Luminous: Your Brain on Shrooms

- [Anne] It's "To The Best Of Our Knowledge," I'm Anne Strainchamps.

- [Steve] And I'm Steve Paulson.

- [Anne] And this is "Luminous," our series on the philosophy and future of psychedelics. This episode, "Your Brain on Shrooms." So where are you taking us this time, Steve?

- [Steve] Well, we're gonna go down the rabbit hole, specifically down the neural circuits that light up on psilocybin and other psychedelics. You know, for scientists who study the brain, these drugs are tools that can open a window into how the mind works, and possibly into the mystery of consciousness itself. And for some neuroscientists, this gets very personal.

- [Christof] In a sense, I'm grateful I had this experience, but it's totally terrifying. You inhale the substance, and then within 5 to 10 seconds, everything becomes black. The visual field is fractured in hexagonals. And then those hexagonals sort of themselves disappear, and you go down into this tunnel, this black tunnel. And the last thing I remember, I said, "Holy , what have I got myself into here?

- [Steve] This is the neuroscientist Christof Koch describing his brain on 5-MeO-DMT, otherwise known as toad venom. Christof is a pioneer in the scientific investigation of consciousness. For years he taught at Caltech, and then became the chief scientific officer at the Allen Institute for Brain Science. He cuts a striking figure in person. A former rock climber, he's tall and skinny, and often shows up at scientific conferences in red pants and brightly colored shirts, and recently he's come to believe that psychedelics may offer clues about the nature of consciousness. And just might also satisfy some of his own deep spiritual yearnings. I'm assuming there was sort of a personal journey that's part of this, and I'm hoping you can go there.

- [Christof] I grew up in a devout Roman Catholic family, and early on in my life I was devout. I was an altar boy, I said all the prayers in Latin, all of that. But I never had a burning bush, I never had a booming voice from the sky, and I prayed for that. I prayed for God to, you know, reveal himself to me in some way, shape, or form. That never happened, and then over the years I lost my Catholic faith, particularly being a scientist, but I never lost that yearning to experience the absolute. And of course, many people claim that under various types of substances they have so-called religious experiences. So that was probably, come to think of it, the deeper motivation for why I did what I did.

- [Steve] One of the things I've always liked about Christof is that he doesn't dodge the big existential questions. He once wrote a book called "Consciousness: Confessions of a Romantic Reductionist," where he described his fascination with Teilhard de Chardin, the Jesuit priest and paleontologist who believed the cosmos is continually evolving toward greater complexity, and ultimately to the Omega Point, when the universe becomes aware of itself. So it's not that surprising that he'd go down the psychedelic rabbit hole. And yet, Christof Koch is in some ways the last scientist you'd expect to get interested in psychedelics. To explain this, I need to go back to the 1980s. Consciousness had been pretty much a taboo subject in some science, too soft and mushy for any real scientist to touch. But when MRIs and other brain imaging technologies came along, it was suddenly possible for the first time to peer directly into the brain. And one of the world's most eminent scientists, Francis Crick, the Nobel laureate famous for his discovery with James Watson of DNA's double helix, announced a plan to map the neural correlates of consciousness. This launched a revolution, and Christof, Crick's brilliant young protege from Germany, was there at the beginning, taking the first crack at this new science. It was a match made in heaven. Except, well, Crick had no use for heaven.

- [Christof] He was a devout, dedicated atheist. In fact, there's this very famous story of him. They built a new college after the war, Churchill College in Cambridge in honor of Winston Churchill. It was all supposed to be forward-facing, based on science and engineering, mathematics, and then they decided to build a chapel. And he vehemently objected to this plan publicly in a letter. Sir Winston Churchill himself wrote back and said, "Well, no one would be forced to go to it. It would be privately paid and it would be open to everyone." And then he sent in, a very famous episode, he sent in a check for 20 guineas saying he proposed to establish a brothel at Churchill College. It would be open to anyone, it wouldn't be discriminatory, and it would be paid by private means, and that ended their public conversation.

- [Steve] Francis Crick died in 2004, but a few years before that I talked with him about his work in this new science of consciousness. He'd just published "The Astonishing Hypothesis: The Scientific Search for the Soul," and he was pretty clear that in his view there was no such thing. The mind is just a whole bunch of neurons and synaptic connections and nothing more.

