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.
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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, towards the psychedelic state, at least up regulating, which means increasing the availability or sensitivity of the serotonin to a receptor, something I wrote about in a paper called pivotal mental states with a colleague called Ari Ari Brower, but no there are other states of altered consciousness, alter states of consciousness that are somewhat trippy. I know I say that very loosely, qualitatively trippy, where you'll see elevated brain entropy through recording EEG and then looking at, you know, how compressible that. Always,
Nick Jikomes 17:00:00
what if you were to just give someone, say, a series of unpredictable sensory stimuli they weren't engaged in a task or whatever, you know, sound, light, sound, just some, something sort of random and haphazard that's going to, you know, naturally engage their arousal systems, cause their attention to come from one thing to the next as it spontaneously appears. But again, these are external sensory stimuli. With that, what would be the effect there? Do you think
Robin Carhart-Harris 17:00:27
I'm going to guess it would be if anything you know, in a sense, is versus what you know, the comparator is going to be critically important there.
Nick Jikomes 17:00:38
I mean, if they were just, I mean, let's say you're doing a classic sort of monkey style experiment, or human certain human style experiments, where you know at rest, you are meant to just fixate on a fixation cross,
Robin Carhart-Harris 17:00:52
yeah, yeah. Well, I mean, that's like, that's, that's rest, that's not much going on. That would be a relatively low entropy state to then loading in any kind of rich sensory information. I guess that Meg study hinted at this, and I've also seen other hints at it, pull them out of my memory right now, but it's related to the richness of the sensory stimuli that you bring in. So if you imagine a scenario where the sensory stimuli is somewhat unpredictable and complex and rich, like a movie that you haven't seen before. Maybe there's a lot going on that would be likely, more likely to dial up brain entropy than say, you standardize that you're looking at something and listening to something, because you need to standardize for that, but it's regular. That would be lower entropy, or you pull that away to a fixation cross, lower entropy still, but there's always you know challenges to the rule. Now our participant is a you know meditation master who is focusing on that cross like they focus on the breath, dialing in, dialing in, and then all of a sudden, things start to get a little weird. Then I'd start to question whether actually, there might be an increase in brain signal entropy when they enter that altered state of consciousness induced through like, sort of profound relaxation. And it's profound relaxation to the point that you get like a paradoxical excitation or dysregulation. Yeah, so it always sort of depends, yeah,
Nick Jikomes 17:02:44
so, so. So, with some of this stuff in mind, you have a new paper that's recently come out, which looked at the effects of psilocybin on whole brain activity using fMRI in humans. Before diving into some of this in more detail, can you just give us a sense for what was the experiment? How did you set it up? Where was it, you know, sort of coming from, based on past literature,
Robin Carhart-Harris 17:03:04
you know, Nick, I'm not sure which one you're referring to.
Nick Jikomes 17:03:07
Oh, I'm sorry, psilocybin desynchronizes The human brain.
Robin Carhart-Harris 17:03:10
Oh, well, you know, that was a sort of cheap way in for me. I had a nice meeting with the first author, Joshua Siegel and ginger Nichols, one of the senior authors early on, where, where I think I might have, I like to think I suggested a couple of controls. And one of the things that sort of bugged me a little bit about psychedelic research and being a psychedelic scientist is, well, I love the fact that psychiatrists were interested, you know. And for me, that validated a view of these people as caring. They wanted better treatments, and so they could see some interesting findings in the early psychiatry work, you know, psilocybin therapy for depression, for example, they give me a lot of time. They were really interested cognitive neuroscientists, you know, people doing human brain imaging with fMRI and so on. They'd be much more standoffish. You know, it's almost if, by looking at psychedelics naturally, you're less of a scientist. That's a bit of a sure chip on my shoulder there, but it's felt like that. And so I like to think I might have said something along the lines of, show that try, you know, what would you do to show that the psychedelic state is novel, and here, that's what they've done really well. And that's, you know, one of, one of the, the sort of, you know, superpowers of this team is to do what they call precision, fMRI, doing a lot of scanning within the same individuals. And so what. They showed us that if you without any drug, repeat scanning, if you keep going down Nick, you just keep Yeah, just keep going down, we'll go down again. This one I like, almost there, but we lost it. Mate, there it is, there it is, you know. So these are all scans, and there's like 18 per participant, p6, they're looking at here. You can see that with B and C, and there's only two psilocybin scans, 215 minute ones. And by this metric, whole brain normalize global spatial complexity, which is a sort of spatial entropy measure. Psilocybin is off the charts weird. And those are the two red blots blobs. It's doing something that ordinarily you don't see if you just keep scanning. Which are these empty black circles, or throw in methylphenidate Ritalin, you know, an ADHD drug, a stimulant, another good case of throwing a pro arousal intervention at the brain and seeing that it doesn't do what psychedelics do. And so those are the four blobs in you could just about make them out in blue under MTP, methylphenidate. So this was really neat. You know, it was the quality of the controls. And I say these days, you know, never underestimate a good control. I think we're seeing that more and more in the psychedelic space, is that if you're little loose on your control, people are going to really, you know, fly into this with, you know, fierce bearing their teeth and tear it to shreds, special viciousness to to that, you know, in the psychedelic space in particular.
