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Episode 46: Manesh Girn: Psychedelics and Brain Networks
49 Plays1 year ago
Manesh Girn talks to us about the effects of psychedelics on the brain, based on his recent paper, "A complex systems perspective on psychedelic brain action". We discuss the current state of psychedelics as therapeutics, and how information theory can model changes in brain states that result from taking psychedelics.
Special Guest: Manesh Girn.
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Transcript
Introduction to Manesh Gern and His Work
00:00:10
Speaker
Welcome to Cog Nation. I'm Joe Hardy. And I'm Rolf Nelson. On this episode, we're joined by Manesh Gern. Manesh is currently finishing up his PhD in neuroscience at McGill University and has authored over 20 scientific publications on psychedelics, brain networks, and related topics.
00:00:28
Speaker
He collaborates, collaborates closely with some of the leaders in psychedelic science. And we'll join Dr. Robin Carhart-Harris at UCSF as a postdoc in August, 2023.
00:00:40
Speaker
Manesh is also chief research officer at the Canadian psychedelic bioscience company and Theo tech bioscience and runs a YouTube channel and Instagram page called the psychedelic scientist.
The Neuroscience of Psychedelics and Psychotherapy
00:00:52
Speaker
I highly recommend his YouTube channel. Uh, he does some really great explainers on some of the topics in psychedelic science and yeah, he's just really good there, which is part of why I wanted to have him on the show. I thought, uh, you know, you'd make a great guest. So thank you, Manesh for joining us. Yeah, thanks so much. My pleasure. Excited to chat with you guys.
00:01:10
Speaker
We talked about just having a pretty broad-ranging conversation on the neuroscience of psychedelics, and there's a very exciting field right now. There's a lot going on. I particularly want to talk about how our evolving understanding of the neuroscience of psychedelics impacts the way we think about treatment and the use of psychedelics in psychotherapy and other related
00:01:31
Speaker
you know, treatment modalities. And we wanna take a paper that you've written recently as sort of the guiding document for the conversation.
Complex Systems Perspective on Psychedelics
00:01:40
Speaker
The paper is a complex systems perspective on psychedelic brain action. So I thought maybe I could start by just asking you to kind of at a high level talk about what was sort of the thesis of that paper? What's the big idea behind that paper?
00:01:59
Speaker
For sure. Yeah. And I could, I can get into that by first describing the motivations, why we decided to write this paper, where the ideas came from. Um, and it came from two distinct, you could say distinct streams of research. One is psychedelic brain imaging research. And, um, a lot of people might've heard or maybe not about how psychedelics can make the brain more integrated and how they can disintegrate certain brain networks, such as the default mode network.
00:02:27
Speaker
And that's usually how it's portrayed in the media. It's like either the brain turns off this particular network related to our sense of self, related to our concepts and internal dialogue, and frees up the brain to be more integrated and share more knowledge and between different.
00:02:43
Speaker
you know, systems of your brain. So some some listeners might be familiar with the idea of the default brain network and maybe other brain networks like the salience network. Maybe just want to take a moment to describe what what those mean. And okay, yeah, yeah, like what what is a brain network in this context? Okay, for sure. For sure. Let's back up a little bit. Okay, so
00:03:04
Speaker
So that thing in your head is called the brain. So the brain can be separated into distinct regions. Each region has a distinct function, you could say. Something might be specialized for converting the light that hits your eyes into a visual theme. Some of it might be more related to language processing. Some of it might be linked to sense of touch. And so we can separate the brain into a whole variety of regions, which do different things.
00:03:32
Speaker
And the interesting thing about these sets of regions is that they seem to group into clusters of sets of regions which interact more with each other than they do with the rest of the brain. And so you can separate, let's say there's 50 regions in the brain and 1 to 10 is the first network and then 11 to 20 is the second network. And these are networks because they're networks like sets of different regions which tend to share information with each other, interact with each other more.
00:04:00
Speaker
and like work in a coordinated way towards shared functions.
Brain Networks and the Modularity of Mind
00:04:04
Speaker
So we'd see these as, or at least my familiarity with these might be also like Jerry Fodor's idea of modularity of mind, that you've got these informationally encapsulated modules that sort of defines their isolation from other modules and then they might be interconnected as well.
00:04:22
Speaker
Yeah, totally. Yeah. Yeah. It aligns with the idea from cognitive science of a partially decomposable system, right? It's like, there's, there's modularity, there's different modules, but they're, they're more connected within themselves, but they're also connected to each other to some extent, right? And so you have a set of networks, yeah, which, which communicate with each other, but it can be separated. And then the default mode network specifically, maybe you can describe what that
00:04:46
Speaker
has been shown to do because these things are, I mean, they're, I think they're old hat for some neuroscientists, but they're relatively recent in the long history of neuroscience. Yeah, totally. So the default mode network is this particularly interesting one, because one, it consists of regions that are most expanded in humans relative to other primates, and which are involved in these kind of
00:05:09
Speaker
human defining aspects of our thinking. So, um, default mode network is involved in a whole variety of processes, including our ability to daydream and mind wander and think about things that are not here physically in the here and now, um, to reason and think about the mental states and beliefs, um, above all of other people. And, um, also our ability to kind of construct a self narrative and say,
00:05:34
Speaker
You know, these traits, this story, this is all me and that's not me, and it links to memory. And then more broadly, it's involved in our ability to imagine new experiences planned for the future and also remember past experiences and several other things. And this has been linked with psychedelics before. What's the connection?
00:05:55
Speaker
Right. Because, I mean, there's two ways we can go about this. So one is, if you think about what I just described, all these functions of thinking of mind-wandering daydreaming imagination, clearly that's altered when you take a psychedelic, you know, just experientially, subjectively, these basic aspects of our thinking and how we conceptualize ourselves in the world are altered when you're under a psychedelic. And so on the basis of that, people just kind of inferred that very likely you would even more network is being disrupted.
