we're in an attention economy, and have been for a long time in terms of print media, but certainly in you know, video media, starting with TV and progressing through now to sort of everyone being on TV, and somebody asked to write now, of course. But in order to keep attention, one really effective strategy is to present risk, we were evolutionarily attuned, to pay attention to messages of risk to potential danger. And so being constantly inundated by messages of of risk, I think, very likely a component of this. Also think, and again, this is sort of a worldwide phenomenon, but also very prevalent around us here that economic inequality, and being constantly exposed to what the great things that other people have, or you perceive them as having, while at the same time being confronted with extreme poverty, I think leaves a lot of folks who aren't on either end of that, striving in a way that they're reaching for something they're unlikely to ever grasp, of the same time having to look down literally beneath them on the streets, and see what happens if they don't just keep grinding.

Nick Jikomes 38:16

And what about, you know, just just talking about abundance itself? I think, you know, it's very easy for people to think, oh, we live in this world of abundance, there's lots of food, there's lots of stuff around, then that's why things, you know, are comfortable. And that's why the modern world is what it is we've we have used, you know, our brains to create technology, integrate social structures that give us an abundance of stuff. And therefore, it's it's often counterintuitive to think like, well, if we have all this abundance, why are we becoming less healthy in many ways? But is it possible that abundance itself is the problem? You know, if we sort of think about, think about that question. And then, you know, in parallel, think about, you know, early hunter gatherers, the types of people that we evolved from, you know, they had to go out every day and there was many signals of danger in their environment, right? Like they didn't didn't have billboards and Facebook and social media, but you know, you actually had to go out into the woods or into the savanna and there were actual monsters that would eat you potentially, and, you know, you really had to think about getting food, not because you just want something tasty, but because it was a matter of, of life and death. And does abundance play a role here where, you know, all of these sort of basic survival things are there, and they may not be equitably equitably distributed, they may not be you know, where we want them for everyone but we don't have to, we don't have to go out into the world and and move our bodies for literally life and death reasons like our ancestors did. And so that abundance creates space for a lot of other mental health problems to to just bubble up because we we aren't focusing our minds on literally life and death day by day, week by week.

Daniel Karlin 40:05

Yeah, it's certainly possible I mean, this is this is something where I often wonder what it would be like to engage with phenotypically Gino typically modern humans, you know, as they expanded across their the creek crossing the Bering Strait with 30,000 years ago, and what that experience was like, of course, communication would be somewhat difficult, and we'd have a common common means of communication. But even just watching social interaction would be incredibly interesting. Where Where does dissatisfaction come from? Sorry, in the hard question, and if we had easy answers to this, we would certainly, you know, we'd probably be better off if there were modifiable factors. alienation from one another, I think, though, is is the sort of, you know, last 500 years of, of human history is probably dominated by increasing alienation from each other, and an alienation from self, which which of course manifests as this defense mechanisms I was talking about earlier, and just the fundamental feelings of unease in the world, when I was used to practice Addiction Medicine aided addiction clinics in the Boston area. And the best conceptualization that I heard from the nature of addiction through that was lack of connection that addiction sort of replaces true human connection. And certainly, as we look at what sort of masquerades as human connection today, a lot of it isn't a lot of it isn't the sort of connection that she'd hoped for, and that you can derive satisfaction and comfort from and you know, certainly, while you can have a large count of people on your, your Facebook, your Instagram or LinkedIn, I wonder how much of that actually causes the feelings of satisfaction that come from a real sense of of connection?

Nick Jikomes 42:07

Yeah, yeah. I mean, it strikes me that, you know, on, on the one hand, we live in a hyper connected world and social terms, but on the other, but in another sense, it's actually the opposite, you know, so if you think about, you know, our ancestors are the type of human being from which we evolved, that we still are sort of under the hood, in many ways. You know, we evolved in bands of, you know, dozens, maybe hundreds of people, most of them, you knew, and probably knew very well, you know, family, very close friends, you know, most of those people were not mere acquaintances. But today, right, it's much more likely that you have many, many, many, many more connections, many more people that you know, or know of, but the strength of your connection, the thickness of the line connecting you is much weaker today. And that that does seem to be a trend for a lot of people. And so we're in this, I guess, somewhat paradoxical situation where the opportunity for connection is sort of more abundant or easily available. And yet, the the number of strong connections appears to be going down. I think, for a lot of people actually, despite that,

Daniel Karlin 43:14

and maybe even the strength of those strong connections, you think about what ought to be sort of, if you just said, well, automatically, who you're strongest connections with and family, either family of birth, or a family that you've created through bonds, like marriage, 50% of marriages ending in divorce, and as much inter familial birth family acrimonious, exists, it does seem that even in those places where the strong bonds ought to be identifiable, or where we would point to and say, well, that's those are the strong bonds, maybe they're not. And and I think that I think that both the sensation of those bonds not being as strong, and or the worry that they might go away is is a huge, huge source of distress. This relates to narcissism, of course, which is experiencing the self through the reflection of your own projection, our projection and how it's reflected back. There's a whole interesting thing about character development, personality, that sort of is a through line, I think, from very much what you're describing the sort of modern, modern evolution of our relationship to one another, and to and through technology.

