Psychedelics, Consciousness, Psychiatry, Psychology, Mental Health & the Entropic Brain Hypothesis | Robin Carhart-Harris | #173

About the guest: Robin Carhart-Harris, PhD is a neuroscientist & psychopharmacologist. His lab at the University of California-San Francisco studies the effects of psychedelics and other drugs on the human brain, using neuroimaging and other approaches.

Episode summary: Nick and Dr. Carhart-Harris discuss: psychedelics & the human brain; functional connectivity & entropy in brain patterns; the “entropic brain” hypothesis of psychedelic drug action; psychiatry & depression; psychology, Carl Jung & Sigmund Freud; the FDA’s rejection of MDMA-assisted psychotherapy for PTSD; latest research on psychedelics; and more.

*This content is never meant to serve as medical advice.

Related episodes:

* Anesthesia, Placebo Effects, Consciousness, Subjectivity, MDMA, Ketamine, Opioids, Psychedelics | Boris Heifets | #163

* DMT, Serotonin, Inflammation, Psychedelics, and Past, Present & Future of Psychedelic Medicine | David & Charles Nichols | #137

* Support M&M if you find value in this content.

* Full audio only version: [Apple Podcasts] [Spotify] [Elsewhere]

* Full video version: [YouTube] [Odysee]

* Episode transcript below.

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

Robin Carhart-Harris 3:46

So my name is Robin Carhart Harris. I am a professor of neurology and Psychiatry at the University of California San Francisco. I study psychedelics and how they work in the human brain. I use brain imaging techniques to look in the human brain under these drugs and also before and after. And the other important other string to my bow would be the clinical trials research with psychedelic therapy, testing its potential value as a treatment for for example, depression, anorexia, chronic pain and so on.

Nick Jikomes 4:28

Yeah and yes, you're very well known as one of the major players in the psychedelic science realm. A seemingly simple question that I want to start with, but which people disagree on and people have different views on, is, what are psychedelics? How do you define that term, and how are you going to use it here today?

Robin Carhart-Harris 4:48

Yeah, it's an important question these days. I go with a double barrel definition, and that actually probably speaks to my kind of. A more general approach to mind and brain, and so one barrel focuses on the brain action and on the pharmacology. And I would be inclined to define classic psychedelics as compounds that have some appreciable activity as agonists at the serotonin two a receptor so very, very technical there, but it's quite a crisp and precise definition of what many people would call the classic psychedelics, or serotonergic psychedelics, and it points to the pharmacology and a specific serotonin receptor subtype, and that these drugs will stimulate that that receptor. But that's not enough, because, as a colleague said to me once Pedro mediano, the brain is only as interesting as the mind, and he's absolutely right, and so just pointing to the brain and such specific pharmacology isn't going to tell you why Humphrey Osmond came up with a term psychedelic, which means psyche revealing or making manifest or visible the psyche or Soul. Some people say mind, but soul is the most literal translation of psyche. So what's going on there? Well, it's referring to something psychological, something subjective, and I think that needs to be another component or barrel to our definition. So how do we index that? And we're in the realm of subjectivity, so I think with the subjective rating and so what would what kind of items would we have in our subjective rating scale to sample a dimension that is pointing to psyche, revealing or making manifest the psyche. And what I've been learning, because I have put this question to empiricism, to developing an operational definition of psychedelic what I've been learning is that the classic psychedelics seem to be differentiable from near neighbor compounds, like, for example, ketamine or MDMA by two dimensions. Principally one is the visual quality of the classic psychedelic experience. And more specifically, for example, the induction of geometric patterns most vividly seen with eyes closed. They can also color perception with eyes open, distort, you know, things that you're looking at, but with eyes closed, very clear, very crisp, very elaborate, very complex. Often have a fractal quality, but geometric visions, but also more complex forms, more complex visions of scenes of people, landscapes. So there's a visual component that's one dimension, and the other one is insight, psychological insight, so a sense of being able to see aspects of the mind, the psyche, that ordinarily aren't so visible. And we can have items like, I'll name one from my my scale in development, I experienced insight into the nature of my environment. Now that one surprised me, but two of others, I could see deeply into the human mind, and the other one, I could see especially deeply into my own mind or psyche. So, yeah, I have found that those items will pass between the classic psychedelics, where a good example might be psilocybin, LSD, DMT and near neighbor psychoactive compounds like MDMA and ketamine, they seem to load on two other dimensions, which are also very interesting, but they're they're loading more reliably onto those other dimensions, things like, you know, A sense of being dissociated from one's body, ketamine, a sense of all embracing love, MDMA, they load onto the more reliably, significantly more reliably than they'll load onto these classic psychedelic dimensions. So you know, as I I've heard, and I say these days, there's a time to learn. Lump and the time to pass. And I think there's been maybe a little bit too much lumping in the psychedelic space for a while where we've been a little loose and lazy with the term psychedelic, in my view. So I'm coming from an agenda where I think there is value to pass a bit here and dial in our precision in terms of our definition of psychedelics, some would say, yeah, you mean classic psychedelics. Yes, I mean classic psychedelics, but I think they're the quintessential psychedelics, the prototypical psychedelics. And I think there's value in that passing yeah and just,