00:06:23
Speaker
And then the research to an extent has confirmed that or supported that. And it started in the 2012 paper, the first ever modern functional brain imaging paper on psilocybin, the compound in magic mushrooms, where they found that the deep hormone network out of all networks showed decreases in activity, meaning this network is like less active, which in some way you can understand is like a disruption of the normal way it's functioning.
00:06:50
Speaker
And so, and then people kind of ran with that idea. It was popularized in Michael Pollan's book, How to Change Your Mind, really, really emphasizes the default mode network. And other work has also found changes to the default mode network. But I should say, and I was going to get to this, is that basically every network in your brain is altered. A default mode network doesn't seem to be special in the sense that all networks are disrupted in their activity to some extent and become less integrated.
00:07:15
Speaker
And it might be the case that the default mode network is related to specific aspects of the experience, but this actually hasn't been consistently shown in the research yet either. We just have strong hypotheses. So the short answer is, yeah, the default mode network is involved. Just sort of in reference to this idea that it's happening not just in the default mode network, but it's happening all over the brain. So you're thinking of this as more of a complete sort of state change for what's going on in the brain rather than
00:07:43
Speaker
just localized in any one particular state. And maybe that's an introduction to have you start talking about the perspectives of this paper and some of the findings that have gone into your thinking about this.
Psychedelics and Brain Function Shifts
00:07:54
Speaker
Yes, definitely. And so as I was just saying, the default network is involved in so many things, right? So to reduce the psychedelic experience to just the default mode network, it's more complex than that. You can't just reduce it to one network. And what really struck me was how there's really large reductions in default mode network activity in a whole variety of contexts. You get it with MDMA, you get it with SSRI antidepressants, you can get it with alcohol.
00:08:21
Speaker
As you get older, your default mode network has become disintegrated over time. That's a very common thing. And so there's a variety of situations and contexts where this similar pattern of activity in a default mode network happens, but the experience related to it is radically different, right? So then we can't just say, oh, when the default mode network is like this, it means you're in a psychedelic state or your ego has been dissolved or something like this. Like we can't say that.
00:08:47
Speaker
So it's very, it's, I mean, one thing, it's very hard to map on that subjective state or any of those subjective states to a particular brain state. I mean, that's a, that's a general thing, but I think, yeah, maybe especially. Yeah. Well, if we break it down a bit more, when you take a psychedelic, the enemy takes a psychedelic, you're not having the same experience, right? Like each person in the same room, same environment is going to have a radically different experience. And even you as an individual, if you take it today versus tomorrow, it's going to be a very different experience.
00:09:15
Speaker
And so then how can we expect one pattern, one brain state or pattern to reflect that? It doesn't really make sense if we assume that the brain is mapping onto a subjective state, which we've obviously to expect it is. And so in this paper, we're saying kind of basically the idea that rather than seeing psychedelics as targeting particular brain networks or regions, we just see it as shifting the fundamental ways in which the brain functions and processes information.
00:09:45
Speaker
I think two good concepts to summarize this are the concept of criticality and the concept of metastability. And so these concepts come actually from physics and dynamical systems theory and also complexity science, which just really quick what that is. Complexity science is a study of any network of distinct parts or any context in which something can be decomposed into distinct parts that interact.
00:10:15
Speaker
And you could think of this as an ecosystem. This is the analogy I like to use. Because if you think of, let's say, a jungle, you have all of the plants that grow there. You have in the trees, maybe you have monkeys and birds. And on the ground, you have rodents, bugs, and all sorts of other animals. And the monkeys eat certain fruits. But the fruits need the ants to do their thing to support it. And then the birds keep the rodent population in check.
00:10:43
Speaker
It's a coordinated system. Everything's interacting. If you pull out all the monkeys, it's going to mess with the entire system. The whole ecology is going to be disruptive, right? And so you think about the brain in these terms. The brain is a set of regions.
00:10:56
Speaker
where if you disrupt something somewhere, it's going to affect the whole brain because the whole brain is so interconnected. And so you can really think of the ecology of the brain, uh, in the context of any process really, I think, um, because everything will influence everything else to some
Complexity Science and Brain Ecosystems
00:11:11
Speaker
extent. So underlying this paper is this concept of seeing the brain in this light of like, like an ecology of brain regions, you could think of it. So these concepts, metastability and, um, and criticality.
00:11:23
Speaker
describe the nature of how a system like that, like an ecosystem or the brain, changes over time in response to changes, to perturbations. So it's like a perturbation might be to remove the species from the jungle or in the brain would be to activate your serotonin-2a receptors, which is a receptor psychedelics hit. And I hope this isn't getting too technical, but...
00:11:46
Speaker
No, it's good. The idea is that psychedelics, by doing what they do to certain brain receptors, send cascades of changes throughout the entire brain, which change how the brain functions. I'll just describe criticality and metastability really quickly because they encapsulate what it means. I'll start with concept of criticality.
00:12:10
Speaker
try to make this as relatable as possible. So let's say when you're trying to function in your life, your life needs to be a bit orderly and predictable. You want to feel like you know what's going on. You want to feel secure. And also your body and your mind wants to stay in homeostasis. You want to stay within a certain range of states of emotion and experience. So you're stable over time. You're not just
00:12:32
Speaker
full elation and then depressed and then this and then excited and sad. It doesn't happen usually within a rapid pace all the time. And so the brain is in the business of keeping us within this relatively constrained world that works for us. And obviously that could be healthy for some people, it could be unhealthy for some people, it could be connected to reality, it could be disconnected from reality, all these things, but the brain is trying to minimize the unpredictability of your experience in your life.