- [Francis] Basically, it's a very old idea. It goes back to the Greeks. It says essentially that all the feelings you have and what you see and how you feel pain and what you think about yourself and your emotions and ambitions and so on, basically the behavior of the enormous number of nerve cells in your head firing away and interacting, and, of course, the molecules associated with them. And I suppose to put it into focus, you could contrast that with the view that Descartes put forward that there was something immaterial, some sort of immaterial soul, which was necessary for you to be conscious and for you to be a person.

- [Steve] Do you think scientific knowledge will gradually replace religious beliefs as we know more and more about how our brains work? Will there be less reason to believe in spiritual things?

- Well, first of all, I wouldn't accept the word spiritual, but let's forget that for the moment.

- [Steve] I don't want to! Why do I have to-

- [Francis] Well, 'cause I think what you call spiritual I think is various activities of the brain. Whereas when people use spiritual, they like to think it's something very special outside in some way. But let's forget that.

- [Steve] But it sounds like a very kind of physical description of what's going on, but it doesn't really get at the mystery of what happens in the mind.

- [Francis] Well, of course it's the mystery we want to get at. The problem is, is it approachable scientifically, and if it is, how you go about it. The view that my colleague Christof Koch and I have taken is maybe we have some tools, and at least we can answer if not every question about ourselves, much more than most people would think.

- [Christof] He knew at the time I was still going to church, but we got along fabulously well.

- [Steve] Actually, Christof's views were not quite as reductionist as Crick assumed.

- [Steve] We sort of had this mentor-mentee, father-son relationship. We got on famously well and we decided, sort of the implicit understanding is not to go there.

- [Steve] Hmm. So you can kind of agree to disagree.

- [Christof] Yes.

- [Christof] But you said that as you became a scientist, as you learned about the way the brain works, the way consciousness works, that essentially your old faith, your old beliefs just didn't hold up.

- [Christof] Yeah, I don't think you need a supernatural explanation, in the sense an explanation that's outside space and time, you know, like the conventional conceived of God. I grew up with the idea of a soul as a soul and the real Christof is the soul, and once Christof's body's died, then, you know, the soul is gonna be resurrected in the eschaton at the end of time. Well, that doesn't really make any sense where the souls were, where were they before? Is there only a finite number of souls? How does the soul actually communicate with the body? How does my soul make me do something or not do something? None of that really coheres. And so we don't think, I mean, scientists today, if you think about conscience, you don't think in those terms anymore.

- [Steve] Francis Crick's reductionist views have shaped the field of consciousness for the past four decades. It's probably what most neuroscientists believe today. In fact, there's a mantra I've often heard: the mind is what the brain does. And for the scientists who study psychedelics, that tends to be the starting point. And yet, psychedelics are famous precisely for conjuring up more expansive views of consciousness, what Aldous Huxley called mind at large, what Carl Jung called cosmic consciousness. I mean, you might be able to map the brain activity during a psychedelic trip, but does that really explain someone's mind-blowing experience? It's a question Christof Koch wanted to understand, and he knew the only way to do it was to go tripping himself. I know that you've used psilocybin, I know you've used 5-MeO-DMT, toad venom, or probably the synthetic version of that. I'd love to have you talk about your experiences with each of those. I mean, psilocybin, what happened when you had that?

- [Christof] It's a magical experience. In both cases, I was outside in nature. You have this remarkable transformation. It takes some time, one or two hours, and then suddenly, the world just looks fundamentally different. There's still a tree there, but the tree now, these colors are enhanced, the motion is enhanced, you see these motion trails, et cetera. But everything is so much suffused with a sense of connectedness, with a sense of beauty, with a sense of meaningfulness. You can get totally lost. Your attentional focus that usually constantly shifts around, goes to your iPhone and my fight with my boss and the thing I had was my wife and all of that, all of that is gone. Your sort of ego doesn't dissolve, but it's greatly reduced, so it's certainly an ego reduction, and you're just focused on the outward world and you discover, or you rediscover the deep beauty of it. Particularly sort of organic fractal patterns. Blades of grass, the canopy of the tree. There was a bench with moss and it was moving about and was just the most beautiful thing, and you become totally overwhelmed by the beauty of it. You cry, but you cry out of joy. You can hear sort of the heartbeat of the universe. You can actually hear it, you can actually listen to it, it's right there! Boom, boom, boom, boom, it's the most amazing thing ever, and the world is just transformed. It's one of the most meaningful experiences I've ever had in my life.