Nick Jikomes 44:30

And, yeah, I mean, so when we think about mental health and social connections, and start to try to tie that into, like how, how psychiatry approaches treating things today, oftentimes with medications that are taken chronically, that are sort of just just, you know, nudging, nudging things one way or the other, and if you think about something like an SSRI, right, they're just, they're, they're essentially just elevating serotonin levels, and the hope is that that's gonna sort of nudge you in a certain way or another They have some level of effectiveness that we can talk about. But you know, now, you know, the subject that that you work on, and that will sort of come to and tie into this is you've got a very different kind of medication being talked about in the mainstream now, which is psychedelics, and they aren't sort of like, there aren't these drugs that have sort of specific and and you know, what would you say they have sort of, you know, an SSRI sort of is a drug that has a sort of broad, weak effect, it's just sort of meant to like, kind of nudge you in one direction. Whereas, you know, when you take, you know, LSD or psilocybin at a sufficiently high dose, you know, you're going to have, you know, an hour's long experience that you'll remember for the rest of your life. So it's a very different kind of beast in terms of how it works acutely, at least. And so how do you start to think about some of these things? And how does that inform sort of the direction that you've gone?

Daniel Karlin 45:56

Yeah, again, that opens up just so many interesting doors that we could walk through. I'll start with SSRIs, I don't include selective in there, because you know, they're not pretty. And so here we have serotonin reuptake inhibitors, right that have we know that they do that. And when they were developed and approved, we said, Okay, well, that's the mechanism, we're gonna call them SSRIs. And they start blocking the reuptake of serotonin after the first dose, and you can see fMRI changes and to make their hyperreactivity after the first dose, they're doing something right away. But we all now know that they take weeks and sometimes months to get to the rate to get up to a high enough dose that they actually do whatever it is they're doing, which is clearly not reuptake. It's not mediated through the blockade of the reuptake of serotonin, it's mediated through some downstream or other process. So even those, since since the very early 90s, the drugs prescribed millions, millions of times, and we're doing all the work, but what they do is modulate symptoms. And I said this about cognitive behavioral therapy before that very much at the same sort of modality, which is, can we make the distressing symptoms in your life less distressing. And, you know, I have to be so careful in what I do. You know, my med is we're developing drugs that fundamentally are different than that are some are and some are more similar to that. To Be careful not to dismiss that the these do add real benefit to real people's lives. And there are people whose lives are a lot better because of cognitive behavioral therapy, or an SSRI that they've taken chronically, and their life is more livable, and they're more functional because of it. So we never want to dismiss that out of hand, we got to have a lot of tools to deal with the reality that a lot of people are suffering, and they're suffering differently from different underlying pathologies. But then you look at a drug like mmm, 20, their mind meds, pharmaceutically, optimized LSD, and as you say, multi hour experience after taking it, and then lasting change. What's really needed is, again, as you said, people have experiences potentially, while they're on drug that can be extraordinarily deep and meaningful and memorable. And again, memorable cases for the rest of someone's life and maybe describe as most important experience of their life. And I think it's really a nice idea that they work, at least partially by that mechanism. There is a debate in this space that in between, I think, a false dichotomy between they work via some psychological effect, and they work via some sort of neurobiological swla of what the drug does that are receptor level, I think the answer is probably both, and different in different people. But they are LSD, specifically, very, very potent, all of all of the class is able to to result in strong perceptual and mood and effective changes. So the, you know, that we're talking about drugs that are drugs, still producing, and, you know, do have these these very, very profound acute changes associated with them. The hope, of course, and I think as, as more and more research is done, as our research comes out, as others does, and as we look at retreatment over time, and disease trajectory over time, the hope, of course, is that these drugs are more like, say dynamic psychotherapy, and that they create lasting change in how it is to be the person who who's been treated. And you know, we're always hesitant to talk about your or, you know, does even disease modification little strange when it comes to psychiatry, but lasting change really is the highest hope for any psychiatric intervention and these drugs more than any other I've seen, offer promise in that direction.

Nick Jikomes 49:58

And so can we talk about You know, some of the specific work in the trials that you're doing at mine Med, get, you know, to give everyone a basic overview of what my man is and sort of where it comes from. And maybe let's just start with the one that you mentioned the mm 120 drug.

Daniel Karlin 50:13

Yeah, so mm. 120 is a pharmaceutically optimized form of LSD. It's been my meds leading drug for as long as I've been with my metrics almost two and a half years now. We are currently conducting a sponsored regulatory grade phase two trial with M and 120. And the point of this study is to look at different doses. So we have four different dose arms, 25, micrograms, 50, micrograms, 100 micrograms, and 200 micrograms and a placebo arm as well. And it's a single administration. Now, interestingly, now that you've heard me go on and on about psychotherapy, in our drug studies, we've really de emphasized psychotherapy to the point that we don't have psychotherapy happening in our studies. You know, you hear ideas like preparation, integration thrown around, I think they mean so many different things to different people that they're almost not meaningful terms anymore. So if we call preparation, something that happens before someone takes a psychedelic trip, well, we have an informed consent process as someone joins the research study. And that process includes things someone might experience while they're on drugs or not on drug, of course, because some folks are they're getting a low dose or a placebo. It includes what the folks in the room who we call dosing session monitors there to in every session might do if someone's having a tough time, or has an anxious reaction, or if they need to go to the bathroom and don't feel super comfortable getting there on their own, or they want to snack. And then we have assessments after after the session. And what we're looking at as our as our premier outcome measure is the Hamilton anxiety score, which is the standard regulatory grade, FDA facing instrument for assessing anxiety. And we're looking at that at primarily four weeks, and then also following out to eight and 12 weeks to see about sustained change. And we're doing we're doing some tests earlier on as well to look at the rapidity of the change, and how quickly people experienced that that change.

