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Bryan Roth 6:00
Yeah, I'm a professor of pharmacology at the University of North Carolina Chapel Hill School of Medicine, and my lab studies, sort of CNS, medications and technologies for discovering new medications for serious mental illnesses. I'm also a psychiatrist by training. And I spent many years treating treatment resistant schizophrenia.
Nick Jikomes 6:33
And, you know, one, one major component of what your lab does is study psychedelics and how they work in the brain and and things related to that. So, how long have you been studying psychedelics in your lab? Slash? How long have you been studying this yourself as a scientist?
Bryan Roth 6:51
Since 1983. So I, after I finished my PhD in St. Louis, I did a postdoc at the National Institute of Mental Health in the late or minio, Costas lab, and that's where I began my studies on five HT to a receptors in psychedelic drugs.
Nick Jikomes 7:13
And so you know, many people a long time, yes, longer than most too long. I don't know about too long. So serotonin to a receptors. These are the so called psychedelic receptors, as they're often referred to. These are the ones that many probably most listeners of this podcast will have some level of familiarity with. But can you give everyone just a very, very basic short overview of what these receptors are and why they're famous in the context of psychedelics and psychedelic drug action?
Bryan Roth 7:45
Yeah, they're, they're particularly important for psychedelic drugs, because I would say there's overwhelming evidence in both preclinical models as well as in humans, that the psychedelic actions of classical psychedelics. So these are drugs like psilocybin, mescaline, DMT, LSD, and so on, all mediate their psychedelic actions by activating this receptor in the brain. The best evidence for the involvement of five HTT to a receptors in psychedelic drug action comes from studies that were done by in France vole, inviters lab by Dr. Vollenweider and Dr. Preller, over the years. And what they showed is that pre administration of a five HT to a preferring antagonists drug this drug to cancer and which in Europe is approved for treating hypertension, but has five HT to pretty strong five HTT to a blocking activity, that when humans were pretreated with this, and then given I would say fairly substantial doses of either LSD or psilocybin, that the psychedelic effects are completely gone. And I have heard sort of anecdotal reports of, of humans who have taken selective, more selective five HT to a antagonists and 100 907 for example, when recruit basically reported the same thing. So in animals, basically all of the the, quote unquote psychedelic effects can be blocked by pretreatment with five HT to a antagonist or in mice, where the five HTT to a receptor is genetically removed. So I think so I think it's pretty, pretty solid that the five HTT to a receptor is responsible for the of the psychedelic actions of these drugs.
Nick Jikomes 10:03
Yeah, so for you in human being to give them psychedelics, they have a psychedelic experience. If you give them a drug first that blocks 5g to a receptors gets in the way of the psychedelic interacting with receptor that basically gets rid of all of the psychedelic effects. And if you do comparable experiments in mice, or you remove the receptor in mice using genetic tools, you get the same basic result, the behavioral effects of the psychedelics that we take as proxies for the hallucinatory effects go away. Yes. And can you remind everyone, so in mammals in the mammalian brain, how widespread are 5g to a receptors and where do we tend to see them in the brain.
Bryan Roth 10:47
So they're, they're most highly concentrated in the cortex, both in in mice and in humans. Which I would say makes sense, because psychedelics alter how people perceive reality. And the receptors themselves are finally found in a particular type of cell in the cortex called pyramidal neurons. And there, they appear to be preferentially localized to layer four and layer five pyramidal neurons in the brain. And, and within those neurons, they're highly localized to the cell bodies, and what are called the apical dendrites. And when psychedelics activate those receptors, they cause the neurons to fire in a very disorganized fashion. And this disorganized firing, is thought to be responsible for the psychedelic actions, because these neurons basically integrate information from multiple cortical and subcortical areas to give us a, the experience of reality that we experience it. And basically, what psychedelic drugs do is they inject noise into these neurons, thereby are therefore making it apparently more difficult to basically classify internal experiences and external experiences differently so that people when they're under the influence of a psychedelic, they, they they believe the experience, basically. So this is another characteristic of psychedelic drugs. That they they cause an experience, which for many people have a very deep meaning for them. We're not, we're not at all clear why, why this occurs, but likely it's through the five HTT to a receptor.
Nick Jikomes 12:58
And normally, when we think about receptors, we think about them as being on the outside of the seller in the cell membrane, you know, listening to things coming from the outside. Are they only found are these particular receptors? Are they only found in the cell membrane? Or can they be found inside the cell as well? And what what do we know about that?
Bryan Roth 13:18
Well, they're always membrane bound. Because they're, they're what are called integral membrane proteins, so they can't exist floating around free in the cytoplasm of cells. But we've known for decades now, that receptors for psychedelics as well as receptors for many other drugs are found both on the cell surface as well as inside the cell. And it varies tremendously from receptor receptors, some, some receptors. I think that delta opiate receptor, for instance, appears to be primarily intracellular. Whereas other receptors appear to be primarily at the cell surface. But all basically all receptors in the brain and elsewhere, exist in intracellular pools as well as plasma membrane pools. So this is this is very common. And we've also known for decades that these receptors inside the cell can signal. So for historical purposes, this is something I studied in my PhD thesis. I studied opiate receptor sub cellular localization. And I found that opiate receptors were also were found intracellularly. So this was in the early 80s, basically, and that they were capable of signaling through canonical signaling pathways Um, so this is, this is a thread that has, you know, has been around for many, many years. And it was shown, I think, in the, in the 80s. There was work by the group at Janssen Pharmaceuticals, that did some cellular localization studies of five HT to a receptors in in rat brain. And what they found was that a significant proportion of the receptors were intracellular. So I think this is an and we we, in, you know, previously published studies with antibodies that were relatively specific for the five HTT to a receptor. This was work done in the 90s. We also showed they were intracellular some of them were in complex with the Reston which is a transducer protein. And that various drugs, so drug administration could change the sub cellular distribution of the receptor, both in in cell culture as well as in in neurons in vivo. So it's, I would say, it's, it's pretty well accepted that these receptors are intracellular as well as plasma membrane bound.