00:13:03
Speaker
And in doing that, it's keeping your brain in a certain level of functioning. And so one way of understanding this, relevant to criticality, is that the brain can be more orderly or more disorderly or chaotic. It's like structure, order, chaos, disorder. And the brain usually operates at a good balance between these two.
00:13:25
Speaker
And where you need some chaos for new, for not being super rigid, but you don't want to be, and you don't want to be super rigid. You don't want to be too chaotic, don't want to be too rigid. You have to find the balance. And so the idea is that the psychedelics push that a bit more to the chaotic side to this threshold between pure disorder and an order. And at that threshold, it's called the critical point. And we know from a variety of systems that at that point, um, it's the best for, um,
00:13:55
Speaker
having a greater complexity of activity. So you're more flexible in responding to things. You're very sensitive to information that's coming in in that state. And it's better for information sharing in the system. And so the idea is that psychedelics put it in a state where the entire brain is more flexible
00:14:16
Speaker
more dynamically changing over time, more sensitive to incoming information, and to be able to process it in a variety of different ways. And it's more integrated, which allows better information propagation throughout the system. Information has to be able to go from region to region. And so this high-level description encapsulates how the whole brain functions in the psychedelic state.
Creativity and Cognitive Flexibility Post-Psychedelics
00:14:37
Speaker
I love that description of chaos and stability, too.
00:14:42
Speaker
I guess when I thought about something like integrated information theory, which I think of as having to do sort of with the amount of information in a system and the entropy in a system. So just sort of reaching that point at which you can sort of have the most information in a system, which would obviously be a useful thing, reaches towards that point of chaos, right? Where it sort of extends out.
00:15:08
Speaker
I really like the way that you explain it like that with the jungle analogy too. I think that's really helpful. I guess to relate that to psychological functioning, the idea is that in the state that is slightly more chaotic, that is past that point of criticality or in that direction,
00:15:30
Speaker
The idea is that there's an opportunity for a therapeutic opening because when the brain is in that state, it's essentially more plastic, at least from a psychological perspective, open to change. So if there are rigid patterns in the way that you've been thinking about certain things or there are patterns of thought that you have that are recurring, that are negative,
00:15:55
Speaker
deleterious, there's an opportunity to repattern those in a more positive way. That's sort of the theory, right? Yes, totally, totally. It's allowing us to shift out of our usual frame or in the usual constrained set of mental states and experiences we operate in and explore new lines of thinking, new perspectives, and escape our kind of habitual ruts we might fall into in our mind. So does this seem to you as similar to
00:16:21
Speaker
sort of like electroconvulsive shock therapy where I mean that's you know sounds a lot worse or TMS in frontal lobe where what you're trying to do I mean it's a little different because what you're trying to do in those situations is stop persevered of thoughts or just kind of
00:16:37
Speaker
Yeah, no, I'm with you. I think there's something similar there, right? You're trying both have this at this very gross level. I think the level at which this this type of this theory and these sets of theories that you are sort of combining in this work, really why it's becoming popular and more popular and why it's intuitive is that it relates to this idea. It's almost like what you're doing with with whether it be, you know, TMS or electroconvulsive shock therapy or psychedelics is shaking the snow globe.
00:17:04
Speaker
Right? There's some, you've got some patterns that are kind of entrenched in the brain and ways of thinking that are entrenched and you're basically shaking it up. I mean, right at a very, like very basic, analogical level, right? You know, you're, that's kind of what you're doing. Yeah, definitely. I think like, ECC, electro-convulsive therapy is a bit more crude, obviously, you're just relaxing your system. Whereas psychedelics, you're in this state, but you're still conscious.
00:17:30
Speaker
you're not strapped to a chair with muscle relaxings, you know, usually, hopefully. But, uh, and, and then what psychedelics is they can lead to insights. And like, actually you're, when you're in that, like this kind of show can shake it up state while you're still there, you're able to see things and have insights and process emotions and memories and stuff. And that's really important. Yeah. Talk about that a little, talk about that a little bit more, uh, relationship with creativity too, because, um,
00:18:00
Speaker
I think often we talk about creativity as having sort of a generative stage where you're trying to think of as many things as possible and then sort of starts out as divergent and then becomes more convergent. And that's when you sort of assess things and see what's going on. So how does this relate to what's going on under the influence of LSD?
00:18:26
Speaker
Yeah, I think, um, and actually wrote a review paper on psychedelics and creativity a few years back. We linked it to the generative and evaluative phases. And kind of the idea is that, um, uh, what we propose in that paper is that psychedelics are really good for the generative phase, right? They reduce our kind of rational constraints. They reduce our evaluative mechanisms and allow it, allow us to entertain possibilities that might've seemed ridiculous. Otherwise we just wouldn't have access to. And so, um, I think,
00:18:55
Speaker
more creative generation is the volume of ideas and a kind of range of ideas like dogs can be potentially good for that for the reasons I just mentioned. But also it's like just because you're making a lot of ideas doesn't mean they're all good or any of them are good, right? Right. You got to go through them afterwards and see what actually turns out to be a good idea and what was
00:19:15
Speaker
you know, the light of day. And interestingly, the research so far looking at it, I have actually suggested that creativity, like in terms of divergent thinking is more improved in the week after a psychedelic experience than acutely.
00:19:29
Speaker
I think this could be a dose-dependent thing. I think part of it is, especially if you're not somebody who's a seasoned psychedelic, who's taken psychedelics many times. When you're in the psychedelic state, it's going to be a hard time. You're going to have a hard time concentrating, focusing on what you're actually trying to think about. These kind of generalized deficits in cognition and attention might lead it to be hard to think about creative solutions to a problem or something like this.
00:19:55
Speaker
Whereas afterwards in the aftermath, you still have this lingering flexibility and openness of mind, which is called the afterglow effect. And that's when it's a good idea to introduce sort of tested therapy and structured situations for that evaluative stage kind of. Yeah, totally. Or even just to then try to engage in your creative process in that few days after. That seems to be very effective, yeah.