- [Steve] So this is the psilocybin experience you're talking about?

- [Christof] Yeah.

- [Steve] So then, I think more recently, you've tried 5-MeO-DMT, this very powerful, fast-acting psychedelic. What happened there?

- [Christof] That's very different. In a sense, I'm grateful I had this experience, but it's totally terrifying. I had this remarkable experience. Some people call it a non-dual experience. So I ended up in this space. There was a bright light of overwhelming blue intensity. And I don't know whether space had disappeared, collapsed, sort of like in a singularity. I couldn't look away because there was no away, there was no left, right, there was no up, down, there was just this point of unbearable lightness. There was no ego, there was no memory, there was no Christof, there was no dreams, there was no fear, there was no desire. There simply was no I, I was gone. I was sitting there with eyes, you know, lotus seat with eyes wide open, being totally blind, not seeing anything, not feeling anything, not hearing anything. And then the other thing, so there was a bright light of overwhelming intensity, there was terror and there was ecstasy. Those three things, bright light, terror, and ecstasy. And if you think about it, if you go back and read, for example, "The Knowing Cloud" or some of the mystical literature, when you think about the word awful, full of awe, when you're supposedly in the presence of something overwhelming, you're full of awe. But awe itself is this combination of terror and ecstasy. It's a very strange thing.

- [Steve] How long did this last?

- [Christof] There was no time. It wasn't too short, it wasn't too long. It wasn't that, "Oh my, I wish this would end, this is terrible. How long is this gonna last?" No, there was no time. So in that sense, time had come to a stop, complete stop. There was no space, no time, no world, no body. There was just pure consciousness. Now, objectively, from an outside point of view, because I put on this beautiful music by this Estonian composer, Arvo Part, "Spiegel im Spiegel," and this lasts roughly nine minutes. And the first thing I realized about the external world, I heard the ending of that chord.

- [Steve] And how long does that last, that piece?

- [Christof] Eight and a half minutes.

- [Steve] Wait, this whole experience, objectively, was eight and a half minutes?

- [Christof] From the outside, yes. And then you very quick, you know, within five minutes, I mean, of course, you're completely confused. Sort of what I did, I stripped naked. I don't know, I had this desire to get rid of all my clothes. I cried. You know, you go into a fetus position, and 'cause it's so, you know, you've just died, psychologically speaking. Right now you are reborn, you're given back to the world of the living. So it's, you know, it perturbs you profoundly. In fact, there isn't a single day I don't think about this experience.

- [Steve] Wait, you stripped naked, you stripped off all your clothes?

- [Christof] Yeah, I mean after I came through. Because first you're completely confused, you don't even know, now consciousness is coming back, you realize, well, there is an external world present, yeah. And then somehow it was oppressing me, so I just slipped off within 20 seconds my entire clothes and just lie there. And then, you know, you go into fetus and you cry and you try to reconnect. I remember then someone gave me something to eat because he says, "This is good. This helps you center, just to eat something. You can feel the taste of it," et cetera.

- [Steve] Would you wanna do this again?

- [Christof] No, no. I mean, it's a near death experience. It's totally terrifying. In some sense I'm glad I did it because it's an experience that's, of course, near death experience is pretty rare. You know, typically it happens on the battlefield or operating table or when people are about to suffocate or drown or something. Yeah, it's not something you wanna experience again, no.

- [Steve] Do you feel like you came to some new understanding of what death means or how you might sort of approach death in the future?

- [Christof] I totally lost my fear of death, which was never hugely pronounced. You know, I know I'm gonna die and I'm, you know, I don't want to die right now, I wanna experience life. But once it will happen, yeah, that's okay.

- [Steve] So I wanna come back to where we started by talking about your religious upbringing, this search for the divine. I mean, you wanted to see the burning bush, which never happened earlier.