Nick Jikomes 16:21
And so the ones that are intracellular within the cells, are they? Are their endogenous functions that have been worked out there? Or are they mostly just sort of sitting there waiting to be deployed to the cell membrane? When the appropriate conditions are triggered? Or can certain drugs or endogenous compounds actually get inside cells and activate them?
Bryan Roth 16:43
Yeah, usually, the way this occurs is that the receptors are at the cell surface, a drug that activates them binds to them, this causes the receptors to be internalized. And then when they're internalized, then they can continue to signaling. So typically, this is the way it happens, there are there are reports of a have Direct Activation of intracellular receptors, by drugs that can cross the plasma membrane. So this was shown for opiate receptors and beta adrenergic receptors some years ago,
Nick Jikomes 17:24
in terms of the the endogenous ligands for these receptors, so let's just talk about serotonin to a receptor, and serotonin is serotonin, mostly, or always activating the receptor via the extracellular space outside the cell, are there instances where you can actually get inside and and initiate signaling within the cell?
Bryan Roth 17:43
Well, certainly, serotonin itself will cause the receptor to be internalized. And so if it after the receptor is internalized, if the serotonin stays on the receptor, then there could be continued signaling. I don't know of any data showing that this occurs. But it's, it's certainly theoretically possible. But typically, serotonin is positively charged and would not cross plasma membrane. So in most experiments, if you apply serotonin, it's only going to interact with surface receptors.
Nick Jikomes 18:24
And one of the right so there's good evidence, as you said, that the 5g to a receptor is critical for the psychedelic the psychoactive component of what psychedelics do. So there's that side of it, they have these they have these very remarkable, subjective effects that they induce this receptor is very important for those. There's also the the effects on neuroplasticity that psychedelics have, and that's an intense focus of study. And, you know, one of the sort of major areas of focus, I think, for many people right now is to address the question of the extent to which the psychedelic effects the psychoactive effects, can or cannot be dissociated from the neural plastic effects that these drugs have. So with that in mind, what what is the evidence that the 5g to a receptor is important for some or most of the neural plastic effects that psychedelics are associated with?
Bryan Roth 19:23
Yeah, the best evidence for that comes from a series of studies that were done by several several groups now. Showing that pretreatment with a five HT to a antagonist basically blocks the effects of psychedelic drugs on spy information or dendritic elaboration. So there are now several of those studies in vitro that have shown that by different groups And then there there, I would say there's mixed data in vivo. So there are there's a recent paper that was published in Nature by gi Dolan suggesting that the plasticity inducing effects of psychedelic drugs, on a measure that they call social social plasticity, is due to five HTTP receptors, because that was blocked with a five HT to a antagonist. By contrast, there is a report by Thomson comsenz lab a couple of years years ago, maybe three years ago now showing that the enhanced plasticity that's seen by psychedelic drugs in the hippocampus, so different brain area, is not due to five HTTP receptors. And I would just make a little aside at this point that hippocampus doesn't really express five HTTP receptors to any extent. So it would, it would not be surprising that there if there's an effect of psychedelic drugs on hippocampal plasticity, it's not due to five HTTP receptors. It turns out that drugs like psilocybin and LSD interact with dozens and dozens of different receptors. And so it's quite possible and even likely, that in brain areas where there aren't five HTT to a receptor is that the main effects would be mediated by some other receptor. By I would say by Cohn, by contrast, there's one report that was published in Nature Neuroscience, earlier this year, suggesting that in both the cortex and the hippocampus, that the effects of psychedelic drugs on plasticity are not mediated by any conventional receptor, but are mediated by Direct Activation of or direct modulation of the track B receptor. This is a neurotrophin receptor by psychedelic drugs. So there is this other other report that's that would appear to be contradictory to the, to the prior reports, of the, you know, a central role of serotonin receptors and psychedelic drug actions, both therapeutic and, and psychedelic.
Nick Jikomes 22:44
So so a couple of things, you know, to think about when we're thinking about all of these results. You know, one is the difference between in vitro studies and in vivo studies. So, it sounds like people have done multiple experiments in vitro in a petri dish, basically, where they give psychedelic drugs, and they see neuroplastic changes, they see new new spines forming and things like this. If you block the five HTT to a receptor, you basically block most or all of those effects, and then experiments in vivo when they're inside of live animals. It sounds like the results are a little bit more mixed. And Is that Is that surprising? Or is that common? Where you see, you don't necessarily see the in vitro studies lining up with in vivo studies?
Bryan Roth 23:26
Yeah, that's, that's sadly, all too common. So neurons and culture, of course, are not neurons. There, if anything, they're immature neurons. So just to put this in perspective, many, many years ago, I studied the developmental regulation of five HT to a receptors in rats. And what I found basically was the receptor really wasn't expressed until around 14 days post natal. And so if you're studying neurons, in culture, neurons and culture neurons are usually harvested from days, you know, embryonic day 18 mice, so mice that that are that have not been born. So the neurons are very immature. And what we have found in preliminary studies is that if you quantify the amount of five HTT to a receptor, in cultured neurons, there really isn't any, any receptor until day 14. And so, in these various in vitro studies, it's it'll be very important going forward to actually make sure that people are studying neurons that actually express the receptors. So that's one sort of complicating factor But the other thing is that there are, I would say the, the field of in vitro neuroscience is filled with studies where they see something in in neurons in vitro that they don't see in vivo. And typically, this is because of developmental considerations or things like that. So it would be fairly common, not not unsurprising.