00:20:22
Speaker
Awesome. So I think we derailed you after you described criticality. I think you were going to talk about metastability. Right. So it all relates to what we're talking about. So this idea, I think it's very helpful for me at least to think of our brain and then our experience as kind of this space of possible places you could be, right? It's like you can be in a constrained box where your mind goes from here and there and here and there, but it's always within this small area.
00:20:49
Speaker
And people with mental health conditions, or just not even like a condition, quote unquote, but like who struggle with some kind of thought pattern that re-emerges, or some behavior that's very automatic, that we can't escape from, we have a hard time escaping from, that our brain is like tending towards certain states and getting stuck there, and it's unable to kind of get out. Or it's staying in the same neighborhood of states, and it's hard, there's like a gravitation pole.
00:21:14
Speaker
local minima kind of thing, I guess, if you were to describe it in mathematical terms, but I think your way is probably better. Yeah, I mean, only to describe it is like there's attractors in the landscape, right? There's like these gravitational pulls where you just always seem to end up in the same area of thought and emotion.
00:21:32
Speaker
And so the context, sorry, the concept of metastability refers to this tendency to be able to navigate states very easily and very easily switch between them. And actually to the extent that it implies a state of a system where it never gets stuck in a given state, it always transiently kind of, as soon as it gets into that state, something above that state pushes it out.
00:22:00
Speaker
And so it's always alternating between different states. And you have this really big, great flexibility of mind. And there was some actually brain imaging research done by a friend of mine. His name's Parker Singleton. He did that Cornell. And this was published in a journal called Nature Communications. And they found using some sophisticated data analysis techniques that the brain actually seems to use less energy to transition between brain states in the LSD state.
00:22:29
Speaker
And it's just this more fluid ability to switch and share and switch into different configurations or states. And this was handheld metastability, which again, is like, you can find it, you can understand it as you're, you're stable, the unstable. That's a way to understand it. Like you're, you have a stability in the fact that you're always switching between states and it's fluid and easy way.
00:22:52
Speaker
And so just a quick question here. So sorry, does this relate to and I know there are some studies that show sort of suppressed or reduced action in parts of the brain from psychedelics. Do you think something like this might be at play there, where it's just lower energy? So it doesn't it doesn't show up as heavy activity? Oh, that's interesting.
00:23:16
Speaker
Hmm. No, no, it's an interesting concept. It comes down to how energy is being defined. Yeah. Because there's like, what you're referring to is more maybe metabolic. That's what I was thinking of is metabolic energy. Yeah. And actually, this study wasn't a metabolic base. It was based in the nature of the network and it gets free mathematically. It's like graph theory applied to the brain and engineering concepts. But yeah, it is interesting concept. I wonder,
00:23:43
Speaker
Does the brain become more metabolically efficient in a psychedelic state? I don't know. That's an interesting question. But yeah, there's this idea that the constraints on brain state shifting are relaxed a bit and you're just switching between them. And so bringing this all together, what we're proposing in this paper is it's more meaningful to describe the brain as entering into this more critical and metastable way of functioning, which is again conducive to
Predicting Responses to Psychedelics
00:24:12
Speaker
flexibly responding to events that are going on, being very sensitive to what's going on, not getting stuck in usual patterns and having more information sharing and integration. And what's interesting is that in complexity science, the science of these concepts, which again, it goes far beyond just the brain, they have a lot of quantitative metrics for characterizing these kinds of things, such as like entropy, that's an easy one. It's like how unpredictable is the signal, how much information is in the signal at each point.
00:24:40
Speaker
And measures like this we're posing might be more useful in finding signatures of psychedelic brain effects that are common across people and data sets and that distinguish psychedelics from other states more than looking at specific networks. So rather than looking at specific networks and patterns of brain regions, look at the nature or how the whole network changes over time.
00:25:09
Speaker
if that makes sense and that's us drawing from dynamical systems theory and complexity science which have are more kind of closer to physics sometimes information theory to help describe again the whole brain under psychedelics well i guess one of the uh ways to think about this you know is sort of summarized in your uh in your paper and i think i just want to read a couple sentences from this because i think it kind of really captures intuitively
00:25:36
Speaker
you know, taking a step back higher level perspective on what's going on here. So psychedelics are known for their ability to induce potent subjective effects that vary widely across individuals and across experiences for a given individual. Assuming the existence of a direct mapping between the dynamics of subjective experience and the dynamics of brain function, it is reasonable to expect that this subjective variability is mirrored by neural variability. And this kind of gets at what I was saying before.
00:26:07
Speaker
taking a step way back, we all sort of have this intuition if you've done psychedelics or if you've observed anyone on psychedelics or if you've done any research in the domain.
00:26:16
Speaker
that something is getting shaken up in the system, that things are getting in some way chaotic. That seems like a very intuitive description of what's happening subjectively when one takes psychedelics. And so then if there's this idea that it maps onto some sort of chaotic state or set of state changes in the neural systems, then it's intuitive.
00:26:45
Speaker
Now that is I like that and that's what I really like about this approach also makes me nervous. It makes me nervous because there we're talking about things at very different levels of analysis like your point that like your analysis is coming from information theory and you know complex systems theories approaches and what chaos means or entropy means in those systems
00:27:09
Speaker
is not necessarily the same as what we mean psychologically, right? The fact that they're, they feel similar is what's kind of compelling about the theory, but also makes me a little bit, honestly, a little bit nervous. Just because when you see these things that are so kind of like, they're appealing at that level of, you know, taking a step way back, 30,000 foot view.
00:27:36
Speaker
But there's no reason in principle why the concept of, you know, entropy at the, at the neural level needs to map to something that feels like chaotic psychological level. Yeah. No, I like that. That's a good point. It's interesting. Cause we were using these as metaphors for executive metaphors, metaphors at the end of the day. And.