- Is this a burning bush?

- Yeah.

- [Christof] I don't know, it's more like a naked singularity then a burning bush. There was no booming voice. So I did not have what some people have in these when they, you know, see Jesus or they experience whatever their religious upbringing is. I did not have that.

- [Steve] Your whole life you've been yearning for something larger, larger meaning, some sense of the order of the universe. Did any of that come through for you?

- [Christof] No. I guess what what you realize, Wittgenstein says this in his "Tractatus Logico-Philosophicus," that once you understand the meaning of life, you don't talk about it anymore, because you understand the meaning of life is in living life. That is the meaning of life.

- [Steve] There's a reason we call experiences like these mind-blowing. They're outside our normal understanding of how the mind works. You could say, yeah, this is just what the brain does when you ingest a psychedelic molecule. You get strange sensations and all kinds of wonderful and terrifying visions. But for a scientist like Christof Koch, this isn't just mental fireworks, it's evidence. So coming back to your work as a scientist then, you've been studying consciousness basically your whole professional life, trying to understand the science of this. Does that change anything about how you understand consciousness or how the brain works or anything like that?

- [Christof] Well, so once again reaffirms the primacy of consciousness. 'Cause in that space there was no world, there were no object, there wasn't even a body. There was nothing except for consciousness. So you have to start with consciousness, which is very different from the conventional point of view, which is also different from the way I used to start. For example, with my work on Francis Crick, you assume there's a brain. You start with physics or biology or neuroscience, and then you point at some feature of the brain, 40 hertz, or this part of the brain or those neurons, you say, "Well those are the ones that are involved in consciousness." And then of course you get to this hard problem, why these neurons and not those? Why 40 hertz oscillation and not 30 hertz oscillation? But here, once again, this reaffirms the point of you gotta start with consciousness.

- [Steve] Okay, so I'm trying to come back to sort of-

- [Christof] What can we learn about this from-

- [Steve] Well, I mean, of course the standard neuroscience model is the brain generates consciousness. Fireworks in the brain, that's what creates this conscious experience. Are you saying that's not what you believe anymore?

- [Christof] No, I mean, I use slightly different language, because I've learned to be careful. The brain, of course, is the physical substrate of consciousness. And what this drug did, it went to various receptors, such as these famous serotonin 2A receptor, and then it did something that we have right now absolutely no understanding of, okay? For me most striking you have this radical experience like I had, which is not uncommon, you know, under this 5-MeO-DMT, also called the toad. So you expect some radical change in the underlying neural basis, which so far we haven't quite seen. So we are trying to still come to grips with this. Given this radical change in your perspective doing some of these psychoactive substances, you would expect an equally radical change at the level of the brain.

- [Steve] So it sounds like you're saying, correct me if I'm wrong here, that clearly there is efficacy in psychedelics, psilocybin say, to treat depression. I mean, there are lots of clinical trials that suggest that. We still don't really know why.

- [Christof] That's entirely correct. But of course, we also still don't know why lots of other things, like deep brain stimulation, even Parkinson's, right? It's a very popular technique. You put in these stimulators in your brain, you know, it's a serious brain surgery operation, and they seem to relieve the tremor. Why does it work? There are all sorts of hypothesises, but we don't know. So typically if you look at medical history, therapy almost always comes before a detailed understanding of why this actually works. That's why I'm so excited about mRNA vaccines, et cetera, because that is based on a rational, mechanistic, causal understanding of molecular biology. We are very far away of that in the brain, because the brain is the most complex piece of active matter in the known universe. So it's gonna take us a while to get to that level of understanding.

- [Steve] That's Christof Koch, the pioneering neuroscientist at the Allen Institute for Brain Science. I'm Steve Paulson.

- [Anne] And I'm Anne Strainchamps. Coming up, an unlikely origin story of psychedelic research, not in a lab, but an ancient Tudor manor on the edge of an English fen where the daughter of an eccentric British aristocratic family grew up, and later jumpstarted research into altered states of mind. Amanda Feilding is in her 80s now. We'll have her story next on "To The Best Of Our Knowledge," from Wisconsin Public Radio and PRX.