Nick Jikomes 10:38

just for reference, for people this type of controversy, if you even want to call it that, is certainly not unique to this field. There's always a sort of a battle between lumpers and splitters. And almost any field you look at and you know, where people want to draw lines and how they want to use terminology, is always a bit of a sparring match among scientists. But yeah, so when, when you say psychedelics, you mean classic psychedelics, in the sense of agonists of the serotonin two, a receptor, which also have these uh, characteristic sensory effects, these vivid things, yeah, and so forth,

Robin Carhart-Harris 11:14

yeah, subjective effects, because the psychological insight, It's a sensory it's arguably a little higher level and more abstract, but yes, those two components particular subjective quality and that pharmacology. But, you know, I'll keep an open mind as to whether you can get with a novel compound like, say, Ibogaine, some of the subjective stuff I'm describing without an action through the serotonin to a receptor, and then it would be a very interesting challenge. Or, you know, all models are wrong, in a sense, and they're sort of targets to be shot at and to find where they're vulnerable. And so Ibogaine is a really interesting test case here. It's not clear that it works via the serotonin to a receptor as a very complex pharmacology, yet it does seem to promote psychological insight. So yeah, there's always interesting challenges to models.

Nick Jikomes 12:21

Yeah. So for the purposes of our conversation, that's how we're going to use the term psychedelics. Much of your research uses the so called classic psychedelics, psilocybin, LSD and so forth. That's what we're basically going to be talking about here, unless we state otherwise before we get into the nitty gritty of the science and some of your ideas and some of the published work that's been out there recently, I want to go back to what you said earlier. You said the phrase was shared with you that the brain is only as interesting as the mind. And one of the things that brings up for me is when I look at your work and what you seem to be spending your time on, you aren't 100% focused on reading just the scientific literature of today, even in some of your published work, you are referencing not just neuroscience and neuroscientists, but work from the past, work from psychologists. You've referenced people like Sigmund Freud and Carl Jung a lot from from the realm of psychology. What, in your view, is sort of the difference between psychology and neuroscience? What does neuroscience have to learn from psychology. And what sort of value do you find in reading people who've actually been dead for quite some time.

Robin Carhart-Harris 13:30

They're dead and their stuff is, I've found is timeless. I mean, if it's the you know, as founders of psychoanalysis, like Sigmund Freud or Carl Jung, their work is just it speaks to it speaks to me personally, but I think it speaks to the human condition. You know what it is to be a human being, and it's hard to get such like affecting insights into the nature of oneself and one's nature as a human being, from, say, cognitive psychology from, you know, 1970 onwards, or whatever. It's just flat, you know. And sometimes people come into psychology that way, and maybe have a behaviorist approach and perspective, but that psychology, in my view, is so thin, it's almost like it sometimes confused me, like, why are you drawn to psychology when you're only interested in in behavior? It's almost like trying to kill or quash the very subject that you're going it, don't understand it. But the deep stuff is, you know, some somewhat poetic sort of crosses over into. To art and anthropology very much,

and it speaks to me. And so, you know, when I want to understand something as difficult and complex as how psychedelics work, or the nature of mental illness, I have to go to that stuff, because it speaks to me. It resonates and it's like nourish. It's like nourishment. It it that resonance I listen to and take very seriously, and tend to think, in time, will start to better understand its biological flip side as well. As difficult as that is, I think it's it's doable. It's achievable.

Nick Jikomes 15:52

And you know, one of the things we'll talk about today is how we understand the action of psychedelics in terms of brain function. So for those listening, right, I've done a lot of episodes on psychedelics. We're not necessarily going to take the time in this one to go over all of the basics, or the psychedelics 101, stuff. We'll do the best we can. But you know, I want to talk about some of your work looking at whole brain changes in response to psychedelics, how psychedelics are affecting the dynamics of the brain, how that compares to other drugs, how it compares to psychiatric conditions and things like this. One of Well, there's two things that are related that feature in your work. One is the concept of functional connectivity between different brain regions, and the other is the concept of entropy or complexity. Can you give people just sort of a basic breakdown of what those two things are? Sure?