00:27:56
Speaker
Yeah, it just comes down to how hard it is to describe internal states, right? You can't quantify them, you can't, well, you can try, but it's usually pretty like, you know, use proxy measures, and it's not it's not what we're actually trying to measure. It's harder to operationalize, right? And so, yeah, that's why these things are compelling as intuitive metaphors to help people understand it. But yeah, it's, it's
00:28:19
Speaker
We have to remember that they are. Just because, yeah, as you're saying, physical brain activity is entering these different states and like, yeah, it makes sense that then you're mentally entering different states. But these are whole different realms of explanation here. And I think part of it is a need for more refined subjective measures, right? We need better ways to capture the moment to moment variability of the psychedelic experience subjectively.
00:28:42
Speaker
which is extremely tough and I know Robin's very interested in that. And we actually have some stuff planned at UCSF getting at that a little bit more and a very, you know, starting simple and working way up. But it's very difficult because if you ask somebody what you're experiencing, you automatically disrupt that experience. So like, how can we find something not too disruptive, find a way that's not too disruptive for somebody to report on a regularly, you know, every five to 10 seconds or something at least to get a sense of that variability.
00:29:12
Speaker
Um, in that, yeah, I don't know. It's a, it's a difficult question, right. It gets you in your head too. If you're doing that, you're making those responses. Exactly. Yeah. I mean, there is something that does seem plausible about that connection. So, I mean, it's, you know, it's kind of an empirical question. I mean, if, you know, if you do the right experiments, you should probably be able to find out what the, what the correlation is or, you know.
00:29:34
Speaker
Yeah. Well, and Ralph and I were just talking earlier before the show about how you might use like psychophysics, for example, to get at some of the ideas of, you know, the role of say,
00:29:50
Speaker
entropy, you know, at different levels of the of the system, based on how different types of visual patterns, for example, are distorted or not distorted, based on what your priors are about those things. If you can create a system, psychophysical system where you have an idea about like, whether someone should have a prior about something visually, so something they see all the time, a natural scene or something like that. There should be some prediction about
00:30:17
Speaker
distortion of that relative to another type of pattern that is not so doesn't have those higher level priors so established. Right, right. Yeah, that's really interesting. It's something I'm quite interested in because evidence suggests that that's related to the default network. And my PhD dissertation is actually on the default network more generally as well. So it's really interesting concept. Yeah, how it disrupts the
00:30:40
Speaker
our own perceptual filters or how we organize experiences. And here's an interesting thing, you may know this, you've probably heard of the binocular rivalry task, right? Where you, in each eye is a different image, and when you give that to somebody, your brain is trying to settle on the interpretation, but what it ends up doing is alternating between them. It doesn't, like, one might be a triangle, it might be a square, and then it goes square, and then at some, you know, periodic kind of rate, it switches between them, probably related to some kind of rhythms in your brain,
00:31:10
Speaker
frequency power. But with psychedelics, there's a study that found that it just, it was like an overlay of both those images, it was just stuck at one overlay, it wasn't alternating. That is really interesting. I mean, that's, that's a great, I mean, that's a great experiment that matches up some of these, some of these subjective experiences to what's going on in the brain. I like that. Yeah, we talk about like, like, like a meta stability kind of thing in perception, right? Yeah, I think that's why I use the
00:31:36
Speaker
Like a winner take all network kind of thing where. Yeah, exactly. Yeah. Yeah. Yeah. So it was an unable to converge on a, you know, on a winner for some reason. It's like, you see the doc and the rabbit at the same time. Yeah. Yeah. That was, it was more of the case after suicide in that study. Um, really interesting, but it does, it lends support to the idea that our ability to organize our experience based on our priors is being altered. Um, so yeah, that's cool empirical evidence for that.
00:32:06
Speaker
Yeah, yeah, yeah. Let me jump to another question. You know, this one is about consciousness and I hope you mind jumping into that territory too. Yeah, yeah. So, so, you know, it's hard to measure consciousness and, you know, know what we're talking about. But, you know, some attempts to operationalize this like integrated information theory or
00:32:30
Speaker
Bernie Barr's theory, think of this as when something is conscious, that it's available, it's widely available through the brain. So that sort of spread. And that information is accessible by, you know, every, everywhere else. What does that say about a state of mind where you just sort of have more, more integration, really? Yeah, yeah.
00:32:55
Speaker
It's an interesting question. In a sense, I mean, I don't suggest you're more conscious. This is what the theory says, right? It's like you're more conscious.
00:33:05
Speaker
on psychedelics. I mean, if you take it to the logical extreme, if you take this metaphor to this logical extreme, you're actually more conscious on psychedelics. Yeah, totally. And there's been research applying IIT, like interviewing information theory metrics through psychedelics, and they find that there's more information. It's a quote unquote, a higher level of consciousness in going to that metric in psychedelics relative to normal wakefulness. And so you are getting more informational integration.
00:33:35
Speaker
And yeah, I think it like intuitively corresponds people's experiences of having really rich subjective experiences where a lot of latent aspects of their mind, their memory thoughts are now disappearing. And so I think it all checks out. It's somehow creating this greater informational complexity through the integration and dynamics as well. And this opens up the level of information and consciousness and the richness of things we're experiencing.
00:33:59
Speaker
And there's, and there's some evidence on the flip side, right? Where the, you know, some relating back to your theory, where in the unconscious state, the sort of the inverse is happening, right? Do you want to talk about that a little bit? Yeah, definitely. And there's actually, um, I just mentioned information theory metrics showing that psychedelics are higher in the flip inflexity. But if you look at coma vegetative state, it's on the other side of the spectrum. Right. And so that's like the extreme from rigid.