Nick Jikomes 17:07:00
So the experiment here, if I'm reading this right, hearing you, right? So basically, people should imagine, okay, you're gonna get into an fMRI scanner, and you're gonna do this many times over a course of a study. So they're gonna scan you, scan you, again and again and again and again, several scans where they're just in there, they're not given a drug, and they're just in the scanner, sort of a baseline condition. And then for some number you get methylphenidate, so that would be Ritalin, so it's a psychostimulant drug. And then you get another series of scans where you're not getting anything, and then you get a couple psilocybin and then again, a series where you're not getting anything. And so Robin, if I'm reading this correctly, and tell me if I'm not. So the y axis is a measure of complexity, so how much entropy is in the brain signal they're measuring? So going up means higher entropy. Going down means lower entropy. Baseline conditions, you know, you're at, I'm just going to call it a middle, a middle level. When they give you methylphenidate, which is ritalin, it actually goes down a little bit. And this, this, I think is what you were mentioning before, Robin. It's a psychostimulant. It's giving you arousal, and yet it's not increasing entropy, it's decreasing entropy. Yeah,
Robin Carhart-Harris 17:08:07
I think maybe on average, numerically, it might be a tiny bit down, but not really close to baseline. Yeah, it's very close to baseline. I think by significance, no real change
Nick Jikomes 17:08:19
I see. So it means lower, but it's not significantly different from baseline. It's certainly not increasing it significantly. That's
Robin Carhart-Harris 17:08:25
right, that's right. And yet, you know, then our two, you know, psilocybin scans come along, and all of a sudden, that level of spatial complexity or entropy, the bittiness of the independence of activity, spatially, heterogeneity of activity is going up markedly with the psilocybin. The brain is becoming spatially more more bitty or granular in its activity.
Nick Jikomes 17:09:00
Another question I was going to ask you, but I think the answer is implied here is, you know, when you have people just passively lying in the scanner, you know, these things are famously kind of claustrophobic. Under baseline conditions, people might start to daydream or even doze off a little bit, but the fact that the methylphenidate doesn't cause a big deviation here from baseline suggests that when they're not given any drugs, they are not falling asleep. Say, Oh
Robin Carhart-Harris 17:09:23
yeah, definitely not. And with psilocybin, definitely not as well. And you know what they did in this study, what we've done historically is we'll also measure peripheral physiology, so breathing with a respiration belt, heart rate, so we can put these signals in as well, to further demonstrate that the effect is in the brain, above and beyond any sort of peripheral physiological changes that otherwise, you know, one could argue is, is potentially behind the brain change that it's some, you know, non you. Functionally meaningful physiological change that's driven the brain change, but they did certain measures to control for that, and still, the big brain change came through. Yeah,
Nick Jikomes 17:10:12
I see. And then the other, you know, another piece of this paper is that you did some experiments, which I think these are the ones here. So the idea here is that you're not just going to passively give people psilocybin and scan their brains. Now there's going to be, you know, they're going to get psilocybin or not, and then they're either just laying there doing nothing, or they're actually engaged in a task. Can you set this up for us? Why? What was sort of the purpose behind setting up a task like this, and why did you set things up the way that you did? Yeah,
Robin Carhart-Harris 17:10:42
I'd say it's kind that you're saying you because sorry, I came in at the beginning and the end for this, and at the end it was mostly to say, really cool guys, well done. So yeah, it's Josh Siegel doing all the hard work and but why would they do this? It's very similar to the what we did in the MEG study. And it's, it's again, testing that grounding. I mean, it's there in the title their grounding effects. You know, it's looking at how you might manipulate brain function with something more familiar than a psychedelic, get people to do a cognitive task of some sort. You see how the task itself will change brain activity. If we're looking at baseline here, a bit of a change according to this metric, whole brain functional connectivity. Bit of a change with with the task. It's dipping that whole brain functional connectivity when they do the task. And then I think what we're seeing with the psilocybin is there's a magnitude step, magnitude greater effect of the psilocybin relative to the task. In a sense, the psilocybin is having a much more marked effect on brain function than the Tusk itself. And actually the task gravitates people back to a quality of brain activity that is more similar to what you see during baseline with no drug. So the task
Nick Jikomes 17:12:14
so at rest, yeah, at rest, psilocybin is taking you up the bar here is Yeah. So that's more, well, a bigger change in functional connectivity, yeah. And then when you have them on psilocybin, but doing the task, whether it being at rest, this bar here is basically the same height as the baseline no psilocybin condition,
Robin Carhart-Harris 17:12:34
yeah, it's bringing them down. It's, yeah, it's bringing them down. It's grounding them. And the most stark difference is that big, tall bar in white in the middle psilocybin rest, where, according to this whole brain functional connectivity metric, it's really high, really big increase. And then you compare methylphenidate, you know, more modest psychoactive compound isn't going to so profoundly alter consciousness, and quite a modest difference between whether they're resting on that drug or doing the task on