Robin Carhart-Harris 16:44

Yeah, functional connectivity would be, in a sense, the temporal synchrony of activity cross time in spatially separate regions or networks. So, you know, take a region at the front in the frontal cortex and another one in the back of the brain in the visual cortex, if you're looking at that activity across time, is it fluctuating or oscillating in temporal synchrony, going up and down together. And if it is, those regions are functionally connected. It might be anatomically somewhat separate. They might not even have a clear one to one synaptic connection, but if their activities going up and down in sync, then we say they're functionally connected. And that's functional connectivity. And there's many different flavors and ways to to sample functional connectivity. It comes in in sort of various, yeah, forms or flavors, depending, in a sense, on how we postulate up the brain into bits, spatially separate bits. And then entropy, or complexity, is referring to the it's used in an information theory sense, where it's referring to, in a sense, the amount of potential information carried in a signal. So, for example, if that signal, brain activity signal, is going up and down in a very predictable, that's important, predictable way, the information held within that signal across time is somewhat redundant. There's nothing new. It's going up and down in this very predictable way. That will be an example of very low entropy signal. Nothing surprising, no uncertainty from us as we come in and sample that signal

Nick Jikomes 18:59

is very ordered. It's very predictable. It has low entropy, that's

Robin Carhart-Harris 19:03

right, and people like that translation to disorder, and it sort of works. It's related to the translation into thermodynamics, where entropy kind of has its origin, at least like when it was first brought up. It was applied in that sort of applied way to thermodynamics and and systems being heated up, and how the molecular arrangement of, say, molecules within a system or space might become more disordered with, say, increasing temperature. Or, you know, if the system is just left to itself, it will degrade over time. And that's the second law of thermodynamics, or entropy increases in closed systems over time. So the things that those things. Are kind of related, but actually, the information theory definition of entropy, which, in a sense, even though it's a bit anthropomorphic, in a sense, is uncertainty. It's our uncertainty as we come in and sample something, and if, if the system is more entropic, we're more uncertain.

Nick Jikomes 20:23

Yeah, I see so. So if you sample some brain activity in any given time point, if that brain activity is very ordered and predictable, you know you can sample it at time zero, and you can predict what's going to happen at time one. That would be a state of high order or low entropy. And if all that activity became more disordered, you wouldn't be able to predict what's going to come next from what you just sampled so well, and that would be a state of higher entropy, that's right. And can you give us a sense? So, you know, obviously, use multiple types of tools to measure brain activity, things like EEG, things like fMRI, when you measure brain activity at sort of a gross scale with tools like that, can you give people a sense for how entropy tends to change in different states of consciousness, just just basic normal states, like being asleep versus being awake, being anesthetized versus being awake and very attentive. How does, how does brain activity tend to change in terms of how ordered it is across those normal, everyday conscious

Robin Carhart-Harris 21:27

states? Yeah, yeah, sure. So. So we'll run through this dimension of brain activity, entropy, and we'll start by dialing things down to low entropy states. What's going to happen to the quality of consciousness? Well, it will fade. One would get more sedated, and at some inflection point, one will become unconscious. That's what happens when we fall asleep. And the entropy of spontaneous brain activity, or ongoing brain activity, very reliably mirrors that fading of consciousness, fading of consciousness the reducing of spontaneous of the entropy of spontaneous brain activity, very, very reliable, dose dependently with anesthetics, again, it will dose dependently dial down brain entropy as consciousness fades into nothingness, Disorders of Consciousness take a healthy personal brain subject to illness or injury, a disorder of consciousness coma at an extreme entropy will be exceptionally low as some semblance of consciousness comes back, say, intimately into a minimally conscious state. You know some behavior, maybe some tracking of a pen in front of someone's eyes, then entropy will come up accordingly. If you actually track someone in a disorder of consciousness who emerges or regains conscious awareness, then entropy will essentially normalize into what you would see in a in a healthy individual. So on that, on that side of the gradient or dimension, the low entropy side, very, very reliable. Now what we found in, let's see 2017, I think it was a collaboration with Anil Seth Michael Shatner, was we applied a measure of the entropy of spontaneous brain activity. That measure is called Lempel Ziv complexity. It's a data compressibility algorithm, in a sense, how easy, or otherwise is it to zip up that data file? If the signal, the file, the activity, the activity is very simple and low entropy is very easy to zip it up because there's loads of redundancy in it. But if it's very entropic and full of bits, novel bits. It's harder to zip up. There's low redundancy. What we found in that study with Anil and Michael was we threw three, well, two psychedelics and one psychedelic, like compound ketamine, we threw this measure at those drugs, and found that all of them dialed up brain entropy. And it did it somewhat in relation to the subjective intensity of the so called trip induced by those compounds. And so that was exciting. It was, to my knowledge, the first obvious demonstration of brain states of increased entropy. And in a sense, it sort of validated why these psychedelic or psychedelic like states are interesting and like why they're novel, in terms of what's going on in the under. Neurophysiology. And you know, that was a sort of validation of an earlier paper, an idea of mine called the entropic brain hypothesis, first put out in 2014 which was based a lot on intuition the brain activity might exhibit this increase in entropy, systems would become less ordered and more granular in their activity. It was part based on intuition, and part based on certain observations. And it was only in time that it came together, that 2017, empirical demonstration of the principle was really helpful for me, really sort of shone a light on this, as you know, valid. And here's a metric that can index it very nicely that level positive complexity algorithm. And so after that, I knew I had to put out a update which was this entropic brain revisited paper in 2018 I think, which dialed in the definition on Yeah, on a certain metric and a certain modality. So I was realizing that EEG and Meg, with their higher temporal resolution, might be better modalities for sampling this phenomenon. So, yeah, yeah, hopefully that's helpful, yeah.