00:34:28
Speaker
to chaotic again almost. It's like in the sense of informationally low versus informationally rich. But of course, if you get too chaotic, then it becomes informationally low against this randomness. Hence the criticality where you need to find that balance. But yeah, it's this interesting spectrum and then it's cool to try to map
00:34:46
Speaker
other states onto that spectrum as well to see where they stand. Cool. Well, I mean, I guess one of the questions that comes up for me is or, you know, things to just talk about with regards to your paper, you're really pulling together a few different threads of theories that are out
Rebus Model and Therapeutic Contexts
00:35:03
Speaker
there. Do you want to talk about that? Some how some of the existing theories of the neuroscience of psychedelics are sort of integrated by by this work?
00:35:13
Speaker
Totally. Um, so the one that comes to mind the most is the rebus model, which is the relaxed beliefs under psychedelics model. And we've kind of been implicitly talking about it a little bit. And so this model basically proposes that, um, through their effects on the serotonin 2a receptor, that psychedelics, um, disrupt brain processing, particularly in the deflammon network that's related to encoding our kind of bleeps and assumptions and expectations about our experience, our priors.
00:35:42
Speaker
as you might call them, like our prior beliefs and expectations, you could say. And by disrupting them, they kind of free up information that we had previously been explaining away or that weren't in our model of how the world is and who we are.
00:35:55
Speaker
because we created this idea of certainty of this is how things are, but that can never be complete, right? It has to be a constraint. And then when that's disrupted, we start to realize all these things and remember things that usually didn't fit in before. And that this process then allows us to change our beliefs and assumptions in our priors to be more inclusive perhaps or more healthy. And then when you go back after the experience, you have a new set of expectations about yourself and your life.
00:36:22
Speaker
And this stuff tells a lot with this whole thing of the whole brain becoming more flexible, dynamic, a bit more chaotic, perhaps. And because it's a shake up of our usual models of reality, which can screen our reality. And so then in that sense, it aligns with this rebus model idea of relaxing our beliefs, relaxing our habitual ways of filtering our experience. So then they could be revised in new ways.
00:36:48
Speaker
So that's the Rebus model. Another popular model is the thalamo-cortical model of psychedelic effects. And very briefly, this is the idea that, well, let me back up. So there's a region of brain called thalamus, which one of the things it does is it takes information from our senses and then sends it to more advanced parts of your brain. And in doing this, it kind of filters it. It's a filtering mechanism to prevent us from being overloaded by our senses, let's say.
00:37:16
Speaker
The idea here is that some of these psychedelic receptors are in the thalamus and they influence how the thalamus gates information and that it leads to a kind of influx of more information. So the cortex, a more advanced part of the brain gets overloaded and this leads to too much information being spread and this makes the brain more interconnected, dissolves boundaries and can lead to ego dissolution and this kind of stuff.
00:37:43
Speaker
Blinking that to this complexity science perspective is the idea that through this increased information, sensory information flowing into the cortex, the brain is like pushed to have to respond to it. And so these network changes integration and flexibility is in some sense, to some degree related to this influx information coming in that the brain now has to deal with. And that what we're seeing is a greater sensitive information is just a greater openness and less gating of information.
00:38:11
Speaker
How can we do that theory? That's great. I love that. I love that this work is pulling these pieces, these threads together and doing it in a very intuitive way. It's nice. Naturally, that conversation makes me want to think about the role of set and setting and therapeutic context and the use of psychedelics because I think implicitly behind some of what we've been talking about,
00:38:37
Speaker
is this idea that there's a big movement right now to use psychedelics as medicine to assist in therapy, or just to be medicine on its own. And one of the implications of the model that you're talking about is that with this increased level of chaoticness, if you will, in the brain through psychedelics, very different outcomes can occur depending on what the initial state of the system is. And there's an opportunity to
00:39:06
Speaker
affect the initial state of the system psychologically by the so-called set and setting. And so maybe you could talk a little bit about that in the sort of contextualized around therapeutics.
00:39:18
Speaker
Yeah, so yeah, this this concept that the brain is the way it functions has changed, I think aligns very closely, very nicely with the concept of sentence setting, right? Because the concept of sentence setting basically just tells us that how our experience is going to go is based on the factors that are at play in that moment, or like that, that you're bringing to the experience, it, it's not creating something, it's catalyzing or activating what's already going on. And already the information you're already perceiving.
00:39:46
Speaker
And for that reason, obviously, yeah, like your mindset, your expectations, your emotional state, and then your environment, the sensory information you're getting, the social information you're getting are gonna be thrown into this new way of brain functioning. And that's what leads to your unique trajectory of your experience. And so, and then, you know, theoretically, one thing we can do is if we're able to
00:40:09
Speaker
separate different types of people based on their baseline brain functioning using complexity metrics or whole brain metrics. We can then maybe separate different types of people and have some level of predictability, ability to predict which trajectory they're going to go on after the experience. Are there more likely adventure into states associated with challenging emotions and fear or mystical states and bliss and this kind of thing. And so I think
00:40:35
Speaker
Um, looking at whole brain patterns in non-drug state and using that predict drug whole brain patterns is a really interesting way to go. And there's actually a lot of research or for example, depression where they scan like thousands of people's brains under depression and they're able to isolate different subtypes based on their whole brain activity. And then, you know, imagine being able to say like, Oh, based on this depression subtype.
00:41:01
Speaker
A psychedelic in this context might work for you, or this psychedelic, you know, ketamine is even better for you, MDMA better for you, based on their brain subtype. And you can make inferences based on receptors and where they're located. There's a lot of potential there. And so I think it's a really interesting avenue for predicting effects as well. I have another question too, which is, so you're doing research in Canada right now.
00:41:23
Speaker
I think you have some experience or knowledge of, of, you know, research that's going on in other countries, because you've been doing a lot of collaborations. So what's the regulatory environment like right now, using psychedelics in research and, and sort of availability and, you know, difficulty in, you know, getting this research going?