Nick Jikomes 25:27
Yeah. And so I guess I guess the basic point for people is, when people are doing in vitro experiments, those are very easy to do. And they can be much more precisely controlled in the lab in many ways compared to trying to do something in the brain of a, of a live animal. But the cells in that dish are simply in a different context than the cells in intact brain, there's there might be at a different developmental stage, there's a different, you know, soup of stuff floating around the brain compared to the petri dish. And you can assume that, that the one set of experiments will translate into the other context. Right. Right. And they frequently don't, yep, yep. And then, you know, the other consideration that you brought up is, you know, different people doing experiments are doing them, you know, in different brain regions, which are gonna have different levels of receptor expression and things. Is there strong evidence in pyramidal neurons in the cortex, neurons, which do express high levels of 5g to a receptors, that in vivo, psychedelics are directly inducing plasticity in those neurons.
Bryan Roth 26:30
So nobody has. So there are studies where people have looked at neurons in vivo. This is primarily the work of Alex Kwan. But we don't know if those and what he shows is a psychedelics enhanced plasticity. And it's due in vivo, at least to some extent, to five to five HT to a receptors. But the problem is that the cells that he's looking at, probably do not express five HT to a receptors. So he uses a thigh one reporter mouse, this is sort of a technical thing. And we have, we have made a reporter mouse for the five HTT to a receptor. So we basically have tagged the receptor, so that we can visualize it in, in living mice. And what we find is that there's very little correspondence between thigh one expressing neurons and five HT to a neurons in the brain. The thigh one neurons are mainly layer six neurons, and five HTT to a receptor expressing neurons are mainly layers four and five. So we actually don't know we're, my lab is trying to get those studies up and running. But they're, they're technically very challenging to do.
Nick Jikomes 28:03
I see. So it sounds like basically, people have done the experiment where they can look at literally, through a microscope, look at certain neurons within certain parts of the cerebral cortex. We know that certain neurons in some parts of cerebral cortex have a lot of 5g to a receptors, but not all neurons. So they've run experiment where they give the psychedelic, they, they're looking at certain neurons, and they see plasticity, so they see new spine framing and things like this. But what you're saying is the neurons they're able to look at those experiments aren't actually the ones that have five HTT to a receptor. So it's some kind of indirect thing happening. Yeah,
Bryan Roth 28:39
yeah, surprise, sadly. Unlucky.
Nick Jikomes 28:48
Okay. So so psychedelics have neuroplastic effects. We know that in certain contexts, these can depend directly on 5g to a in other contexts, you know, it's a little bit more ambiguous, and things like, it's just complicated. We haven't fully worked it out yet. You know, on this question of whether or not the psychedelic effects, the subjective effects that they induce can be dissociated from the neural plastic effects. What what do you think the state of the art is there? Has that question been answered yet? Or is it still unknown?
Bryan Roth 29:24
Well, certainly, it's been answered in vitro. Because I think David Olson Scroop has shown that a number of non psychedelic drugs, including glyceride, can induce plasticity in neurons in vitro. And, of course, glyceride is not not a psychedelic drug in humans, so there's, you know, pretty, pretty strong evidence that at least what you're measuring in, in cells in culture And we also have reported a, we and others have reported data in mice with non psychedelic drugs. So John McAfee's group reported that bromo LSD, which is not psychedelic in humans, absolutely not, apparently has antidepressant like actions in mice. And they also show that this drug are yummy, which is, I would say less psychedelics Not, not entirely non psychedelic, but is is a less potent psychedelic also has some antidepressant like activity. And we recently posted a paper on by archive X, showing that lists your eye directly has antidepressant activity in mice, antidepressants, drug like activity. So there, you know there and then there are group published a paper in Nature showing, you know, a non psychedelic compound is ostensibly therapeutic and other groups have reported the same thing. So there's, there's a lot of data in mice, that, that drugs that interact with a five HTT to a receptor activated to some degree are not psychedelic, but they have, you know, therapeutic drug like actions in mice, whether this will ever translate to humans is sort of the big question. So we don't know. There are hints though, that that this is possible, because both bromo LSD and glyceride, which are which are not psychedelic, as well as our yet me and in sort of anecdotal reports, have all demonstrated potential therapeutic actions in humans. So I think, I think the possibility is there, but we don't really have the best compounds yet to test in humans to, to test this hypothesis. So a number of us are trying to test this hypothesis directly by basically making compounds that would be suitable for testing in humans.
Nick Jikomes 32:21
Yeah, and there's, there's lots of considerations for here. So I'll just briefly mentioned some things for people before before we dive into some other questions for you. So neuroplasticity is a pretty broad term, there's many different forms of plasticity and many different mechanisms involved. So it's not just sort of one thing different drugs, you know, are going to interact with different things in the brain and they may or may not induce different forms of neuroplasticity. You know, one of the things I wanted to ask you about related to this general topic is, you know, we know that all kinds of drugs psychoactive and non psychoactive can have neuroplastic effects SSRIs you know, almost any, you know, addictive drug that you can think of, but when we talk about the psychedelics and the effects that people have been seeing and studying in them, in particular, one of the, one of the ways that people have been trying to distinguish them from other drugs, is in talking about the the nature of the neuroplastic effects they induce so one of the new terms that's been introduced recently by certain groups is psycho plastic surgeon. And the idea there is apparently that it refers to drugs that can produce rapid and sustained effects on structural plasticity. So the ability of you know, new spines and things to sprout up or go away. Does that term distinguish psychedelics from other drugs or, or not?