Nick Jikomes 26:45

So to give people a sense for this, if we think about waking up from being asleep, say, when we fall asleep, there's multiple stages of sleep when we're in so called deep sleep, forms of non REM sleep, one characteristic pattern that you see in brain activity is measured by things like EEG. Are are the slow waves of slow wave sleep. So these would be large, sort of slow, synchronous oscillations of brain activity that you can pick up across the cerebral cortex. And they're they're ordered and predictable. So you would say that's a low entropy state. The activities are ordered you are, if not unconscious, you were sort of minimally conscious. The the contents of your consciousness are reduced or less vivid compared to being awake or in REM sleep, say. And then as you transition into something like REM sleep, where vivid dreams are much more likely, and then to the waking state, where you're, you know, awake and conscious, you tend to see a more disordered pattern of activity. There aren't as many big synchronous waves. It's harder to predict what comes next from anything you might measure, and that would be a higher entropy state,

Robin Carhart-Harris 27:47

that's right. And you know, sleep is that nice example, because you've got deep sleep, non rapid eye movement, sleep, generally speaking, not much content. Sometimes you you get a bit of sort of paradoxical dream material coming in, but when you do, there's probably some kind of pseudo REM coming in, so that complicates the picture. But generally speaking, you know, no content in deep sleep and non rapid eye movement, sleep come up into dream sleep, into rapid eye movement. Sleep, rich content often, you know emotional material and things to see and to explore. In dream sleep, in rapid eye movement. Sleep, higher entropy. And just as you say, when you wake up, you know even more so as you're you're actually, you know, processing sensory information, and it's very rich and granular, coming into the into the into the sensory organs and into the brain. Yeah, so,

Nick Jikomes 28:50

so, so I've pulled up here for people watching the video version the entropic brain revisited paper from Robin. We're just looking here at a simple sort of cartoon schematic for for some of these concepts. And can you walk us through this a little bit? Robin, so, so if I'm hearing you correctly, basically, we imagine that the brain can exist with a spectrum of activity patterns. They can be highly disordered. They can be highly ordered when we're when we're sort of in a normal waking state of consciousness. We're right at the middle, middle zone here, sort of a medium amount of entropy, a medium amount of order versus disorder. What we just said was that when you fall asleep, for example, and you go into non REM slow wave sleep, that would correspond to going down in the circle towards a state of unconsciousness, the entropy would be decreasing because the brain activity, the slow waves, are much more ordered and predictable. And then if you were to go in the opposite direction, say, I don't know, would be a good example here, becoming much more awake and alert and aware of your surroundings, that would come that would correspond to an increase in entropy or a more disordered brain activity. Activity. Can you sort of piggyback

Robin Carhart-Harris 30:01

on that? Sure. Well, I mean, psychedelics are the example, because for a long time, and this is why the 2017 paper was quite exciting for a long time, I think most people would have said the complexity or entropy of ongoing brain activity tops out with normal waking consciousness. And yet we found that there are these drugs in these, these states, the psychedelic states, where the entropy is higher still than it's it's high level in normal waking consciousness. So that was quite an an insight, and that was quite exciting. It was tempted to say things like, well, people say of the psychedelic state, that it's a expanded state of consciousness. Maybe this is why they say it. If you want a really simple, kind of glib way to sum up the entropic brain hypothesis, it will go something along the lines of less bits in brain activity, less bits in conscious experience, and flip it on its head, more bits in brain activity across time, more bits in in the quality of conscious experience.

Nick Jikomes 31:13

So, oh, go ahead. Oh, well, I was just gonna say, if we take this at face value, so psychedelics tend to increase entropy, the amount of disorder that you would measure in brain activity as you take a higher and higher dose of a psychedelic like psilocybin, say, you get more and more entropy, and the contents of your conscious experience, in some sense, become richer. But eventually, you know, in your schematic, you've drawn a threshold here, and you've got unconsciousness that you get sufficiently high up with sufficiently high entropy. What would that correspond to, in this view of things,

Robin Carhart-Harris 31:47

a high dose five methoxy DMT experience? Yeah, you know, when I created this schematic, it was with that in mind. And I wish you know I vacillated on whether to put the unconsciousness up in this upper segment, because people will say of the of, say, a high dose five emo experience, extreme, intense psychedelic experience. Michael Pollan called it the drug, the Everest of psychedelics, sometimes people describe it as a white out or an experience of pure consciousness. And so if they're saying that that doesn't sound like unconsciousness. So I very much vacillated on it, and I continue to feel it. This schematic is a little bit problematic. You know, everything's iterative. You're always trying to improve. I am very much due a tropic brain revisited again,