Nick Jikomes 17:13:10
Yeah. So it looks like engaging in the task across the board decreases this change in functional connectivity. I'm not sure if it's significant methylphenidate condition, so,
Robin Carhart-Harris 17:13:24
yeah, yeah, numerically, it does, doesn't it? But, but the real stark difference is psilocybin rest, where there's this big increase in in global functional connectivity, and then they map it in the brain images above. And this is really important as well, because this has been a point of debate in the field, the areas that they saw increase consistently across the different metrics, are areas that that we've seen, I'd say we I mean my colleagues at Imperial across different psychedelics, psilocybin, LSD, DMT, And the regions that seem to be most impacted by psychedelics are what we call high level, transmodal cortical regions and networks. It includes the default mode network. It's not exclusive to just the default mode network, but high level, evolutionarily expanded in our species, recent cortex, cortex that we've got way more than other species cortex that expands within a lifetime from being a human baby into an adult. So it's this high, high level cortex concern with processing, you know, arguably species specific functions like abstract thinking, it's those regions, those cortical regions, that are most impacted by psychedelics, and they saw that very clearly in this, in this body of work
Nick Jikomes 17:14:54
I see so so in parallel. So they do these you engage in a task, or you're at rest, both with and without civil. Side been, and we see this pattern of functional connectivity change. So it's like a pattern by which the extent to which different brain areas are talking to each other changes, yeah, and then in parallel, there's this measure of complexity or entropy. Can you walk us through this one? Yeah,
Robin Carhart-Harris 17:15:14
it's a it's very similar. Those two metrics are quite closely related. And, yeah, it's a similar kind of picture to my knowledge, but you're putting me on the spot, and I'm not so sure. Now. I I think with this particular metric, it looks more consistent rest versus task under drug, whereas under baseline, throw in the task. I guess this, you know, if it's, if it's a more like a complexity entropy measure, it's showing that it's especially sensitive to the task here at baseline, yes,
Nick Jikomes 17:16:14
basically they engage in the task. This goes up. That means higher entropy, more desynchronization,
Robin Carhart-Harris 17:16:19
yeah,
Nick Jikomes 17:16:23
with psilocybin, it's higher here, which my interpretation is that's like, similar to what we saw before. So they're at rest. They're not doing the task. Psilocybin increases desynchronization, known finding. But then they have them in do the task on psilocybin, and desynchronization goes up more, yeah, yeah.
Robin Carhart-Harris 17:16:45
And it seems if, if that, it's difficult to know if that difference is significant. I don't think it is. I just think they're showing difference versus difference. But within psilocybin, I think it's comparable. I think in this particular case, with this particular metric, it seems to be suggesting it's desensitive. It's insensitive rather, to whether you're resting or doing the task.
Nick Jikomes 17:17:15
So would the idea here be that whether or not you're engaging in the task, the amount of entropy increase or desynchronization induced by psilocybin has sort of hit a ceiling or something. And you Yeah,
Robin Carhart-Harris 17:17:29
that it's that it's reliably up whether you're doing a task or not. So, I mean, they, I don't know if they say this in the discussion, but it they might say it's a more fundamental action of the drug the you know, over and above, whether or not you're doing a task, this will just be up, because it's a really fundamental action of the drug that might be, you know, compared to methylphenidate, which is looks markedly lower to me that if you were To sum up, you know, rest task baseline, it looks significantly lower than psilocybin, where it's so,
Nick Jikomes 17:18:06
like, you know, one thing that was confusing to me about this is, so, on the one hand, I was thinking, okay, the psilocybin, it's probably, you know, it's a sizable dose. It's a, they're having a psychedelic experience. So that's a, that's a pretty powerful stimulus. The task is, you know, it seems to be relatively easy. It's, you know, it's, it's not like they're playing, you know, chess against the grand master or something. And so maybe sort of, you know, if there's a tug of war in an attention sense, you know, the task is going to be weaker than the psilocybin trip or something like that, but they're able to complete the task nonetheless. So on the one hand, from an attention desynchronization perspective, it was not surprising to me that the task you know, either didn't increase or mildly increased desynchronization, because psilocybin gives you desynchronization, attention and engagement give you the synchronization. So you expect those two things to travel together. But from the perspective of the grounding interpretation, this one was a little peculiar to me, because I would have expected the taskbar here to go down if there's a grounding effect, yeah,
Robin Carhart-Harris 17:19:03
it doesn't fit the grounding effect as clearly as the other one. The other one seems to show, you know, Mark change task versus rest, and this one less. So that said, when you go to the maps, it looks as though you've got the rest and Tusk at the top, that you've got more, sorry, the maps that we were looking at in that previous Oh, the maps, Yep, yeah, at the top, it's more of a spatial effect. Those heat maps are more spread in B with rest than tusk. But I see, but I guess when you whole brain, it doesn't come through as significantly different, presumably because those bars are quite even with psilocybin.