Bryan Roth 33:46
Ah, I don't I don't really like the term that much. If you think about the term psycho plasticity, what it would what it would infer is any compound that psychoactive induces plasticity, you know, plasticity induced by any psychoactive compound. And we know all psychoactive compounds induce plasticity. Or if they didn't, you would not be able to remember that you took a drug basically. So, if you drink if you if you have a enjoyable drinking experience, that experience is is remembered and it is the the memory is occurs by plasticity. That's how we remember thing that's that's how the brain works. And so I I prefer the term just neuroplasticity. I don't I don't think there's any any data yet that that psychedelic induced plus Diversity is different from that induced by other drugs. You know, we just have to see, I always thought it was sort of a marketing technique, basically, yeah, in my reading of the book, do you come up with a new term, then, you know, if it captures the imagination of people, then it's, it becomes used.
Nick Jikomes 35:27
But in my reading of the term as it's been used, it seems like an attempt to distinguish things like classic psychedelics, from other kinds of drugs, by referring to their ability to induce rapid and sustained structural plasticity. But the thing that confused me about that is, there's many other non psychedelic drugs that we know, can induce rapid and sustained plasticity, right? Yeah, cocaine,
Bryan Roth 35:51
cocaine for one amphetamine. So it was shown by the ROB Malenko is lab decades ago, that a single dose of cocaine induces long lasting, long term potentiation, which is this this type of plasticity? Which, which can be remembered by the by the mouse for a year, basically. So it's, it's not, you know, it doesn't quite I know what they're trying to do, but it doesn't, I, I sort of object to the term. I'll just say, from a philosophical perspective, that ultimately, it depends on how people in the sciences use the term. So if people in, in neuroscience use the term only to discuss psychedelics, then that will be the term basically. And there, you know, there may be a in, in the Oxford English Dictionary there, you know, there may be some paragraph about a debate about the term, but if people use the term, and it's used widely, then it's the term basically. But I, I don't like to use the term basically, because it, it implies something that we don't really know is true, yet. It could be true, but we don't have any data for it.
Nick Jikomes 37:28
And one of the things I'm hoping you can unpack for people a little bit is, so for non scientists listening that, that don't have a background in this, you know, it's a little abstract, we talked about, you know, drug goes into the brain binds a receptor, and then plasticity happens. Right, what's happening in between, so a drug let's, let's just take psilocybin and LSD is an example a classic psychedelic, it gets into the brain, it binds to serotonin to a receptors and other receptors. And then somewhere after that, plasticity happens, new connections sprout up and things like that, what's happening in between that that connects those dots.
Bryan Roth 38:06
So we, my lab with Peter Penzance investigated this in some detail, now 14 years ago. And what we found was that synaptic scaffolding proteins and kinases that are protein kinases that are have historically been involved in new spine formation appear to be involved in that process, and that it was due to the five HTT to a receptor. So there were skin out synaptic scaffolding proteins called MK one, technically a PTZ binding domain protein, which we know interact with the receptor. And then various protein kinase is downstream of that that are activated, ultimately leading to some cytoskeleton rearrangement. And in our paper, which I urge people to read, but no one reads because I don't think anybody reads anything that's more than five years old. We show fairly conclusively the involvement of specific kinases and other proteins in this process. That's that's for the initial phase of plasticity. So we were looking at in our paper, what we found was that psychedelic drugs can induce spine formation which within 30 minutes of exposure, which is very fast. In terms of the maintenance of spines, it's likely that other pathways involving BDNF and track B receptor yours are involved. So it's it's sort of well known in neurosciences that BDNF and track be that that pathway is responsible for the maintenance of new spines and, and synaptic plasticity. And there's a fair amount of data now that psychedelic drugs can enhance the expression of BDNF. And that spine formation is dependent on track B receptors. That that's very similar to plasticity that's induced basically got any drug, including ketamine. So ketamine is another, you know, rapidly acting antidepressant drug, it's, it's pretty well accepted that activation of BDNF and track B is essential for the plasticity inducing effects and the antidepressant effects of ketamine, for instance. So it wouldn't be surprising if, if this system is also essential for psychedelic drug actions.
Nick Jikomes 41:12
And does you know when plasticity is induced by a drug, or an endogenous compound, does that necessarily have to involve changes in gene expression signals that go all the way to the nucleus and turn genes on or off?
Bryan Roth 41:27
Ah, not necessarily. So there there is local protein synthesis that occurs in the spine. One of the people, there's just one the brain prize, basically discovered this process. So under underneath of spines, it turns out that there is there's messenger RNA and rough ER, and so on. And there can be local protein synthesis that occurs. So it doesn't necessarily have to go, the signal doesn't necessarily have to go back to the nucleus and alter gene transcription for the neuron, at least at least initially, you know, long term, of course, there are going to be changes in protein translation, and transcription. But, but how these changes ultimately, are responsible for the plasticity that may may or may not occur with psychedelics is not known.