Nick Jikomes 32:49

yeah. But I mean, you know, roughly speaking, I certainly feel like I know what you're trying to convey here. So with my own experiences with fibromyal DMT, I'm certainly not becoming unconscious in the sense that I'm falling asleep, but the peak of the experience comes on very quickly. And you're never unconscious in the sense that there's a complete lack of awareness. As far as I could tell, subjectively, there is very, very vivid awareness. But at the peak of the experience, it's contentless in the sense of differentiation, I suppose you would say so I'm not seeing different colors and different images. I am experiencing that that white out effect. It's very unitive in that sense. I'm not seeing all sorts of different things. I'm not having different thoughts. There's no linguistic content. There's no logical operations that appear to be going on. And then as you relax out of that peak experience, then you do start to get different colors, morphing different basic, very, very basic shapes, and then eventually that crystallizes into where you started, which in the schematic, would be normal waking consciousness, right here. And so I don't suppose anyone's done the experiment where you measure brain activity with a high dose of something like five mio DMT, but the prediction, if I'm hearing you right, the prediction would be that on sort of a low, medium dose, you would see increased desynchronization. You would see increased entropy. But at a sufficiently high dose, at a full peak five year experience, something should flip at some point, then you should see something. I mean, would you do you expect a continuous increase in entropy or desynchronization, or would you expect the dynamics to change at some point?

Robin Carhart-Harris 34:22

Well, this is the great challenge to the model, and you're right. No one's done it and published on it yet, but a few teams are working on it, and it is a very good test of the model, basically, in a sense, seeing whether we can break the model, which is what you do when you find a model that's useful, you then want to try and break it and see where its flaws are and how to advance on it. The entropic brain hypothesis, or principle, is very, very simple in that glib way I put it, more bits in brain activity, more bits in conscious experience. It's. Simple that some would say it's too simple, and they'd be right to an extent, but then there's something to be said for simple models with not much to them that explain a lot, and I feel confident these days that that's what we have with the entropic brain principle. However, you know, the distinction was made, I think, by Ned block, cognitive scientist, philosopher, a distinction between two types or dimensions of consciousness. Here just to remind everyone, we're looking at one dimension. And I would say this would fit a dimension that's referred to as phenomenal, phenomenal consciousness, or what it is like to be in a thing so subjective experience, or qualia, the quality of any state of consciousness, that's what the entropic brain principle relates to what it is like to be in a state of consciousness. But five is a really interesting and a high dose of five, MEO is a really interesting test case, because if we take seriously this unconsciousness label, it's suggesting that you can dial up entropy to a point where something is compromised, something is lost. And so Ned block coined this other dimension of, I think it's Access Consciousness. So five sort of fits this, this sort of two dimensional model, because they think Access Consciousness is can be lost. And so what is Access Consciousness, the ability to reflect on consciousness, self consciousness, if you want, and then be able to report it back. I don't know if I've imagined it, but I think maybe it's sometimes referred to as report consciousness. Yeah,

Nick Jikomes 36:59

that's interesting. I mean, just Just to riff again on my experiences with five mio DMT. The first time I experienced it, I did two back to back doses one. And this was all spontaneous. I wasn't directed to do this. The first one, my eyes were closed. The second one, my eyes were open. The difference essentially being a blackout versus a whiteout with the first experience, I don't recall the peak experience. As far as I can tell, I don't recall it at all. I simply sort of started to come out of it with the feeling that something very significant had just happened, but I had nothing to report on. There was nothing I saw or heard or any content I could communicate. There was just this sense that it was very significant, and I immediately asked for a second try at it with the eyes open, the visual experience was somewhat different, but this seems to be sort of related to what you were saying. Again, this is my subjective report here, but at the peak of it, I would say there was not a complete lack of awareness, but there was a lack of differentiated content, visual or otherwise, and my ability to remember or encode any of that information seemed to be very intimately related with how undifferentiated the experience was. The peak is essentially unreportable, yeah,