Regulatory Environment and Therapy Models
00:41:44
Speaker
Because I mean, it has opened up somewhat, but certainly not, not available to everyone to research.
00:41:51
Speaker
Yeah, definitely. It's still quite difficult. And honestly, Canada is a bit behind on it. I think Europe is a lot more research. There's like full blown research programs at multiple universities, you know, at University of Basel, University of Zurich, Maastricht, the Netherlands, Copenhagen, and then in London as well.
00:42:08
Speaker
Where there's a lot of buy-in that this is an approach to go for. Yeah, there's a lot of funding. There's full-blown research programs that get through ethics, boards pretty easily, and he's able to do a lot of experiments that really wouldn't apply here yet with healthy subjects looking at mechanistic, non-therapeutic stuff, which I find the most interesting amount of time. There's a lot of that in Europe and in the States, there's a fair amount too, like at Hopkins, John Hopkins, and also now UCSF.
00:42:37
Speaker
And his research, you know, at UCLA and NYU and, and Harvard has their own thing now and Stanford's making one. And it's kind of everywhere, but in the, in Canada, um, there is some in McGill with rodents and there's some human stuff, uh, we do Academy that I know about. And I know there's some things on the way in Toronto at U of T. I think the main barrier is not really, not necessarily ethics boards. It's more so funding.
00:43:03
Speaker
These studies are extremely expensive. You have to purchase the drug, which is very expensive because you get a GMP certified high quality, and there's not that many companies, so the prices are quite high. Currently, it is not enough competition.
00:43:16
Speaker
And also, if you think about it, you bring somebody in and they give them a high dose of psilocybin, it's about eight hours, eight to 10 hours. You have to be responsible for them for that whole time, right? Yeah, yeah. And you need a physician usually who's there, you need a guide, and then you need all the support for eight to 10 hours per person. And then you scale it up to 30 people, then you add in brain imaging, which is expensive itself, usually 500 an hour if
00:43:42
Speaker
And then it scales up to really expensive studies and the federal government is not really providing that much funding for it. It's a tough time. So where are dollars or Canadian dollars coming from for this?
00:43:58
Speaker
In Canada, it's usually, well, again, there's not that much work, especially in humans in Canada. It's mostly through grants that PIs, like researchers already have, and they just kind of construe psychedelics as fitting under their existing grants, perhaps, and finding a way to make that work. So that's one way to do it. But the CIHR, so Canadian Institute of Health Research, recently did a funding call where they provided a million dollars for three studies, specifically for psilocybin psychotherapy.
00:44:29
Speaker
And so that was a great development for in the federal government point $3 million into it. That was just that that was last year that funny call went out. So that's showing a shift in federal funding towards it. But still, it's very hard to send and send the grant and get approved for it. And
00:44:44
Speaker
It's already hard enough to get grants, now you're throwing psychedelics in it. It really depends on what reviewers you get. I'm sure you guys are familiar with that. Absolutely. I guess the situation is similar in the US, right? They're starting to be some funding, is that correct? Yeah, but more than Canada, that's for sure. I think Hopkins, John Hopkins University, really set a good precedent.
00:45:06
Speaker
And Matt Johnson down there just got a multi-million dollar grant through NIDA, which is National Institute of Drug, what does the A stand for? Anyway, it's a major drug research, federal drug research organization in the States, and they funded multi-million, multi-year study for psilocybin for tobacco addiction for smokers. And there's other grants and money coming in for other kinds of research too.
00:45:34
Speaker
I think the tide is turning, there's more federal funding being available in North America. And in the years to come, it's going to happen more and more as there's more safety data, there's more reliable evidence that they're suggesting there are useful tools, you know, clinically, but also mechanistically in a more basic science way. And so I'm optimistic and I feel like for me, I'm starting my postdoc in August, I'm coming in right at a good time where stuff is starting to tick off and I hope it continues, which it seems like it's happening.
00:46:02
Speaker
Yeah, absolutely. In terms of the, on the therapeutic side, there's different competing kind of frameworks. I mean, you could call them models, but really, I think it's more frameworks or approaches. On the one side, you've got folks who say it's really inner work. When you take a psychedelic, there's healing that's happening.
00:46:23
Speaker
often as this story goes. But that's really done by some work that the person is doing internally or their brain is doing without any kind of external therapy. So it's just you take the medicine and it's going to have positive effect because there's some sort of collaboration with the ongoing neuroscience that's there. And then the other model is psychedelic assisted therapy. So you've got
00:46:49
Speaker
the idea is, well, you've created this plastic open state, and now you need to apply something positive to that psychologically to like have the intended benefit, because you know, plastic states can go positive or negative or all kinds of different ways. Where do you come down on that? Yeah, I think I do believe that psychedelics are inherently like neutral, relatively neutral, in the sense that it really depends on the context you're in, you know, set and setting, it could take you in a very negative space,
00:47:19
Speaker
take you very positive. So for example, people often joke like, oh, let's give, you know, Trump or some politician, the Iowa story, you know, put acid in the water or something that's going to change the world. But I think it can just make people more narcissistic, more all these things, you know, and there's like people in the KK who get together with the KK bodies and do, um, athletes together or do it, sorry, do LST together, I should call it LST, or do mushrooms together. Uh, and
00:47:46
Speaker
They don't come out of it saying, oh, what we're doing is wrong. They go into it and go deeper into their group bonding with their peers. Right. And so I think the context really matters. And this is where the psychotherapy aspect comes. It's like that plasticity and flexibility can, if you're not supported well, you're not prepared, can take you deeper into depression. It could destabilize you. It could re-traumatize you.