Nick Jikomes 17:19:49
Yes, and I suppose, I suppose, too, like if there's sort of large scale functional connectivity, differences with and without psilocybin, and also modulated by the task. You know, if. This complexity or entropy measure is a whole brain measure. You know, it's, it's sort of averaging. You're averaging together, like everything all at once. But there's, right, there's spatially local changes that probably go in different directions, different regions, yeah, yeah,
Robin Carhart-Harris 17:20:15
yeah. But one thing to that's coming through consistently is the regional distribution of the effect, and it keeps being in that high level transmodal cortex across the across the metrics, very marked impact with with the psilocybin. And I've got to be honest, that was that was quite nice to see. That was validating the past work that we'd done with psilocybin, LSD and DMT, I think that's going to be a reliable principle going forwards into the future. And
Nick Jikomes 17:20:49
are those regions so these sort of multimodal, higher level Association cortices? Are these ones particularly rich in the five, HG, two, a receptors, or some good biological reason why we would expect them to be involved?
Robin Carhart-Harris 17:21:02
Yes, they are. Yeah, yeah. They have a disproportionately high expression or density of the serotonin to a receptors. Yeah.
Nick Jikomes 17:21:11
So in terms of, I think you hinted at this before in our discussion of five mu and some other things, but what do you think is, sort of, what is next for you guys? Slash, what do you think are some of the key experiments that you would like to see next in terms of testing the entropic brain principle?
Robin Carhart-Harris 17:21:30
Yeah, well, you know, we've focused a lot on the acute action and the principle when you're tripping. But of course, you know, psychedelic medicine is still on this upward trajectory, despite the recent setback with the FDA decision on MDMA therapy for PTSD and so that's a slightly different question. Sure, we're going to want to know how the drug works when you're under its influence, but we also want to know how the brain might change before and after a treatment. And so that's, that's, you know, the entropic brain principle ties in there. And the short story would be to say that it seems as though there is a sub acute or after the event, the trip itself, carry over of change into, you know, weeks and say, a month afterwards, where you're seeing something like a semblance of what happened under the trip. Under the trip, you know, I've used the snow globe analogy for the entropic brain principle. You shake up a system, a snow globe, with all these granular bits of pretend snow, and when it's in the trip, they're all over the place. You know, it's really entropic, it's really disordered. But imagine that our snow globe now is more like the actual Earth, and it's not someone shaking the thing up, but a snowfall, and imagine this, you know, before the snowfall, the landscape is very jagged, very peaky mountains and sharp valleys and troughs, so cold and icy that There's not snow as such, it's just jagged, hard ice. Then if you're going to warm that landscape up, you'll go through a snowstorm at a slightly warmer temperature and and so Snow, Snow will form and fall, will fall on the landscape and smooth it out. And then with further heating, you know, you're going to melt a bit of the snow to smooth out some of the gaps between these peaky mountains, and so you've got a smoother landscape. It's less peaky, less trophy. Now, I know that's abstract, but as a metaphor, as an analogy, I think something like that is what's happening in the brain. You're freeing up dynamics that were to the formal term is canalized. But even that's a metaphor, a canal, you know, dug into the earth, where the water only flows in one direction, yeah,
Nick Jikomes 17:24:16
the deeper the canal, the easier it is for a snowball to get stuck in that one canal. Yeah,
Robin Carhart-Harris 17:24:21
or a molecule of water is going to be stuck in there and flowing in only, only one direction. Or you go in there with a human being, and you can only swim or move in, in, you know, forwards or backwards. So you're constrained, right? And whereas, if, if you flatten the landscape, you're unconstrained, and things free up, and the dynamics free up, and that model, again, very simple, but I think that model will will hold going forwards. We've seen bits of evidence from fMRI that hint at the validity of that model. It's a little early to call it a print. Simple, but I think it's a useful model going forwards, and definitely needs to be tested more. But it's useful, I think
Nick Jikomes 17:25:09
I want to go back to the default mode network. You know, this ties into concepts like the ego or the self. You know, gets into things that span neuroscience and psychology. So starting on the neuroscience side, what is the default mode network? What are the regions that compose this network? And can you give people just maybe a short summary of what sort of this field has generally found with respect to the default mode network and the action of psychedelics? Yeah,
Robin Carhart-Harris 17:25:36
I'll give it a shot. That's called the default mode network, because its activity levels, its metabolism, its glucose consumption, is very high in an ongoing, kind of background way. It's always high, and then it dips when we engage in something again, back to that grounding thing, where is activity going to dip a bit in the brain when you focus on some cognitive task? Well, it's the default mode regions, and given that those regions were metabolically, or are metabolically, very active, the fact that they dip in activity when you do something specific led people to think that they're probably involved in some kind of background, cognitive functioning, or consciousness, maybe some kind of freewheeling, daydreamy free association, like quality of consciousness, and That's where we still are, because there are bits of evidence that support that. So that's kind of, you know why it's called the default mode, because you sort of, when you enter that, you're always that those regions, and they include the midline regions like the posterior cingulate cortex, sort of middle, middle center cortex in the brain. It's hard to describe In layman terms without showing an image and midline frontal, medial prefrontal cortex and then a couple of bits bilaterally, temporal, parietal junction and lateral parietal lobule. It's a