Robin Carhart-Harris 38:16

to know, and I think in that description, we have clues about what might be, what might be lost. You know, if you think of entropy and translate it into the thermodynamic space, you could imagine a substance being heated, you know, from a solid melting into a liquid, now into a gas, if that gas is spread evenly, uniformly, homogenously in a space, there's no differentiation. You could feel now somewhat confident and less uncertain about where you know a molecule might be in a space, because you could sample anywhere and find one given that homogeneity. So I think what's being compromised, what's being lost is differentiation, is functional segregation and specialization. And you know, we see clues of that in some of the measures of brain activity that we calculate in the brain imaging data, whether it's fMRI, we see it more clearly in fMRI, actually, that has that spatial resolution we can look at, you know, more granular, spatially granular qualities of activity. So I think that's what's going on. You know, Iit integrated information theory is arguably the most well known model of consciousness, and once upon a time, the entropic brain principle got critiqued by someone saying that it's. It's IIT depurated, which is clever word. I had to look it up, of its integration term. And I thought, Ah, yeah, yeah, I'll give you that. But my cheeky comeback would be, have we nailed down what that integration term is and how useful has it been in measures of consciousness to inform on the qualities of those states of consciousness? I wonder whether five Meo could be a really good test for elucidating what that other component is that isn't covered by the entropic brain principle, and I suspect that it's related to what likes a Giulio Tononi who came up with integrated information theory, theory were intuiting when they they coined that other component, the integration component, the integration, you know, segregation, functional segregation, is going to be key. And I think the ability to stitch things together and differentiate is what is compromised with these, you know, very extreme psychedelic states like you can achieve with a high dose of five Mei. So it's sort of like a hunch that there's a something to find there.

Nick Jikomes 41:25

So going back to this cartoon schematic of the entropic brain model, normal waking consciousness is in the middle. If you take a dose of a classic psychedelic, you're going to move up increase entropy. So basically, a high dose, a heavy trip, would be something close to, or maybe even breaching the divide here, where you know we have what this, what you call this critical zone, so that the higher the dose, the deeper the experience, the higher the entropy. And then coming out of the experience would correspond to relaxing back towards the middle, increasing entropy. One thing that we will come to and probably discuss more, but many people have experienced is this concept of, you know, having a heavy trip, or a difficult trip, being stuck in the trip, in some sense, and then having your your attention directed towards, you know, something right in front of you, you know, touch, touch the ground, touch, hold someone's hand, something like this. This is the concept of grounding in the world of psychedelic therapy. Would that correspond to someone being relatively high up here on the entropy side, going up the scale, and then being brought back down a little bit by attending to something right in front of them? Yeah,

Robin Carhart-Harris 42:30

I think it's very likely. And actually, we have some brain evidence for it now, some we got from a meg study, which is, what's that? It's like, super EEG. What's EEG? It's like the swimming caps you know, that people wear, and you're recording the brain's electrical activity through the scalp. Meg, somewhat similar. It just, it's measuring magnetic properties conferred by the brain activity. And it has slightly better spatial resolution than eg. Anyway, we use that modality to look in the brain under LSD, and in that particular study, we sort of layered on sensory stimuli. We had eyes closed, so the least amount of sensory stimuli, eyes closed, no sound. That was the sort of, you know, lowest sensory stimuli condition. Then we introduced some music. Eyes closed, but now you're listening to music. And then we added in, I think, I think we just leaped up to eyes open, movie and sound so now rich sensory information, sensory stimuli. And what we found was with that layering up, oh, well done. That layering up of rich sensory input, it dipped or decreased the magnitude of the effect of the psychedelic. And you can see that there in this chart and maybe B figure 1b shows it most neatly, where the difference between placebo in green and LSD in sort of purple lilac is squished when we add in more stuff. So, you know, again, it's Pedro, actually, who came up with that phrase. The brain is only as interesting as the mind. He, I think he was lead author on on this, and he wanted to run with a title, tripping is easy, you know, from the Beatles lyric, tripping is easy with eyes closed. But it's not easy. It's just maybe easier. But the idea being, you know, if you if you load in some sensory stimuli. They you'll quash the intensity of the trip. And that's what I'd say we're seeing here in that graphic. It's,

Nick Jikomes 45:08

it's certainly, you know, a common thing for people to report that, you know, a good way to have the most intense trip possible is to consume a psychedelic and you know, as Terence McKenna famously said, in silent darkness, with your eyes closed, and you just sort of let everything absorb you. So this makes intuitive sense if I'm reading the graph right here. So basically, the experiment is you give people LSD, and either they or you don't they either just lie there with their eyes closed, or you add in some music, or you enable them to open their eyes, or you have them watch a video. And basically, if I'm reading this graph correctly, so complexities on the y axis, so higher complexity would be a more entropic brain, more desynchronized activity. Lower down would be more ordered, less entropic. So basically, as you add in more external stimuli, the amount of complexity, the entropy goes up, and it sort of meets with the complexity that you see when you sort of just give LSD on its own with eyes closed. Yeah,

Robin Carhart-Harris 46:07

that's it. You know, even without a psychedelic on board, if you load in stuff from the world, you know, richer stuff, a movie with music, then you're you'll increase brain brain entropy. And so it fits the principle, you know more in a sense, more going on in experience. If you're loading in rich sensory information, more going on in in the brain. I guess one of the learnings here was the it's the differential that matters. And so the difference between placebo and LSD, the delta, if you want.