Nick Jikomes 52:21

And you said it was it's a clinically optimized version of LSD. So what does that mean? What was optimized about it? How does it differ from regular LSD, whatever exactly that means, and why did it need to be optimized in some way?

Daniel Karlin 52:37

Yeah, so LSD is tricky to make, and it's it potentially in historically has been unstable and doesn't have good shelf stability. And obviously, LSD manufactured in illicit Labs is of unknown quality, and who knows what else can end up in there. But this is, so regulatory grade manufacturing via good manufacturing processes with with very good stability, delivered in a in a medically recognizable way. Some of what we're doing in the development of as the as mm 120 is still undisclosed. But but certainly as we as we work along the way, and as more IP gets published, and things like this, there'll be there'll be more to say about how exactly we're going to deliver to be marketed product.

Nick Jikomes 53:26

So okay, so So one of the ways it was optimized is that we know LSD is sort of a very, it's sort of a complicated chemical, and it's very delicate, right? So it's light sensitive, it's heat sensitive. You know, for those who don't know, it's, it's actually very sensitive, who took a vial of LSD, and put it in direct sunlight or something, it would basically be destroyed. And, you know, I don't know, an hour or two or certainly an afternoon. Okay, so it's a more stable version. And can you just talk a little bit we don't need to go into a lot of detail, but maybe you can't yet but like, how was it? How was it stabiliser? What is LSD de tarde trait mean? Chemically,

Daniel Karlin 54:06

so it's a salt with detailed trade, which is not always with LSD salt is made with but, you know, both the manufacturing process, the conditions under which it is introduced into the capsule formulation that we're using in the in the face to be storage conditions, all of these sorts of things address exactly what you're saying that we want to make sure that the drug we're delivering to participants at the, at the study site, you know, at the time of their dosing, is what we claim it to be. It's the, you know, the right, the right quantity of the, the act of drawing and not, you know, not degraded in any way, you know, at the time of administration, and as I say they'll you know, obviously over time, they'll be able to say more and more about how we're how we're thinking about it to be marketed product.

Nick Jikomes 55:00

And so remind us. So what are the clinical trials that are underway, or that will soon be underway? What elements are you looking at? And what like why did you choose LSD as opposed to psilocybin or something else? And why did you choose these elements?

Daniel Karlin 55:17

Yes, generalized anxiety disorder is the target of our face to be five arm study the dose range finding study. And as I said before, GA D. Historically, a very relevant disease, the primary focus of psychiatry for a long time, really until the SSRI era was anxiety disorders. And it was only through the promotion and sort of mainstream and widespread adoption of SSRIs that MDD became this primary diagnosis. And, of course, as any diagnosis gains. A population binder gains epidemiological relevance because being diagnosed more, more money flows into it. And that's a sort of afford feedback loop that's led to just a ton more focus on MTD, over the last 30 years or so. But we think JD is an incredibly valid and relevant diagnosis. The pendulum does seem to be swinging back to a more moderate, like moderate, moderate, or modulated direction. And thinking about depression versus anxiety and how they fit together and or sometimes don't fit together. You know, there's recent, US PSDF to the Preventive Services Task Force for the United States to make screening recommendations based on disease burden and cost effectiveness and things like this has now recommended over the past past year and a half, that all adolescents and children eight years of age and older gets screened for anxiety disorders, that all adults be screened for anxiety disorders. So growing recognition of the importance of anxiety, it seemed like a good white space for us with most of the other companies in our sort of field are adjacent to us going either in the MDD, or PTSD direction, that seemed like a good place for us to go. Wireless D is a really good question. One, nobody else is really doing it certainly not close to where we are in progressing it whereas there are a lot of psilocybin companies, there are several companies looking at shorter acting, psychedelics, the idea that mm 120 might have more horsepower, to create lasting change than other drugs, right, it's known to have a slightly longer duration of the acute experience. Or maybe that translates into more durable or more pronounced or, you know, stronger impact and symptomology. So combination of being able to go to someplace that most other folks weren't going and both diagnosis and drug and have a very real historically, before the the prohibition era and psychedelics, LSD was by far the most studied, of them all the 1000s that 10,000 plus patients in some form of clinical study are another good efficacy demonstrated against a range of affective and substance use disorders, and anxiety disorders. So, you know, you look back historically, LSD was what folks pick to work with. And then he moved to now and the focus really not being on it, it presented a great opportunity to take a drug that had generated so much historical excitement, and to bring it back into the sort of mainstream drug development processes.

Nick Jikomes 58:23

Yeah, and I'm really sort of intrigued and pleased that you guys are not only, you know, doing try, you know, you're doing other things as well. You know, you're using a hallucinogenic drug, you're actually using, you know, what's probably one of the if not the longest lasting one. And you're doing that even though it's, it's inconvenient. In many ways, the natural incentive for a lot of people doing this type of work is right, people naturally want shorter acting drugs, because then you don't have to have a six or an eight or 10 hour session with someone. But there's a lot of emphasis, and I'm sure you guys are also probably working on these types of things to find non hallucinogenic derivatives of psychedelics because right, that would also be convenient. So if you think about, you know, the structure and the incentives of the healthcare, biopharma industrial complex, or whatever you want to call it, right, the ideal drug is that's short acting, that's not hallucinogenic, you know, et cetera, et cetera, et cetera. And to the extent those can be discovered, great. But but as you said, I think something's very important here. The fact the experience lasts so long is to do with the fact that LSD, you know, sits into its its receptors for a very long time. And right, there's good reason to think that might actually potentiate some of its beneficial effects. So I think it's good that you guys are pursuing this this type of drug.