Nick Jikomes 17:27:23
pretty extensive network, yeah,
Robin Carhart-Harris 17:27:27
covers a fair chunk of the brain and again, specially expanded in our species. We've got way more of it than our nearest evolutionary neighbors. And it's also a connection hub, not just functionally, but also anatomically. A lot of different regions and systems will have terminals coming into the regions that belong to the default mode network, a little like a, you know, road system, where you've got some kind of in the UK, we've got the Spaghetti Junction in Birmingham, where all these roads come together, and there's this hub. It's a hub, you know. So the nodes, the big regions that make up the default mode network, are also anatomical hubs. Yeah. The strength of the connections, functional connections and anatomical within this system strengthen as we develop and mature. That is true more generally, but perhaps especially so within the default mode network. So the network matures as we mature. It's heavily implicated in mental illness, in psychopathology, but also neurological disorders. So really simple, glib way to put it is, it's a really important system in our brains for high level, arguably human specific functions like abstract thinking, imagination, sense of self. And it's, it's, yeah, really important and somewhat, you know, exceptional in our species, it seems.
Nick Jikomes 17:29:07
And when we think about the default mode network, when we think about your ideas around the entropic brain principle, can you give us a sense for, you know, how we how you think about things like, say, major depression or other psychiatric conditions, I would imagine, you know, just on a simple, intuitive level, you know, when I think about major depression, you know, someone is ruminating. They're getting stuck on negative things. They're thinking poorly of themselves. They're not trying new things. They feel hopeless, etc. I would imagine that that's probably going to correspond to higher default mode network activity and lower brain entropy. Is that something that we know, or is that something that we expect? There's
Robin Carhart-Harris 17:29:49
a bit of evidence in the direction of getting stuck in the dmn or a failure to deactivate the dmn, the default mode network in depression. And so. Association between elevated dmn activity and inability to, you know, get out of the dmn and rumination, so particular, you know, phenotype closely associated with with depression, it's like you get stuck in your head and stuck on, often ruminating on the self and negative aspects of oneself. And if it's you know intuitively, and also a bit of evidence that, yes, there's excessive dmn functioning in depression. I think these days, colleagues would say both, we should be careful of being too dmn specific about depression, and also too dmn specific about psychedelics. And both are true. It's that the dmn rules that seem to apply to the dmn whether we're looking at psychopathology, mental illness, or we're looking at the action of psychedelics don't hold for just the DNA. So for example, you know, back in 2012 when we did the first resting state fMRI study of the psychedelics, psilocybin, published that in 2012 we put some focus on disintegration, or, yeah, disintegration within the default mode network, and suggested that maybe that relates to ego dissolution or ego disintegration. And that isn't these days I would say that that isn't wrong. It's just there's arguably more to it than that. It might be a bit too simplistic, a bit too dmn centric. There are other systems that also break down under psychedelics, and the magnitude of that breakdown relates to ratings of ego dissolution or disintegration. So I'm just a little cautious these days about pinning too much on on the dmn, yeah,
Nick Jikomes 17:32:10
yeah. And I want to ask you something that, you know, I'm thinking of that phrase that you shared early on, that the brain is only as interesting as the mind. And, I want to just ask you, what is the mind? Is the mind strictly limited to the brain? Is the mind what the brain is doing, or is it not limited strictly to the brain? How do you think about what the mind and subjectivity are and where they actually come from? Well,
Robin Carhart-Harris 17:32:38
let's be honest, it's a really vague construct, but we use it all the time. When we are using it in ordinary parlance, we're typically referring to subjective experience and but there are things that the brain does that arguably aren't so much of the mind. I mean, keeping us breathing, or, you know, basic autonomic functioning through brainstem nuclei that you don't wouldn't. So obviously, associate that with mind. I think when we go to mind, we're referring to something somewhat holistic, incorporating, you know, a fullness of subjective experience. I think we're relating it especially to phenomenal consciousness, or what it is like to be, yeah, there's something. It's, it's a, it's a very lumpy term. It incorporates a lot. But sometimes there is a time to lump and it's useful. So, yeah, it covers. It covers, covers a lot. I'm trying to think of turns of phrase that say something about mind. Yeah, unconscious mind is a sort of, I don't know why I went there, because it's really problematic term. Because, you know, if taken too literally, it's referring to loss of content. And in psychoanalysis, that's not what's meant. It's more, you know, stuff of the mind that is latent and not necessarily manifest. Oh, there's all different flavors of mind that we could go to. It's a very rich one, yeah.