Nick Jikomes 46:45

So Robin in this condition here. So it's LSD with sensory stimulation with a video. Say you see that the lowest difference between the LSD and the non LSD condition is, is there a significant difference between these two or they are they not a good question.

Robin Carhart-Harris 47:02

I think we're seeing the regions where there's some significance. At least we're seeing t score heat maps in on the bottom there, when we're actually looking at the brain.

Nick Jikomes 47:14

But I guess in any case, they're fairly comparable, so a lot of external, multimodal stimulation coming in can increase entropy in the range that LSD does on its own. Is that basically how to read this?

Robin Carhart-Harris 47:30

Yeah, which it was kind of cool and intriguing, and I guess it

Nick Jikomes 47:35

would also be significant. So when we think about grounding here, I guess the idea would be here, you've got LSD, and then when you you've got a lower amount of complexity or lower entropy with the multimodal stimulation, but no LSD. So the idea is that an external stimulus would sort of pull you down the complexity axis, exactly in

Robin Carhart-Harris 47:58

terms of the difference, you know, the difference between normal waking consciousness with that amount of sensory stimuli going on and tripping with that amount of sensory stimuli going on. The difference isn't there's not much in it. You know, another way to do it, to say it, I think, is that you're going to feel the trip more, and it's novelty with the least amount of sensory stimuli coming in. Yeah, back to that Terence McKenna darkroom

Nick Jikomes 48:31

example. Yeah. So one more thing I want to give people a sense of before we go into some of the recent research. So going back to this basic schematic here of the entropic brain. So for those just listening again, we'll do our best to describe this, but you can see what we're looking at on the video version. So completely sober, state of mind, someone normal, waking consciousness, resting state, sort of not doing much of anything. If you look at brain activity in someone who's in a state of normal, waking, resting consciousness, not engaged in the task, but also not asleep, not dozing off, say, and then you have them engage in a task, or you have them pay attention to something. You have them perform a task, as people often do in neuroscience experiments. How is that gonna where's that going to move you on the entropy scale here?

Robin Carhart-Harris 49:22

I'll move it up a little bit.

Nick Jikomes 49:25

Yeah, I see and that makes sense to me, because higher entropy means more disordered activity. Means more desynchronized activity. In my memories from my PhD days, looking at the visual attention literature, basically, whenever people record from parts of the brain that are involved in an animal engaging in a task or paying attention, they tend to see desynchronization of brain activity there. And so that all seems to fit to me. Yeah, yeah.

Robin Carhart-Harris 49:53

It's sort of like attention. And you'll know that when you attend to something the classic Alpha rhythm or. Relation that you see in EEG measured brain activity, so called idling rhythm that sort of collapses when you attend to something. It's similar. It's a similar effect with psychedelics, but more dramatic, basically.

Nick Jikomes 50:16

And I suppose this might fit intuitively with the the fairly common experience of, you know, when you're really engrossed in something, when you're paying very close attention, you're, you know, totally sort of caught up in whatever you're doing. People often report that's accompanied by a loss of their sense of self. Is that? How you think about

Robin Carhart-Harris 50:34

it? Well, in meditation, yeah, but yes, actually, also, if you get lost in your work, you know the clue in that phrase, you know certain systems that are especially active when we're sort of idling and daydreaming, like the classic default mode network, that activity in that region, which is ordinarily in a sort of background way very high, will dip down when we attend to something. So yes, that's true, seen through the lens of fMRI, but also seen through the lens of EEG, where we would see a drop in in alpha oscillations when you attend. Yeah. So compared

Nick Jikomes 51:16

to a state of quiet, waking, psychedelics tend to increase entropy. Attending to something, engaging in a task, will tend to do that, perhaps not the same magnitude or exactly the same way. And then so I would imagine that, you know, taking something like a sedative or certain other drugs probably would would take you down in entropy from quiet waking Can you give some examples of that? Oh, well,

Robin Carhart-Harris 51:39

very much. You know, when I first was describing the entropy brain principle, we started with dialing down into that low entropy side of the dimension. And it's very, very reliable. It's dose dependent. It also tracks with, you know, level of consciousness and disorders of consciousness. So it That's right, sedatives will drop it down. Now, talk about interesting test cases. We talked quite a bit about five Meo, another one which had needed to be thrown this metric, this model, needed to be, you know, that test case needs to be thrown at. This model was stimulants, because there wasn't an example of it. And recently, there was a nice paper. First author, Connor Murray, last author, I think Harriet Devitt, I think at Chicago. And they tested two other psychoactives, not psychedelic, but psychoactive one was, THC, that's going to cause what's going to get you stoned and dose dependently as well. So that was neat, as in, there's more than one dose, and then methamphetamine and different doses. So this was a really important test, because one of the sort of points of uncertainty, maybe critique about the entropic brain principle was, Is it is it really indexing, you know, the richness of conscious experience, or is it indexing some generic arousal thing? When you're tripping on a psychedelic, you're more aroused. Maybe that's all it is. In a sense, you're

Nick Jikomes 53:23

just engaging with whatever's popping up in the trip. Yeah, yeah.