Daniel Karlin 59:39

Yeah. I mean, your point is well taken, it's a very, very potent, very, very potent drug given in microgram, 10s Hundreds of microgram level, not milligrams, and it does sit on the receptor in a in a different way. There may be other drugs and can obviously have a bit of a longer, acute duration dose dependent to some extent, the idea that shorter acting drugs better fit into the existing paradigm for for care. Okay, yeah, that's probably true. And it is this the existing paradigm for care is that some inviolable thing that has to continue to exist forever? Well, now it's an emergent property of a system that had certain treatments available and incentive structures set up. So, you know, what we're confident in is that if we can show strong rapid, durable effects, that the system will accommodate getting that to people who need it, and we're awfully focused on things like health economics and outcomes research, to really starting even now in the phase two, to look at longitudinal utilization and be sure that we're actually able to induce lasting change in how someone accesses and needs healthcare services, because ultimately, those data will be the ones we bring efficacy and safety data to the regulators for for drug approval. But probably, if we just get drug approval, and folks in need can't get drug, because we haven't done the groundwork to show economic benefits to payers. And we haven't really done our job, this has to be accessible to folks who can't just, you know, can't pay out of pocket in order for us to have been successful, both as a company financially, but I think as drug developers who actually want to see change in the world. So there's sort of an both ethical and financial incentive to make sure that we're really delivering something to people suffering that they can get access to.

Nick Jikomes 1:01:32

Yeah. And, you know, thinking about LSD itself, I don't know if you've completed any of these trials with LSD, or you have results to report there in terms of the trials you guys are doing. But what's what's known about LSD both from human and animal research in terms of how it's working, and why it might be a good candidate for something like anxiety disorders.

Daniel Karlin 1:01:52

Yeah, well, we've hit a couple of these points already in the historical, we pointed the historical research at mostly academic historical research as more hypothesis generating than hypothesis answering. And that's true even of academic studies that are done today. But again, like I said, you know, 10,000, plus patients dosed in various clinical studies in the pre prohibition era, and remarkable efficacy against the whole wide range of conditions toasted, lots of different dose ranges, I mean, people talk and again, this goes back to the very beginning of our conversation about what we know versus what we sort of claim or think we might know. And so people talk a lot about set and setting as the sort of set of concepts around psychedelic administration. But there there's a historical LSD study where people give me the 800 micrograms is our highest dose in our study, is 200 micrograms.

Nick Jikomes 1:02:46

And let's, let's remind people like a slow at a standard recreation recreational dose be something like 100 250 micrograms,

Daniel Karlin 1:02:53

I think, yeah, 100 100 to 200 100 is considered it. And again, this is, you know, anecdotal, and who knows, to some extent, you don't really know what people are getting in terms of precise dosage ranges from from an illicit supply of drug. But sure, 100 is is a is a certainly a perceptual perception altering dose and 200. Pretty profoundly perception altering, meaning for 100 can be two. The ISO 800, a

Unknown Speaker 1:03:22

lot a lot.

Daniel Karlin 1:03:23

This was an experiment, again, never talking in the in the 50s, done with folks with what we would today call alcohol use disorder, and then alcoholism, where folks were given 800 micrograms and strapped to a gurney in any er, and like left to write it out. And it showed good efficacy in those studies, too. So it's, you know, again, there's so much here that we don't know. And that hasn't been investigated in a rigorous modern way. And it's one of the reasons our Phase two is is set up the way it is, particularly particularly things like multiple dose arms and taking psychotherapy out of the equation. So we know we're just testing, to the extent possible isolated drug effects, not a complex interaction between drug and a psychotherapeutic process. A lot of what we had even if you look at it, we have another mm 120 study where we're looking at 20 micrograms every third day, in a couple of sites in Europe, against ADHD. And the hope there is to investigate in a in a rigorous, sponsored way, does some perceptible or perceptual threshold dosing, create change? And there's a lot of anecdotal reports one way or the other, there's there's some not you're talking about micro dosing. Yeah, you'd notice that kind of consciously didn't say micro dosing is another in which sometimes stay away from some of this language because it carries a lot of implications. Right. So there's, you know, drugs like cocaine iOpener Seroquel, can be dosed anywhere from about 20 milligrams up to about three grams a day is the use it does not have labeled for but you know that for higher than labeled suddenly think about the difference between the even 20 micrograms and two grams. That's bigger by a lot than the difference between 20 micrograms and 200 micrograms right? There. We're talking about a 10x difference. So nobody talks about micro dosing, Seroquel. And so we're very much. I mean, it's almost

Nick Jikomes 1:05:24

what's the sub sub perception?

Daniel Karlin 1:05:28

Or well, and so we say some perception of what we mean in this case, it's, well, we know it doesn't create

Nick Jikomes 1:05:36

hardcore perceptual hallucination. Yes,

Daniel Karlin 1:05:38

it would cause someone to be unable to function normally in their daily life. But if you have ADHD, and now you're better able to do the tasks of your daily life, well, that's a perceptual change. It's just not the same as you'd get if you took 10 times the dose or like that at all. So just doing the legwork to figure out, does this low dose, this sub sort of perceptual dose to something that enables folks to be to be able to function better, and that's another study that was expected to read out to the, you know, the phase two for GA D, we expect read up by the end of the year, the ADHD study, which is a smaller study, but but very much a proof of concept study, we expect to read out by the end of the year as well, asking two fundamentally different questions about mmm 120 LSD, but both of which fill gaps in our in our modern knowledge base about about the drug.