Nick Jikomes 42:37
And, you know, another concept I wanted to ask you about that's relevant to some recent findings is that we're talking about neuroplasticity, that's, that's the actual, like physical changes that happen, per se. So a new spine, a new a new structure, new synapse forms, there's also the concept of meta plasticity. What is that?
Bryan Roth 42:58
I have no idea. I don't study it.
Nick Jikomes 43:03
I say. So, so the recent paper from Google Dolan's lab that looked at social reward learning was looking at and so in plastic, so I just looked
Bryan Roth 43:17
it up and Wikipedia. And it refers to the plasticity of synaptic plasticity.
Nick Jikomes 43:29
So, yeah, I, you know, I think people would say, it's the, you know, it's the extent to which plasticity can happen or how easily, you know, a new synapse can form or something like that. One thing that I was hoping to ask you about, related to that was, so when we talked about synapses forming the connection between two neurons, we talked a little bit about the intracellular side, some of the proteins and kindnesses that are involved in synapse or spine formation. What about the extracellular space and sort of the physical structure of that how, how much relevance is there to the extracellular composition in terms of you know, whether or not new synapses conform?
Bryan Roth 44:10
Yeah, well, it's, it's key. Of course, when a when a synapse forms it has to meet the adjacent neuron basically. And to do that, it has to, you know, it's guided across by the extracellular matrix. And so, extracellular matrix proteins are essential for all types of plasticity ultimately, or involved in all types of plasticity.
Nick Jikomes 44:44
I see So, so, you know, not only does the inside of the neuron need to need to change but it needs to be able to, I mean, essentially physically move across a scaffolding of physical substrate in order to to move around things
Bryan Roth 45:00
right, right. And there's recognition by, by basically the presynaptic membrane and the postsynaptic membrane. So there are adhesion proteins that that cross the synapse. And these were first discovered by Tom suit off, and he got the Nobel Prize for that some years ago. So, so basically, it's, it's a fairly complicated, you know, as you can imagine, it's like everything else, it's a fairly complicated situation, which is regulated at multiple levels. So there's extracellular matrix there, adhesion proteins, there are signals, diffusible signals that go both ways. So there are lots and lots of processes that are involved, including, you know, extracellular matrix proteins.
Nick Jikomes 45:54
Another thing that's interesting, I think, in this general field is you've got results on things like rapid antidepressant effects from different kinds of drugs that work in different ways. So something like psilocybin, that's a classic psychedelic with, it binds the fiber sheet to a receptor and other receptors. Then you got something like ketamine, which is a dissociative anesthetic, and it's operating at least in part through NMDA receptors, and also has these rapid antidepressant effects. So how do you start to think about this, where you kind of have the same endpoint being measured the same effect, but it's coming from drugs that have at least that would appear to have very different mechanisms of action?
Bryan Roth 46:41
Yeah, I think ultimately, if we focus on the glutamatergic neurons, so five HT to a receptors are on pyramidal neurons, these are glutamate expressing neurons. And one of the one of the peculiar things about ketamine. So ketamine is an NMDA receptor antagonist. And what it does, at sort of sub dissociative levels of administration is a preferentially interacts with NMDA receptors on GABA neurons. So GABA neurons are inhibitory. And it blocks the excitatory input to the GABA neurons. So it's basically blocking inhibition. And what that does is that that relieves a inhibitory break on pyramidal neuron firing and promotes increased firing of pyramidal neurons basically, okay. And psychedelics do the same thing. Except they do it directly. And we have recently found using a publish this but I presented at meetings that NMDA receptors are the receptors for ketamine appear to be in close proximity to five HT to a receptors in in those neurons. So there could actually be a direct physical link. And its previous It was previously shown by Rex Wang's lab in the 90s that psychedelics alter NMDA currents. So I think, I think we're getting sort of converging evidence that it's, it's basically a final common pathway related to firing of pyramidal neurons. Ketamine does it sort of indirectly. And psychedelics do it directly. I see. That might, you know, it could be in part why psychedelics appear, apparently have a longer duration of action and ketamine, at least clinically.
Nick Jikomes 48:54
I see. So, so ultimately, you know, when we're thinking about effects in the brain, we're talking about changing patterns of activity of neurons. And there's more than one way to do that, if you want to, you know, increase the amount of excitation a circuit, you can increase the activity coming from the excitatory neurons, you can also decrease level inhibition going on to them from the inhibitory interneurons. Right?
Bryan Roth 49:16
Right. You can go directly or indirectly, basically, and in the data, the data that we have and others have suggests that, you know, ketamine does this indirectly and classic classical psychedelic stood directly.
Nick Jikomes 49:33
And is it common for a drug to have dose dependent effects like that, where you know, at a low dose, it's interacting preferentially with you know, one cell type, and then at a higher dose starts interacting with with others.
Bryan Roth 49:45
It's not uncommon. Yeah.
Nick Jikomes 49:49
And how does that work? Do different cells have like different receptors with different levels of affinity for the drug or why does that happen?
Bryan Roth 49:56
So I don't know why that is, but it's it's a phenom. anon that I think was initially described by betta Moghadam maybe 15 or 20 years ago, and has been, you know, recently replicated so it's it's a, you know, you would probably have to ask betta she's sort of the world's expert on this, why it is that low doses of ketamine particularly target inter neurons and, you know, inhibitory interneurons in higher doses interact with NMDA receptors on excitatory neurons. So I don't know why that is, but it's something that's, you know, been described multiple times in the literature. So it's, it's a real phenomenon.