Robin Carhart-Harris 53:27

But the stimulant was a really good test, because that's gonna that's pro arousing, it's energizing. And, yeah, it didn't increase the entropy of spontaneous brain activity. They used the same metric, the levels of complexity.

Nick Jikomes 53:40

Well, I may have missed it. What was the stimulant?

Robin Carhart-Harris 53:44

What the drug was? Methamphetamine? Yeah, so, so, yeah, numerically, maybe a bit, but it was nowhere near significant and no dose dependency. In the same study, they had LSD low doses, but up at 26 mics, people were feeling it. That was very clear. And at that higher dose, it was doing what we're used to, significantly increasing brain entropy. So psychedelic did what we're used to, and the other test cases didn't. So again, you know, testing the resilience of the model, and it came through in that test.

Nick Jikomes 54:22

I'm not sure if this work has been done, but an interesting case here would be maybe something like MDMA, because it has some activity at five HT to a but it's also a psychostimulant. What has that been measured? Or do you have any predictions there? Not

Robin Carhart-Harris 54:36

to my knowledge, another really good study to do. I'm I think it'll be like right on the threshold, and it will be very much dose dependent. I don't see MDMA as a classic psychedelic, both subjectively and pharmacologically. It's going to be doing what psychedelic. To do, but indirectly through releasing serotonin. So it's, it's right on the edge case. And I would actually say MDMA, arguably more than ketamine, is, is right on the edge of whether you'd consider it a psychedelic or not. You know, if you want to go with something loose and poetic and descriptive, which is, which isn't quantitative, which is that MDMA does reveal the soul or psyche, you know, then I would say, Okay, I'll let you have that you can Yeah,

Nick Jikomes 55:36

but I think you're basically right, like, if, no matter how any individual wants to demarcate what is and is not a psychedelic or some other drug, MDMA is probably near the border of any reasonable definition of psychedelic, at least in my view, and one of the things that points in that direction, at least for me, is if you compare basically a classic psychedelic like LSD or psilocybin to both MDMA and MDA, because MDA just has a bit more 5c to a activity than the MD, Ma. And people also report that their effects are a bit more psychedelic, a bit more visual, and so forth. Yeah,

Robin Carhart-Harris 56:08

yeah. And same with like the, you know, two CB and so on. There you are getting a bit of direct to a but also, I think you're getting some serotonin release. So, yeah, there's some interesting edge, edge cases. For sure, entropy will be a really interesting index, and it may well work, meaning, you know, there may be a way to sort of set a threshold on the magnitude of increase in brain signal entropy that above a certain threshold, you'd say, okay, psychedelic

Nick Jikomes 56:48

when we so when we think about the relationship between brain entropy and sensory stimulation, so what would be the effect of so we talked a little bit about paying attention or engaging in a task, this will tend to desynchronize brain activity somewhat. This will tend to increase entropy. What would happen? Or has it been done? Where you just have someone in a scanner, or you have them wearing the EEG net, and they're not doing anything, they're not engaged in a task. They're not instructed to do something, but you are just passively giving them sensory stimuli, white noise, visual noise, auditory noise, whatever it may be. What kind of effect does that have on whole brain dynamics?

Robin Carhart-Harris 57:29

It's an interesting one. It sounds a little bit like sensory deprivation, if you're doing it for long enough so I would predict that you would see an entropic brain effect. There are other cases of altered states of consciousness induced through other means than psychedelics, where you do see increases in brain entropy. Breath work, Holotropic breathwork, or similar, has now been found to do it experience meditators entering very deep meditative states. So Vipassana, Star meditation, where there's some evidence of increased

Nick Jikomes 58:10

Yeah, that makes that makes sense to me, because, you know, they're focusing attention in those types of practices, they're engaging in rhythmic behaviors, which will, you know, also have be inducing some rhythmic brain activity, some more order, less entropy. That makes sense. What if you were just sort of random?

Robin Carhart-Harris 58:24

So sorry, it's the opposite. Oh, it's

Nick Jikomes 58:27

with Holotropic breathwork. Yeah, yeah,

Robin Carhart-Harris 58:29

yeah. And I don't it's not so much. It's not like an in training thing. It's more probably to do with the alteration of, you know, oh, two CO two levels in the blood, and how that's now translating into dysregulated population level neural activity and doing something somewhat similar to what psychedelics do, breathing higher concentrations of CO two than we typically do, has been found to manipulate the serotonin to a receptor that psychedelics work through. There's a few other kind of physiological manipulations that seem to tune the brain, in a sense, somewhat endogenously, to