Nick Jikomes 1:06:33

I see. So so we should expect to hear the results of some of these later this year.

Daniel Karlin 1:06:37

Yeah, that's, that's what we've been guiding is that we'll have top line readout from both of these studies by by the end of this year. Yeah.

Nick Jikomes 1:06:44

I see. And what is what is top line read up exactly means like a paper is published, or does that mean the results are shared publicly? Well,

Daniel Karlin 1:06:50

no, that would be we vary the publication process takes awhile, but then we would announce primary readouts from from the unblinded data and there's a whole process when she's when she finished running people, through whatever outcome measure you're gonna run through, then, the unblinded analysis in the data, of course, because today, we we, of course, have stayed blinded to the treatment allocations. We don't, you don't have any. And in fact, no one has unblinded has been looking at the data from an unblinded perspective. So that's what happens as you go into the the sort of analysis and readout phase of the study.

Nick Jikomes 1:07:25

You know, another drug that's very interesting that people are very excited about as MDMA, obviously maps, the Multidisciplinary Association for Psychedelic Studies they've been, they've been doing the very large phase three clinical trials for PTSD. And they've gotten, you know, really striking, really promising results there. And you guys, I think, are using it for autism spectrum disorders, which I think is very, very interesting. So for those who don't know, maybe give a little bit of background on why MDMA would be a good candidate for that particular disorder. And just talk a little bit about what you're doing there.

Daniel Karlin 1:07:59

Absolutely. And I'm glad you raised maps, because one of the important things to point out just from the get go, there are two critical differences between how maps PTSD study with MDMA is being conducted and what their their study procedures are, and, of course, what their commercial target will be. And our our MDMA programs where mmm 402 is the right enantiomer of, of MDMA. So maps is using racemic, MDMA. So it has a right and left enantiomer. And, folks, I'm sure listening will either remember or not remember from high school chemistry that molecules can have chiral centers, which means that fundamentally they become non superimposable mirror images. So I think your hands right that they are non superimposable. And they are mirror images for the most part. The other difference, so we're just using the right enantiomer. And I'll talk in a minute about why we picked the right and and tamer. The other difference is that maps is using racemic MDMA as a psychotherapy, enabler or enhancer, which historically it had been used as before it was scheduled, you know, made schedule one. And fundamentally what that does, in having talked to folks who have been involved in current study, and historically I was trained by some people who had used racemic, MDMA in the in the pre ban era. And it builds a sense of rapport, a sense of trust and connection between therapist and patient. And for a lot of psychotherapeutic processes. They depend on that openness and trust and willingness to share and even things like in the psychotherapeutic encounter a transference feelings, right, I'm now feeling something about you. But saying that can be really hard in psychotherapy, right? What you need to you need to experience the transparency and communicating to the psychotherapist so you can interact with the transference together. And so things like that are enabled by the dose of MDMA that that is being used in those PTSD studies. As those studies use a, you know, some form of psychotherapy that maps is of trade folks in and all of this, we are so right enantiomer. Let's start there. So it looks like the left and right enantiomer is based on animal data, some limited human data, the left handed tumors seems very much to drive the amphetamine like effects of MDMA to the stimulant quality. So in animals that can be measured by increased locomotor activity, they walk around more, they're moving around more in higher doses that seems to drive hyperthermia that can be associated with higher doses of MDMA. The right antemer, and this is very, so this would be called the stereo specific pharmacodynamics. Right that the receptor action, you think two molecules that are very simple, fundamentally non superimposable, mirror images of one another, would have relatively, you can sort of intuitively say, Well, shouldn't they do the same thing? But often in neurobiology, we find no that, in fact, different there is a lot of stereo specificity. And the right enantiomer seems to drive in these animal studies, including an animal study that we recently conducted, looking at a fragile X model of autism and mice seems to drive a lot of the pro social activity

Nick Jikomes 1:11:20

of MDMA. So in other words, so people have done experiments where they give mice just the R version, and just the or just the S version, and they see differences in the amount of pro social behavior change with the

Daniel Karlin 1:11:34

two that's exactly the aim differences in the amount of locomotor activity. So that you see that the left translates like walking around moving about interesting, right tries the social social behaviors.

Nick Jikomes 1:11:45

So that makes sense of why you're you chose this enantiomer the are MDMA to do the autism study with.

Daniel Karlin 1:11:51

And so then the other key differences, we are thinking of mm 402 as a repeat daily drug for folks with autism spectrum disorder. And what we know FDA did a patient centered drug design workshop with folks with ASD and caregivers and other stakeholders in the communities. And social communication, social connection, social relatedness all float to the top is things that both caregivers and of course, people with autism spectrum disorder, want help with, in in the current and there there are psychotherapeutic interventions that can help there their occupational therapy interventions that can be helpful there. But But fundamentally, from a from a drug perspective, the drugs approved for ASD to date are really oriented around behavioral disk controls and things like second generation antipsychotics, that for someone who has ASD and as difficult difficulty with behavioral this control a drug like a second generation psychotic, which is sedating, and as a mother receptor effects that might help with behavior of this control. But it's not fundamentally an enabling drug. It's really about suppression. And the hope is that that our MDMA is a daily drug for folks with ASD can be an enabling drug, that it can enable folks to engage in educational, vocational activities, activities of daily living, that involve social interaction, and be better able to perceive social intent from others to engage in social activity with others to possibly perceive their own internal state better.