Nick Jikomes 17:34:40
So when we think about so obviously, one of the most striking aspects of psychedelics are their subjective effects. Major area of interest here, among everyone, people just watching from the sidelines, as well as people in the scientific trenches on this stuff, there's a lot of interest in figuring out to what extent are the. Subjective effects actually necessary or important for some, or even all of the therapeutic benefits that psychedelics seem to bring for things like psychiatric conditions like depression, PTSD and so forth. And there's also efforts to say, Well, that might not be the case. Perhaps we can engineer next generation psychedelic derivatives and things like this, which, you know, have we've subtracted out the subjective side of it, but we still retain the therapeutic benefit. I know this is certainly not settled science, but how do you what do you think about this issue about, you know, creating non psychoactive or non psychedelic, psychedelic derivatives, the efficacy of the subjective effects of psychedelics? Do you have a strong opinion here, or a way to start thinking about it that you think is useful?
Robin Carhart-Harris 17:35:46
I guess I do have a strong opinion. One should always be careful with strong opinions. But the opinion that I have is that the subjective the quality of the subjective experience, is arguably the best predictor that we currently have for therapeutic outcomes. So for example, emotional breakthrough experiences, emotional catharsis, when measured, are strongly and reliably meaning across studies, predictive of, say, drops in depressive symptom severity with psilocybin therapy for depression. So that's what we've got. That's evidence. It's just because of certain, I guess, cultural perspectives and values within psychology and psychiatry that those subjective measures are sometimes looked down on and considered, you know, less scientifically rigorous than, say, I don't know behavioral measure, or better than that, you know, an objective, biological One, I just I would say this, that things like the emotional breakthrough experience, emotional catharsis or psychological insight, which we also measure now and find, is robustly and reliably predictive of therapeutic outcomes. It's a matter of time, and maybe we're there already, until we can give a satisfactory, satisfying account of its underlying neurophysiology and neurobiology and so in time, Maybe we'll borrow more from that, then we will referring to the qualities of subjective experience. But that won't change the fact that, at the moment, you know, those are the most reliable predictors that we have in human beings, which is, you know, the species that we are and that we're most interested in and that we're trying to treat. So it's a little absurd at times I find that we wait rodent behavior ahead of human experience. And what do I mean by that this idea of non psychedelic psychedelics is really born from rodent research, usually mouse research, where they'll have some assay of whether the mouse is depressed or not, you know, something like whether it's exploring it's it's maze or space. And you know, they'll have an assay of whether the mouse is tripping or not, it's usually whether it's shaking its head as if it's trying to shake off the trip. And then, you know, if they give a drug that doesn't make the mouse shake its head yet, after having given the drug, it's moving around and it's maze more, they'll say, ah, we have a non psychedelic, psychedelic. They won't use that term because they know it's nonsensical, yet it's it's antidepressant, like in its effect, and honestly, I just take it all with a massive, you know, dose of skepticism. It's just so much that happens in preclinical neuroscience doesn't translate into human beings, and we've already got pretty clear and compelling evidence for things like the trip mattering in human beings. So in a sense, what the hell is going on here? It's a bit absurd, but, you know, there's a lot of people banging that drum and raising money, setting up companies and so on to develop these non psychedelic psychedelics. Why would they do all that? Well, wouldn't it be convenient if we could do away with this problematic, trippy stuff and then get the good. You know, multi billion pound therapeutic stuff, and do away with all that hippy dippy psychedelic stuff. And, you know, still have our block blockbuster money spinning, you know, therapeutic. And I think that's, that's what's going on. Yeah. There's also the fact that this is this round peg psychedelics hitting this square hole, and it isn't a good fit. The system isn't used to this psychedelic therapy thing. Is it a drug? Is it a psychotherapy? Oh, it's both. Have you shown that it's both? Oh, no, we haven't. We just all assume it. So you know, you have this tricky situation where it's a paradigm challenge on multiple levels. It's hard to blind for psychedelic therapy trials, and people are highlighting that and saying, maybe this is all some kind of placebo phenomenon, or super placebo phenomenon. That's a that's a thing that can be addressed. There are different ways to address it. But that's another reason why it's a paradigm challenge, because it's exposing, for example, things like the inherent limitations and weakness of the gold standard way of assessing new treatments, the double blind, randomized control trial. What do I mean by that? It's exposing the myth of blinding integrity, that people don't know what they're on when they're given something. And that's really obvious with psychedelics, because most people work it out when they're on something. And you know, I know I'm covering a lot here, but there is a lot here. You know, one of the issues here is that if there's functional and blinding, if you work out what you're on that is a