00:48:08
Speaker
That's why a lot of cases especially if you're dealing if you're some you like some deep trauma or Persistent kind of chronic mental health issues. You got to be careful And really this is why it's a good outside the therapy is so You know, there's so much in it. You're getting therapy beforehand You're healthy support during your support after you're given integration practices concrete steps to take I think all that is an important part of it like the therapy is an important part of psychedelic therapy and
00:48:35
Speaker
This is not to say that any recreational use is still totally reckless. I think it just needs to be done with care and preparation and respect and knowing that these things aren't just going to magically heal you. You need to really put in work before and after to really reap the benefits in a lasting way.
00:48:52
Speaker
So maybe thinking of this in the exact flip side. So I don't know as much about it. And this is just history. But the weird LSD experiments, the MK-Ultra was it, experiments in the 60s were, I mean, they would be sort of the opposite, using LSD for evil, right?
00:49:13
Speaker
Not for therapy, but some other sort of change. Does the effectiveness of those kinds of programs say anything about the potential effectiveness of therapeutic programs? Yeah, I think so. I mean, it comes down to behavior change, right? Like mental and behavior change. And I think, you know, combining psychedelics with a coordinated set of, I don't know, techniques, practices, interventions.
00:49:39
Speaker
can, I think, can synergize really well and create really powerful outcomes wherever those things are leading them, right? And so I'm not sure, you know, I don't think who knows MK Ultra success in the end, like we don't really know. But we don't know, we don't know anything about all that stuff. Yeah, but I think it does suggest the power of these things as behavior change molecules and making like a catalyst for personal transformation, which I do believe is possible with them.
00:50:08
Speaker
Particularly possible with them a when using the right way and certainly as you say Joe with with the use of Therapist who guided something guiding it. Yeah, I think there's yeah, that's that's sort of where I come down on it for sure It's like, you know having some skillful guide or approach at least Is extremely important and helpful in getting some benefit out of out of use of psychedelics I guess that yeah that kind of brings up the other piece of this for me, which is
Cultural Impact and Future Research
00:50:38
Speaker
How do you think about the use of psychedelics over time? So for example, in my own personal experience, the very first time I took LSD was absolutely transformative, really changed my entire worldview. And it was a lot of the reason why I pursued visual psychophysics in my research, in my PhD training and things like that, trying to understand how the brain constructs the world around us.
00:51:06
Speaker
getting that sudden insight that actually the brain is constructing our perceptual world. And to have that deconstructed in real time and being able to experience that was just absolutely transformative for me. And then, you know, that whatever nth time that you do it, that there's less of that. So I guess, how do you think about that in terms of use of is it you get you get the message and then you you put it aside or Yeah, exactly. How do you think about that?
00:51:35
Speaker
Yeah, it's a good question. I think it's very different for every person, right? And I think some people, yeah, they have one profound experience and they just never feel called to do it again. And that's totally fair. And that can be what that person needs, right? And again, it depends on the setting and what you're doing it, what your intention is.
00:51:51
Speaker
Because if, you know, people can do it many times and have fun and go to a festival with their friends or use it to connect. And I personally think there's absolutely nothing wrong with doing that. But I also, um, if you're using it in a therapeutic way, I think the danger is just chasing a peak experience. And so I think it's really important to emphasize that what matters in the end is how, how are you starting up in your life differently? How is your everyday today? Are you really using as, you know, the phrases, using those, are you going from altered states to altered traits?
00:52:20
Speaker
Are you just pursuing these altered states over and over again? And so I think eventually, for a lot of people, you don't really need to do it anymore, except for in a more recreational fun context, or as a refresher, perhaps. But I think each person needs to find their own way to pursue it and be mindful of using it as a crutch or an avoidance mechanism or chasing highs.
00:52:44
Speaker
as opposed to using it as a means of real growth and transformation, you know, independent of the drug. But yeah, in the end, it's all the same. It comes down to what some of these intention is and why they're doing it. Yeah, absolutely. All right. Well, we want to be sensitive of your time. So I want to ask you one last question, which is, what are you really excited about next, like in terms of research directions or where, you know, the space is going or what you're particularly doing yourself that you're excited about? Like what just what gets you excited right now?
00:53:12
Speaker
Yeah, totally. So like me, I'm really interested in effects and healthy people and like the concept of human potential and of growing beyond just being functional, right? Because like, we have this slow pathology focused conception of psychology and everything in neuroscience medicine, the cat can we just be normal, functional and not unhealthy.
00:53:32
Speaker
But that's like setting the bar super low. There's so many ways we can grow beyond normal adult functioning in a capitalist neoliberal economy and being a good person in the machine to generate, to push the economy forward. There's so much more to being human and so much more to human development that's being talked about by so many theorists and thought of stuff, going back a long time, different cultures, et cetera.
00:53:56
Speaker
So with psychedelics, I'm interested because they are spreading the idea of personal transformation and growth. I think they're a mechanism for that and telling people that it's possible to radically change how you respond to and interpret life, that there are ways and avenues to actually get real healing. Getting those ideas into the broader culture through psychedelics and psychedelic research can have a lot of, I think, downstream effects, which are very positive. And so I'm really interested in the research just further
00:54:24
Speaker
showing us or telling us or providing evidence for how evidence how psychedelics can mechanistically in terms of the brain and shift people into new ways of perceiving and relating to the world and conceptualizing themselves. And I think by providing more information on how it might be happening, it's more compelling to a lot of people. And then you're like, Oh, yeah, this actually makes sense because the neuroplasticity and the complexity and the flexibility, etc. And that could be really
00:54:50
Speaker
like a positive placebo for a lot of people in believing in their own growth. And so I'm quite excited about that. And that's why I like the mechanistic research and think it's really important to understand how because that's, again, it's super compelling for people. That's great. I love that. I love that. Manish, thank you very much for being on the show. Yeah, my pleasure. It's a lot of fun. Thank you, guys.