Nick Jikomes 1:13:29

Yeah. And what's interesting about that, too, is sort of the acute effects of increasing pro social behavior, the ability to just go interact with people in a in a good way, you know, to the extent that that does happen, that you know, that would actually sort of unlock downstream benefit, because then those social interactions themselves will have neuroplastic effects and lead to learning and plasticity on their own.

Daniel Karlin 1:13:53

You sure hope so. I mean that. So the analogy that I often use for this development paradigm is psychostimulants for ADHD. And we've had those for quite some time now. They've certainly you know, not, it's not a totally clean like, this is great for everybody. And then somebody should have them and I'm not I'm not advocating or not advocating for psychostimulants. They're very appropriate in some cases. But when we give folks with ADHD, psychostimulants, they're better able to engage in their lives, and to pay attention and to and to be less hyperactive in schools and things like this. And whether that leads to last thing, neurobiological changes are not not going to have a dog in that fight. But the idea that by being able to better participate along the way that people's life trajectory changes, we've been very much have seen evidence of that. And so it would be absolutely awesome. If our MDMA treated folks then were better able to have the same social exposure uses off drug over time, if it were disease modifying that would be awesome. I don't have evidence one way or the other, of course, we'll look for that as we develop the drug further, but at the very least trajectory change. So if you think about someone who's engaging in school and better able to communicate and make friends in school, well, that's going to change the experience of being in school and make it more pleasant, more desirable experience, it'll change the ability to learn from peers. And so whether there's lasting neurobiological change, which again, I just can't tell you, there's very much my you know, I'm very hopeful that trajectory change life trajectory change as possible just by being able to be more functional in one's life.

Nick Jikomes 1:15:35

And I can't remember if you mentioned it, can you remind us the doses that you're using for this study, and then after that, maybe talk about how you guys think about things like whether or not there's any any risk to chronic administration of MDMA, especially in the context of the sort of colorful history in MDMA research around neurotoxicity, and dose and different views on that?

Daniel Karlin 1:16:01

Yeah, so we haven't we haven't talked about dose yet for because what we're doing first is, of course, phase one, or MDMA has not been in clinical trials before, certainly not sponsored clinical trials. So the first step is phase one, where we look at at dose tolerated dose, and we'll start to do regular, what's called sad and mid so single ascending dose and multiple ascending dose study to look at both low dose effect because we can start to look at this neat thing about pro social effects, we can look at it in healthy folks to you know, unaffected folks. So we'll, we'll start relatively low doses and dose up to look at side effect profile and dose limiting, of course, we get to dose limiting side effects, stop. And then in the mid do something similar, just look at day by day by day dosing. And then the hope is to and so that that study, the Phase One will start by the end of the year, as well. And then we'd like to have a cohort of folks with a as the, as a third cohort, is the third part of that study, to look for what we would call ESOP early signs of efficacy, to sort of gain internal confidence that we're headed in the right direction that this drug at a dose that's tolerated and and, and safe creates the the effects we're looking for in terms of the ability to interact socially. So that's where we're at in that development program.

Nick Jikomes 1:17:26

So what kind of doses are you using? And how would those compare to say, what a what we think a standard recreational dose is lowered. So you will

Daniel Karlin 1:17:37

certainly will start lower the point of a phase, the point of the phase one is, is also to get to what dose we'd like to use to test efficacy. So where we'll end up with the actual dose that we bring into to look at efficacy, I can't tell you because that's part of the experiment we're going to be doing.

Nick Jikomes 1:17:53

But are we talking like ones or 10s of milligrams?

Daniel Karlin 1:17:58

10s 10s Plus, yeah. And part of Phase one is getting safety coverage above where you think you'll need to go. So that those doses can be pushed. reasonably high, of course, we're monitoring carefully to be sure that we're not exposing anyone to risk. The and this relates to the second party question that I didn't answer before, which is, how do we think of toxicity and a lot of this sort of breathless ad is coverage of, you know, MDMA, and neuro neuro toxicity and Swiss cheese brain and all this sort of stuff is just not, there's not evidence for that is really relies what you call a reliable way. And so we are doing a very standard ind enabling tox package so you know, investigational new drug applications that you file with, with FDA to be able to take a new drug into people, we're doing the animal tox now that's required to go into human studies, and looking at a whole range of potential toxicities. So far, the you know, we have some animal tox work that will be published. And so far, what we're, what we're finding is that we expect that will again, as I said, we'll be able to open that ind and head into a phase one. You know, certainly the Phase One start by interviewers something that we've said consistently.

Nick Jikomes 1:19:23

And so, you know, on your website, there's also like a section on digital medicine. And so what is that? And what is that all about?