Nick Jikomes 50:43
And then, you know, another another drug we're talking about, in a similar vein, so you've got something like a classic psychedelic, which we've been talking about when we're thinking about private key to a receptors, ketamine, a NMDA receptor antagonist, and then you've got something like MDMA. So how does MDMA basically work? And do you think of MDMA as a psychedelic or what? What type of drug is it slash, you know, how should people think about classifying drugs in terms of their mechanisms?
Bryan Roth 51:17
Yeah, so an MD or MDMA is, you know, no, ordinarily you would put it in the benefits of psycho stimulant because it has amphetamine like actions. So it causes the release of dopamine and serotonin. That's how it works. It does it by interacting with transporters for dopamine and serotonin. So and MDMA also has, I would say, low affinity for five HT to a receptors. It has a metabolite MDA, which has higher affinity for five HT to a receptors but they're still sort of weak. So they're because MDMA primarily causes the release of serotonin and dopamine. You know, there's data in the literature that that drugs the block, dopamine and serotonin receptors can block certain effects of MDMA. So some effects of MDMA are blocked by five HTT to a receptor antagonists some are not. I think five HT one a receptor antagonists may block some effects. And the locomotor activity of MDMA can be blocked by dopamine antagonists. So it has sort of a complicated mechanism of action. It's not entirely clear how this leads to the potential therapeutic actions of MDMA. MDMA also interacts with a family of receptors called Trace amine receptors, which are found in the brain and as you know, it's possible that interactions with trace amine receptors psychedelics also interact with trace immune receptors. To some extent, it's conceivable that that actions that trace amine receptors are responsible for the therapeutic actions of these drugs, but we just we just don't have any data on that. We consider I started consider MDMA as just a psychostimulant. I think people that study um, de MDMA refer to it as a intact region or in pathogen, because it didn't, you know, increases one's empathic processes. But it's not it's not a psychedelic, because, as far as I understand, it doesn't induce hallucinations. Right, right. I haven't heard that.
Nick Jikomes 53:58
Yeah, I don't think anyone I have never heard that.
Bryan Roth 54:02
Yeah, so psychedelics induce hallucinations, right? As a minimum, in MDMA doesn't. So ordinarily, we would not classify it as a psychedelic. Again, I think it's sort of this this branding, if, if people can brand MDMA as a psychedelic, it makes it sound more sexy,
Nick Jikomes 54:35
I think. I mean, it's in the
Bryan Roth 54:38
past. So when, in the past by like, five years ago when no one was studying psychedelics, other than my lab and two other labs in the world? Nobody, none of us considered MDMA, a psychedelic. But now that there's this huge universe of people that are interested in these compounds. They're sort of bending them all together. Yeah. And again, it it. You know, if ultimately, you know, people decide that any drug that that causes you to feel strange as a psychedelic, then that's that's what they'll be basically I sort of have been advocating a more a farmer, Patrick. Classification of drugs of the of these drugs, basically because that's the way we in pharmacology, that's how we define drugs is based on their biggest olfaction. So but again, it will we'll have to wait for 10 years to see how the word psychedelic is actually being used.
Nick Jikomes 55:54
Yeah, I mean, I mean, ultimately, we're just you're describing a linguistic phenomenon, which is not specific to this field by any means. But it sort of seems like the word psychedelic in my view of the read of the last few years of usage, it's almost evolving, just to mean something like, rapid acting next generation psychiatric medicine or something.
Bryan Roth 56:18
Yeah, I don't. I don't know if people that went to the psychedelic science conference would use that definition. I think, you know, my sense is those are the people that that are sort of in quote, unquote, the psychedelic community would consider ketamine, you know, Ibogaine, salvia, classical psychedelics, MDMA, dextromethorphan, etc, would consider all of these drugs, psychedelic, quote, unquote, psychedelic. So they're sort of CO opting. So we used to have this term psychoactive. To describe those to describe those drugs, I would everybody would agree they're psychoactive. And, you know, it, you know, ultimately will depend, it's, it's sort of like, say, 20 years ago, if you wanted to refer to somebody as as having a good a good sense of empathy, you would say they're empathic, right? And then, about 10 years ago, people started using the term empathetic which was not the preferred term. But isn't it now Yes, basically, if you go to the dictionary, now, empathetic, which was a non preferred term, is now the preferred term. Okay. And it may be as we go forward, that instead of using the term psychoactive, we'll use the term psychedelic. And then, and then I would recommend that we we we refer to drugs like LSD, mescaline and psilocybin DMT, as classical psychedelics and the others as a typical psychedelics. This is the approach that the European Commission on drugs has taken. So they're sort of the European equivalent to the FDA, the Food and Drug Administration, so they have they define classical psychedelics, and then other psychedelics.
Nick Jikomes 58:46
So classical psychedelics would be 7582 A, like serotonergic psychedelics like LSD, psilocybin? DMT. And then you've got the other one so XL via X through a completely different receptor. Yeah, and so on.
Bryan Roth 58:58
Same thing. Yeah. Yeah.
Nick Jikomes 59:01
Another interesting question here is related to the duration of the subjective effects of these things. Something like Ibogaine lasts a very, very long time. LSD also lasts a long time, not quite as long, but even within the classic serotonergic 5g to a receptor, activating psychedelics like psilocybin, LSD DMT. There's, there's a lot of there's a lot of difference between them in terms of how long they last. And what is how does that actually work? Because it just has to do with how long they are sitting at the receptor.