problem. If what then happens is it activates your prior expectations that this is a good thing that you've got and it's going to get you better, yeah, and that would be the expectancy effect, the so called placebo effect, the positive expectancy effect. So what do you do with that? Because that thing is the snake oil phenomenon. It's believing through some storytelling, some salesman up on a soapbox, saying, Come on, everyone, take this magic potion and it's going to cure all your ailments, you know? So is that what this is, there is the way to address that is to measure some of the components here. So snake oil, if it's inert, shouldn't do anything. Shouldn't do anything to the important systems implicated in, you know, change from illness to wellness. So the snake oil shouldn't change brain function. So that's a thing that's now going into the mechanisms. And the question of, how does this work, which we should remind ourselves, is why we have the double blind RCT in the first place? It is to control for the possibility of a snake oil phenomenon by having a control, which is a snake oil control, a placebo, where you're controlling for the snake oil phenomenon, the positive expectancy phenomenon, which accounts for a good chunk of therapeutic improvement, but that placebo shouldn't have as marked effect on brain function as a truly effective, potent therapeutic. And so through better assaying, through better measuring and sampling of candidate mechanistic processes, we can demonstrate that psychedelic therapy is above and beyond a snake oil phenomenon. It doesn't take a double blind RCT, which is inherently flawed, to do that, and it's really his point of some frustration is communicating that to people, they don't always get it. They they sort of reified the double blind RCT as something, you know, even more important and essential than a mechanistic test to control for the snake oil phenomenon. When I say there are other ways to demonstrate, you know, mechanisms than the double blind RCT. They're not ready to hear it yet and consider it. There's another way to address it, which is measure expectancy. A priori. You're coming into a trial. Good practice, you tell people what they might get, and then you measure what they're. Expecting in terms of how that intervention would impact on their mental health. And there's a there's a good way to do it, and when you do that, and we did it in one of our previous trials, you can then see whether those who have really high expectations are those who do really well with psilocybin therapy. And what we found is that it, it didn't hold. In fact, numerically, it was those who had more modest, lower expectations that actually had the best response. It's really surprising. I didn't expect that, but that's why you should measure things. You know, because surprises is the essence of learning?
Nick Jikomes 17:45:41
Yeah, yeah. I'm surprised at how few people mention that approach. Why don't you measure expectancy?
Robin Carhart-Harris 17:45:48
You know? Yeah, it's sort of an obvious thing and but people don't do it instead, they sort of work around it, trying to get cute with active controls. I think that's good. You can do that. That's good too. But just measure expectancy. Others are getting cute with knocking out consciousness and giving the drug, but that's that doesn't solve things, because you could sort of eclipse the underlying mechanism that's important. If part of the assumption coming in is that the trip is important, then why should the drug alone work? You just wouldn't expect that. So it's a sort of, it's not the right test. Yeah, so, so there's things to work out in this space, but I often bring it up because I'm a mechanistic person. You know, ultimately I'm trying to answer how things work, but also when you're trying to communicate to people why that's important, it's not always easy. So sometimes I go off on one a little bit about why it's important. So maybe an imperfect example, but I bring it up because it's a sort of potent example. It might be steel manning the principle a little bit, but you know, you look at life expectancy across time, and you see that massive, you know, hockey stick inflection around whenever it is 1850, or whatever. What happened then? Well, germ theory happened. Then, you know, we worked out that people get sick because of little things. You know, whether they're microbes, bacteria or viruses. But there was a mechanistic realization that then translated into, oh, we need to keep our water clean. We need to be more hygienic and around all aspects of things, surgery, childbirth, and through that, you know, mechanistic realization of what, in a sense, kills people and makes people sick, we could have such a profound impact on something as basic and important as how long people live for. And I wonder whether, I know it's very lofty, but I wonder whether something similar could happen in mental health that it's so smudgy, so much debate, so much uncertainty about what it is and what's going on when people are unwell psychologically. But if we could work it out, you know, and find an intervention that is really on target, that really hits the core denominator of suffering, then maybe it could have an impact, like, you know, how germ theory and realizations there had an impact on on longevity?
Nick Jikomes 17:48:32
Yeah, you know, you know, building on your notion that there's a sense in which we're trying to fit, you know, square peg in a round hole here, because psychedelics are a new beast for the whole drug approval apparatus of the government. It's not merely psychedelics, at least with the map studies that people are talking about right now. It's MDMA assisted psychotherapy. It's not merely a drug. Yeah,
Robin Carhart-Harris 17:49:00
that was a brand new mistake, by the way. But, but hey?