Daniel Karlin 1:19:32

Yeah, and we didn't talk about this at the beginning, which is the how I came to my med at all and why why you're talking to me about this stuff. I was not in the psychedelics world in any real in any way. I had been developing drugs at Pfizer in the past, and it's like psychiatric drugs and Pfizer left, left neuroscience and so one of the things that I worked on at Pfizer after Pfizer left neuroscience was what we call digital medicine and the ability Do you use digital devices and digital tools to do better measurement? This goes all the way back to the beginning of the conversation, we're talking about disease definitions, and phenomenology and signs and symptoms. And so my thought, then and and subsequent to leaving Pfizer, when I found a company called Health mode was how do we use digital tools to best measure the signs and symptoms of systemic illness, not just psychiatric illness, because all not all, but a lot of systemic illness suffers from the same definitional problem, which is that the disease definitions are built on signs and symptoms, we don't have terribly accurate or precise ways to differentiate in a fine grained way between sizes and that might look similar or even have the same name, but not be the same thing. And so when mine met acquired health mode, and brought me in as chief medical officer, we brought digital capacity in from health mode as well. And we're looking at a number of different angles that we can use that digital technology to measure things that can assist in understanding the diseases that are anxiety and affective illnesses, as well as, are there things we can do at the point of, of care where a drug is being administered, and someone is having a dosing session to help the folks monitoring the person know things about what's happening with them. And that can ultimately that will lead to some regulated labeled digital devices called software as medical device that can assess folks who are working with people at the point of care with with mm 120 and other potentially other drugs.

Nick Jikomes 1:21:45

And you know, this is, this is kind of a hot topic, it's very general, there's multiple ways to think about this and where we could go with it. But the the idea of whether or not the psychedelic affects the hallucinogenic perceptual changes of things like LSD, psilocybin, and so forth, whether or not they are basically just side effects, and they're not they're politically relevant, or whether they are very relevant to therapeutic outcomes. How do you? How do you just start to think about that problem? In general terms? I'll just leave it there.

Daniel Karlin 1:22:24

Yeah, and a lot of people think and talk about this and talk again, and, again, we talked about the idea of a sacred plastic surgeon before I try as much as possible to go back to some basic principles. Our brains are plastic. They would neuroplasticity is a thing. I mean, this is what Eric Kandel won the Nobel Prize for it right was that memory requires structural changes in your brain. That's a good thing for a lot of reasons. Because if encoding memories didn't require changes at a structural level in your brain, where are they being stored? Right? And so it's easy in psychiatry centers to drift into this sort of functional dualism of like something other than the brain being the mind, I think we have to sort of abandon that and accept that the brain and the mind live in the same place. And so this conversation, or even folks listening to us have these conversations, it, they remember it, we've created physical change in the brain. So that's the constant thing, right? How does that relate to healing or getting better or feeling better? Open questions, all of them. There are drugs in psychiatry that are known to be very plastic genic. Like lithium is one of them in the themes of remarkably effective drug for bipolar disorder, it's also shown efficacy has depression that doesn't have a label for that. So the the idea that we know the I don't think we know the answer, as I said before, I hope that the experience I have the psychological mechanism of the drug, it would be, I think, like, a nice thing would be a great thing, if that mattered, and that was part of the mechanism. I think that we are increasingly aware that there are downstream long term changes that can be induced by by using existing psychedelics, whether those changes are, are the product of the psychological experience or the product of some downstream signaling and neurobiological processes. We know yet. I understand very much the appeal to companies of going and looking for non hallucinogenic drugs that create similar downstream changes to the existing psychedelic drugs. We will only know once those drugs get to people if they're actually psychoactive and resulting in dirt, as I've said about mmm 120 in rapid, profound and durable change in people's psychiatric disorders. So, you know, I'd say that the jury is out there. People working hard to try to answer these questions. And the nice thing about having mm 120, which is, again, has this historical efficacy data, a lot of evidence for safety, and now increasingly emerging evidence for efficacy, even from some collaborators bars in Switzerland to have published on both efficacy against anxiety disorders and depressive disorders, you know, academic studies, of course, but valuable nonetheless, that we almost, we get to dodge that question a little bit of psycho psychological versus neurobiological and say, Well, okay, if we can move a clinical, a valid clinical outcome assessment, in a strong way, rapidly and durably, then we've got a good drug to bring to market that will help people. And of course, we were very conscious of having a pipeline behind that. But currently, what we're really mainly focused on is this drug that it's striking early, likely to show efficacy.

Nick Jikomes 1:26:02

And, you know, for a lot of these drugs, like you're referring to this mm 120. And this is another name for this particular LSD salt that you guys have developed. And you know, what ties into that is the idea that, you know, this is going to be a particular version of LSD that is patented, and owned. And so if clinical trials turn out the way we hope they do, and these drugs are brought to market, how do you how do you think about, you know, the questions around accessibility and cost? And how does that tie in? You know, how do you have to think about that as sort of the science, the science person doing the clinical trials, as a business who has to keep itself going and running. And then also patient accessibility and making sure things aren't, you know, exorbitant or inaccessible to the people who actually need the treatment?