Bryan Roth 59:34
So to a great extent, it's, it's due to what's called pharmacokinetics. Basically, how fast they're cleared from the body. So DMT is cleared very quickly. It's degraded by monoamine oxidase silos and slower and LSDs hardly at all. So that's, that's a main driver. Another driver Are for LSD in particular is that when it binds to the receptor, it binds in what's called a pseudo irreversible fashion. So once it's bound to the receptor, it doesn't come off for like eight hours. And that's because a lid comes over the top of LSD and basically locks it into place. We don't see that with other psychedelics, it appears to be peculiar to just LSD, like compounds which have this long duration of action. So we think it's, it's pharmacokinetics, as well as the fact that that it's when it's on the receptor, it doesn't come off. Drugs drug like DMT has fairly low affinity. So it's going to, it's going to come on and off the receptor in the second, within a few seconds, basically. So that, as its metabolized, basically is completely eliminated. And this is not the case for LSD.
Nick Jikomes 1:01:04
And so you've got these different durations of action you've got, you've got human observations, where, you know, some of the clinical results with things like psilocybin show a correlation between the reported intensity of the subjective effects and the actual duration of of the therapeutic outcome. That was also the subject of that recent paper about critical periods and social reward learning where they looked at various drugs, things like psilocybin and LSD, classic psychedelics, as well as things like ketamine and Ibogaine, and MDMA. And they found this interesting relationship with respect to the social reward learning model they use were basically the the length of the subjective effects was proportional to the duration of time of the drugs being able to open this critical period for social reward learning. And, you know, this, this relates to this question of the efficacy of the potential therapeutic efficacy of the subjective effects themselves. What do you think about that recent results? And what would What's it? What's it going to look like when we have more definitive answer to this question of the relevant therapeutic relevance of the subjective effects?
Bryan Roth 1:02:19
Well, I would say that the, what they report is that the duration of action of the drug is correlated with the duration of the effect on on social learning. And I would say that's unsurprising, if a drug has a longer duration of action is going to have a longer duration of action, basically. So if it so this is, that result was not particularly surprising to me, was interesting. I, you know, I think we really, this is a situation where you're really more human data. So we only have, we only really have human data for a couple of well controlled phase two trials for psilocybin basically. And in the most recent, one of the most recent ones, it appeared that the therapeutic effect may have tended to wane. Actually, at the end of the study. I think this was the one that was in the New England Journal of Medicine. Psilocybin versus S ketamine. So I think right now, what we need are adequately powered, adequately controlled human trials to see really what the duration of action it really is. And I would just at this stage of the game, I would, I would be agnostic, because we just we just don't have any data on that. But I would say that the the findings in the paper are not unsurprising that the that the pharmacokinetics of the drug appear to be correlated with the duration of action that that's sort of classic pharmacology dogma.
Nick Jikomes 1:04:26
So, another thing I wanted to ask you about related to recent results, has to do with you know, so we've talked about fiber sheets, five HTT, to a receptor serotonin to a receptors with respect to the classic psychedelics, they're very important, they seem to be essential for the subjective effects. They're like, they're likely also playing some role in the neuroplasticity, although the in vivo evidence is more ambiguous there. But but as you mentioned, all of these compounds, LSD, psilocybin, psilocin, DMT. Basically, all these things bind to a bunch of different receptors in the brain and each one has, you know, different pattern of affinity for a different set of receptors. One of the ones that you mentioned earlier was this thing called track B. And it's bound by BDNF. Can you give people a little bit more background on on what those things are? And sort of a high level overview of, of what they're famous for in terms of development and plasticity?
Bryan Roth 1:05:20
Yeah, these are growth, what are called growth, they're in the growth factor receptor family. So these were originally growth factor receptors originally identified by Rita Levy, molto teeny. And there was somebody else, but she got the Nobel Prize for basically discovering nerve growth factor and, and the various receptors. And BDNF is just brain derived neurotrophic factor, it's, it's, you know, it's, it's one of dozens of growth factors. And then there are dozens of growth factor receptors. And many of them have been demonstrated to be very important for normal growth and maintenance of the brain and its connections. Track be How has, since I would say Ron Newman's work in the night, the late Ron Newman's work in the 90s has has been a sort of achieved central importance in in the regulation of the effects of a number of drugs. So, that induce plasticity, so drugs like cocaine, and morphine, which cause plasticity have a Derek deleterious type. So they, the type of plasticity they induces is dependence. This is all this is all dependent on track B. This is well described. cocaine, amphetamines, morphine, basically, their, their, their long term effects are all MIDI by track B. And there's there's data compelling data that the long term effects of classical antidepressant drugs also ultimately are mediated by track beat. Okay. So there's, there's data going back a couple of decades, that a final common pathway of the action of many drugs that induce long term changes in the brain is due to activation of the track B receptor direct directly or indirectly. Okay. So it's another one of these proteins, it's well known. If you go to PubMed there, you know, maybe 50 or 60,000 papers on track B and BDNF. It's maybe 100,000 papers on BDNF, basically. So BDNF has been attract me they've been implicated in in every sort of synaptic event almost in the brain. And, as I said, there, there's data now from a couple of groups that, at least, that track B and BDNF may be part of the final common pathway of psychedelic drug action.
Nick Jikomes 1:08:21
And there was a recent paper that I looked at, but I didn't, I didn't scrutinize it in in too much detail. But it had to do with psychedelics binding to this track B receptor, which is what BDNF binds to, and apparently, they directly bind to it. So was that known already? And was this paper? Is this paper contradicting the idea that the neural plastic effects at least some of them are coming through 5g to a receptors, or could it be both, or is one thing upstream of the other?