Nick Jikomes 17:49:03
Well, yeah, I mean, what do you are you surprised that the FDA made the decision it did? Do you think it made the right decision? How would you brand all of that?
Robin Carhart-Harris 17:49:13
Well, my perspective is I was disappointed for those who worked so hard on that, and I was of the view that if it got through, it could benefit a lot of people and be a net benefit for the world. I do think we have a more effective treatment for PTSD, and it would also help the area more more generally. So I was sad, I was disappointed. And I think the advisory committee were influenced by some political interference and some misunderstanding of the science and the mechanisms, things like functional and blinding, and that there isn't clear evidence that there's an expect. Bias driving response to psychedelic therapy, at least we didn't find support for that in psilocybin therapy for depression, and that was neglected entirely. Instead, they just saw a function around blinding and naturally assumed, therefore expectancy bias and snake oil phenomenon, and I don't think they were right to do that. So, yeah, I don't think they read the science right. I don't know, you know, behind the scenes what the what the politics were. I think there was some sort of anti capitalist lobbying around the advisory committee event that was too easily heard and not seen as a conflict of interest, and I think that's a shame by what I've heard since, it seems as though that lobby was heard and not seen through for what it actually was. So that's disappointing. I do think it's a bump in the road, and while it could be crippling for the unfortunate people at the center of that specific effort, I do think the area, more generally, is still on an incremental rise, and will have learnt a lot from what happened there. And when I said I think the assisted psychotherapy tag was a branding problem. It's easy to be annoying and play Dr hindsight like that, but I did feel that for a long time that it's placing too much emphasis on one side of the coin. It's saying all the drug does is assist psychotherapy, but then you're telling that to the FDA you don't assess and license psychotherapy. So yeah, that as a strategy didn't work. And also is it even right? My view is, and it's a bit like my philosophy with with mind and brain, you know, I try to hold both sides equally, because they're essentially just the two sides of the same coin. So why would you're only going to blind yourself if you pay too much attention to one side? And here i My view is that probably I don't know, and we should test it. There's a synergy between the drug action and the context, where context is an umbrella term for Yes, psychotherapy, music, listening, that's easy to gloss over and and the environment, the room, decoration, that's something we can control. It's hard to control stuff that happens after you have people in the clinic, so to speak, after that life happens. Maybe you could do some things there with peer to peer support and so on, but generally, not easy. So you got music, you got the room, and you got the psychological support slash psychotherapy. And I suspect that there's a synergy between drug and those contextual factors, otherwise known as set and setting. And actually, that's my next big study at UCSF, just starting to recruit healthy volunteers, albeit with lower than average well being coming in. Yeah, I'm kind of, what's the term anyway? I'm kind of softly exploiting this opportunity to advertise for that new study. It's going to be recruiting from people in the Bay Area, but it's going to be a fascinating study. Yeah, I'm really excited about
Nick Jikomes 17:53:41
it. Well, we've covered a lot, Robin, and I really appreciate your time. Is there anything that you any final thoughts you want to leave people with? Anything you want to reiterate about psychedelic science, either your work, or just a general message about, you know, what's happened and where we might be going?
Robin Carhart-Harris 17:53:58
Well, I I just
Unknown Speaker 17:53:59
really, I love
Robin Carhart-Harris 17:54:01
what I do. I feel so lucky to have made it work. It wasn't easy. It was damn hard, and it was sort of Mission Impossible for so long. These days people are saying, you know, we're at this, this sort of lowest, you know, ebb, in a sense, sure, it's a big, you know, dip in the road with what's happened with MDMA, but honestly, things so much better these days. Am I just saying that? Personally, I don't think so. There's, there's more interest and resources around there's so many teams looking at psychedelics now people to were to look at the database of clinical trials that registered clinical trials, they'll see, you know, something like 400 trials registered, either planned or ongoing with psychedelics. Back in the day, it might have been two. It's crazy, you know. And I'm you. I'm not that old or young anymore, but the rate of change that's happened since I started out to where we are now is crazy fast, and it's good, and that's where we are right now. So I guess my message would be like a reason to be grateful for where we are, and optimistic going forwards and and also the I didn't come into this space as an advocate. I didn't, you know, I hadn't treated myself with psychedelic therapy, and you know, it saved my life. That's not my story. I guess I was pulled in through a deep intrigue and into the mind and the brain, and then on the job, I realized how positively transformative psychedelic experiences, you know, managed in the right way, could be for people. And I still hold that view very much, that this is potentially a very powerful treatment modality that can get right to the core of the core essence of psychological suffering. And there's every reason to be excited about this and to keep on with the work for sure. Yeah,
Nick Jikomes 17:56:12
all right. Well. Robin Carhart Harris, thank you very much for your time, and I look forward to seeing what you come out with next.
Robin Carhart-Harris 17:56:19
Thanks, Nick, been a pleasure.
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