Daniel Karlin 1:26:47

Yeah, and there are a few components of of access, and that there's a drug price component, and then there, the service prices that sit around around the drug, drug pricing single have to come to, and that's we've hired a Chief Commercial Officer now for quite some time, and are increasingly thinking about how to both demonstrate value and through the demonstration value come through appropriate drug pricing. And then thinking about environments in which this drug might be prescribed and which it might be administered. The kind of thing that I think gets lost a lot of times in these conversations is that it's, well, there's a lot about our current drug Gigan, this entire environment that feels really different. And there are things that are really different. There are a lot of things that aren't that different. And so for a psychiatrist or an advanced practice nurse to see a patient, someone prescribing power, do an evaluation and management visit, build their insurance for that evaluation and management visit Well, there's that's that's going to be probably done exactly the way it's done today, for any prescription. The doctor will meet with someone and maybe meet with them via telehealth and do a robust assessment of their appropriateness for treatment and their safety. There's ability to take the drug safely, they'll prescribe it likely drug will need to meet someone at the place where it will be administered, can be administered in a lot of different kinds of places. You know, there are clinics that have come into existence around interventional psychiatry, like clinics to do as spravato, whereas ketamine as a treatment, and so they have facilities set up for monitoring and for someone to be while they're on the treatment. Individual psychotherapist offices is what? Well, for our traffic studies, of course, we're using study sites, there's no reason in a commercial world that a psychotherapist who ordinarily practices, talking psychotherapy, couldn't be a session monitor and monitor someone while they were in your, you know, having an experience with with drug and Enter. And here's the part that I think you know, in a lot of the talk about billing and coding. What gets lost is that most psychotherapy gets billed today, and it's a time based code. And a lot of this bravado in the world is getting billed as a psychotherapy hour plus a hour long psychotherapy add on code, because there's a two hour monitoring period. And if someone's getting, you know, six treatments is Roboto. And their first two weeks or 12 hours of time in clinic plus the back and forth and travel time starts to make a single day of MMM 120 LSD treatment, that's actually less time and if you have a durable effect that lasts out, you know, 12 weeks, well that's that's going to not be unfamiliar, right in terms of a time commitment from the payer to compensate the provider for an effect that lasts that long. You know, weekly hours of psychotherapy are often covered by many pairs. So while there's going to be a lot of demonstration of value that we have to do, and a lot of engagement with payers and providers is to be sure that it folks are ready and confident comfortable to to engage in a world where or something like mmm 120 is available. It's not that far from from where psychiatry is at times today.

Nick Jikomes 1:30:17

Are there any other psychoactive drugs that are in your r&d pipeline beyond the LSD and the MDMA chemicals that you're working with? And if so, what are they?

Daniel Karlin 1:30:28

There's one other disclosed pipeline component which is a drug that now has a lot of names. Mm 110 18 MC and Zelena cancer all of its different names. It's a non hallucinogenic derivative of Ibogaine, Ibogaine being hallucinogenic compound that has been used to treat addiction and is used in the underground and outside of this country for for addictive disorders does cause pretty profound Hulu stenosis for folks and IBM has an unfortunate cardiotoxic potential. Or some people have what's called prolonged QT and suffer from heart dysrhythmia from from Ibogaine. So 18 MC was Linda can or M M went down, I never know which which name to use, doesn't have the cardiac liability, it doesn't have those intergenic potential, we brought it through this drug was in the pipeline, when when I joined the company, it was in a phase one, we brought it through the Phase One got to two dose coverage and exposure coverage that we believe is likely to correspond to the animal data that suggested efficacy. There's some some more animal tox work to be done to be able to bring this into a into an efficacy study. So right now, because of the capital markets, and really needing to focus our resources on 120 and 402. Zlin against 18. MC has been a bit of a backseat for the last bit here. But we're seeking non diluted funding grant funding to try to do the additional work we would need to do to go to go into any affiliate efficacy study and opioid withdrawal.

Nick Jikomes 1:32:19

And can you give us a sense for like how long some of this stuff takes so like let's let's say the phase two trials for LSD start to finish, you know, from from sort of inception and and really sort of hitting the ground starting those trials, to when you think like the first, you know, results will really come out and be announced, how much time we're talking about there is it a year or two is longer than that

Daniel Karlin 1:32:41

year or two is reasonable for you know, we consider ourselves to be as efficient as anyone in this space. And to be you know, we've got a really fantastic drug development team. We're incredibly competent and capable at running these studies. In our in our studies, we are very close to the sites. So this is not the kind of thing where we hand it to a contract research organization and say Go Go run our study course we have a CRO involved for certain functions. But our, our clean ops and clinical team are in almost constant communication with our sites, I I personally have visited a number of the sites, Roberto, our CEO has been at a number of the sites. So we try to have very, you know, we want everyone to be aligned we want we want these studies run with as high fidelity, as much more focus on safety and adherence to protocol requirements as possible. So but yeah, a year or two for the phase two, you know, again, what we've said is, and what we'll continue to say is read out by the end of this year. Sometimes these studies, startups can be a little more complicated than more like sort of regular drug development startups where you don't have to have scheduled one licenses at the sites and things like that, of course, we're still handling this schedule one drug, lots of lessons learned through the conduct of our Phase Two that we'll bring into the phase three. And we are going to just turn that over as quickly as we can into you know, from when you finished the phase to get the data back, have an interface to meeting with FDA, where you ask questions and proposal phase three plan and transition that into as rapid as steady start as we can, of course have pre existing relationships with sites and sites, we've got phase one licenses, or schedule one licenses at this point. So we're, we're eager to just keep, you know, keep cranking along and to get to get to the phase three and get obviously Submittable phase three data as quickly as we're able.

Nick Jikomes 1:34:31

And can you tell folks just a little bit more about mine med How long has this company been around? Sort of when and why was the started? And I don't know maybe talk a little bit about like, you know, what's your sort of strategic vision that informs like how and why you're making choices around you know, which drugs to test and which drugs to look into?

Daniel Karlin 1:34:52

Yeah, absolutely. So my mid was was founded when three three and a half years ago. So by Folks we think saw that none of these original founders are still involved with the company, but saw the opportunity saw what was happening in space


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