Bryan Roth 1:08:52
So I would say it doesn't. So what it shows is that LSD and psilocybin, which is the active metabolite of psilocybin, can bind to the track B receptor with high affinity and with the same affinity that they bind to serotonin receptors, and that they can potentiate the effects of BDNF on activating track B. And then they show that track B is essential for the neuro plastic effects of psychedelics. So I would say the, the the part of the paper where they say track the is important for psychedelic action. I think most people would probably agree with that. I don't I don't think that's a particularly unsurprising result. The thing that's a little bit surprising is that they find that the LSD binds with such high affinity to track B. It's it's like one animal or poem See, that's that's very high affinity. And it's never been reported before. I don't know, if anybody's ever looked very closely, there would have been, would have been no reason to look. So, you know, we're waiting to see if if those if other people see the same thing, basically. So it's a pretty interesting result, it could be true. But we have to see my lab is, you know, we're working very hard now to see if we can reproduce those findings. Because obviously, if they were true, then that would be another potential target that we could utilize for drug discovery purposes. That being said, there are some downsides to directly hitting track B. So there were studies have been done in the past where people have tried to use BDNF as a therapeutic agent for various neurodegenerative diseases basically didn't work. And there are a lot of bad side effects. So we think that you know, just act of just sort of willy nilly activating track B, and the brain is probably not a good thing. Long term. But since psychedelics are only taken occasionally, you know, if it's if this is true, it could be, you know, something really interesting. We just have to
Nick Jikomes 1:11:33
see it as BDNF. Is that something that gets sort of released widely across the brain? Or is that something that operates in a very sort of specific synapse by synapse? Fashion?
Bryan Roth 1:11:45
Yeah, so it's released. So it'll have local effects, but it's typically only released from neurons that are, you know, that activated, activated through release, basically. So it's, it's not normally sort of activated everywhere in the brain, it's found in every neuron in the brain, basically. So typically, there, you know, there's some pathways specificity about the effects of BDNF.
Nick Jikomes 1:12:15
And, you know, when we think about when we think about drugs like this, or really any drug, you know, whether it's a psychedelic, or an SSRI, or anything that we want to use to treat something, you know, treat a psychiatric condition, you know, presumably, when someone has, you know, depression or PTSD or whatever, there are certain synapses in the brain, certain circuits that you want to be more plastic, and, you know, create new conduct connections, or create, take away some connections, and there's presumably many that you actually don't want to change. But when we administer drugs to people, you know, the drug goes through the bloodstream and sort of gets in the brain and basically goes everywhere. And so how do you, you know, as someone who's sort of a molecular mechanistic laboratory scientist, but also has training in psychiatry? How do you start to think about this, you know, this, this issue of, you know, we want to have very, very targeted changes that we induce in the brain to help fix it. And yet our drugs, you know, basically go everywhere?
Bryan Roth 1:13:14
Yeah. Well, psychedelics go everywhere, but the receptors are not everywhere. And so one way of addressing sort of the question is to make psychedelic drugs that only hit the five HTT to a receptor. And
Nick Jikomes 1:13:32
it's even even more selective. Yeah. So we have those
Bryan Roth 1:13:35
compounds now. And they are therapeutic, at least in mice. So that's one way. Another sort of, futuristic way is to use this technology that my lab invented called chemo genetics. And what chemo genetics allows us to do is to target distinct neuronal populations and turn them on and turn them off with a pill basically. somewhat akin to optogenetics, except that you don't, you don't have to put an optical fiber in somebody's brain and turn it on.
Nick Jikomes 1:14:11
And I think most listeners probably haven't heard of chemo genetics or dreads or some of this cool technology that you invented. Can Can you walk people through how that works at a high level?
Bryan Roth 1:14:21
Yeah, I just have. I have five minutes left here. So okay, yeah, we'll just end it there. Yeah, so chemo genetics basically use receptors like serotonin receptors, that have been engineered, so that they are activated only by a drug which is inert. And so, these can be put into any neuron in the brain. And then they can by administering of a of an inert drug, we can turn the neurons on and turn them off basically in a in a highly, highly robust fashion and I would say in the neurosciences, the technology is used sort of ubiquitously. So if you go, if you go to the neuroscience meeting, there will be literally hundreds and hundreds of posters using this technology. And, and it's also, it's, it's now been shown in multiple papers to be very effective in non human primates, unlike other technologies like optogenetics, which are very challenging when you get to be your bigger brains. So we think that ultimately this, you know, another another approach would be focused. There are focused ultrasound procedures now that are being developed to, to target particular circuits in the brain. And there's focused trans magnetic cranial stimulation as well that that these are not in non invasive technologies to modulate the activity of particular neurons. So that's the approach we're taking is to make drugs that are way more selective for those for those neurons. And then also to develop technologies that where we can, once we find the neurons we want to modulate, we can turn them on and turn them off at will.
Nick Jikomes 1:16:21
So one strategy is tweaking drugs, they're binding fewer types of receptors and they have more activity. In this
Bryan Roth 1:16:28
case, only one, right? Only the five HT to eight, which is only found in certain neurons in the brain, right?
Nick Jikomes 1:16:35
What's What's the name of that drug?
Bryan Roth 1:16:38
ZX something something something. Y'all have code names, we have a ton of them, basically now. And they all seem to work just fine in mice. So at least in mice, it appears to be the five HTT receptor are pretty clear about that now.
Nick Jikomes 1:16:59
All right, well, Professor Brian Roth, I know that you gotta go. You got stuff to do, but thank you for joining me again. This was fascinating and have a good day. Bye.