- [Steve] If you wanna get a sense of the current state of research into psychedelics, one of the big international conferences is a good place to begin.

- [Chairperson] Good morning, let's start. We're a little over time, so-

- [Steve] It's 2022 and I'm in Haarlem, just outside Amsterdam, at one of the major European conferences on psychedelics.

- [Chairperson] So this is the session on neuroscience and psychedelics.

- [Steve] 1,100 people are packed in here, waiting to hear from some of the key players in the field.

- [Chairperson] The first speaker is Amanda Feilding, and she's going to talk about LSD and the importance of changes in the cerebral blood supply. We give her a big applause.

- [Steve] When histories of the modern psychedelic renaissance are written years from now, Amanda Feilding will be one of the more colorful characters.

- [Amanda] Hello, everyone. Forgive me, I'm gonna read my talk.

- [Steve] She's what you might call the godmother of the European psychedelic renaissance.

- [Amanda] I've long been fascinated by the mechanisms underlying the profound shift in consciousness that can be achieved using psychedelics.

- [Amanda] An eccentric British aristocrat with a rich history of self-experimentation, it was Amanda Feilding who helped keep psychedelic research alive during the long years when it was banned.

- [Amanda] I'd been into psychedelics for a very long time. I was introduced to them in 1965. And then in 1966 I met a Dutch scientist of exceptional insight, and we became close friends, lovers, and worked together for the next 30 or so years. And so actually what we did with LSD, there was whatever, the Stones or the Beatles playing in Hyde Park, which was half a mile away. And we were there doing our studies in psychedelics and different levels of consciousness, and that was just so exciting.

- [Steve] What was it that made you decide that this is what you wanted to do with your life, to study psychedelics?

- [Amanda] Well, I suppose my background was very formative. I grew up on the edge of a moor in an old Tudor hunting lodge surrounded by three moats.

- [Steve] Three moats and three towers.

- [Amanda] Ancient, beautiful, but totally isolated. So I mooched around as a child with no one to play with.

- [Steve] Except for her family's friends.

- [Amanda] My father's family were close friends of William James and Aldous Huxley, who used to visit my grandmother and stay talking all night as a young man.

- Oh my goodness, wow. It was, she says, a perfect atmosphere for developing an interest in mysticism.

- [Amanda] Because as a child in a very beautiful setting, but nothing much to do but dream about a future, I had lots of mystical experiences, as most children do.

- [Steve] When you say, I'm just curious about what kind of mystical experiences did you have when you were a child?

- [Amanda] Well, there was a part of the garden which was a mound with the moat surrounding it, very kind of secretive part. And there in my childhood fantasy, I think I was probably about five, six, seven at that point, this God figure lived, and I used to have kind of mystical experiences with him. I think a lot of children slip in and out of mystical-like experiences much more easily than we think, kind of thing. And so I was always fascinated by the mystical experience. It was always my passion.

- [Steve] At 16, that passion led her to set out on a journey to Ceylon, now Sri Lanka, where her godfather was a Buddhist monk. She hitchhiked as far as the Syrian border and spent time living with Bedouins. Then back in the UK she studied classical Arabic, comparative religion, mysticism, and she discovered drugs.

- [Amanda] Then at 16 I was introduced to cannabis, and thought, "This is amazing." And then at 22 I was introduced to LSD and thought, "Well, this is absolutely amazing," because it kind of creates the ground from which you can more easily have a mystical experience, but it's not a way of life, I felt.

- [Steve] In the 1970s, Amanda Feilding became briefly famous, or infamous, for her interest in trepanation. That's the ancient practice of drilling a hole in the skull in the hope of inducing a higher state of consciousness, which she did on herself.

- [Amanda] Now I just have to clean up and wait and see what happens.

- [Steve] With an electric dental drill while filming the entire process.

- [Amanda] Making the film was a sort of mantra to detach myself from the natural reluctance I felt.

- [Steve] But her real lasting interest has always been the science of psychedelics.

- [Amanda] I mean, I realized the benefits of psychedelics in 1966, and that's when I decided I'd devote my life to understanding their underlying mechanisms so that we can use them as useful tools.

- [Steve] Mm-hmm.

- [Amanda] So prohibition, which one saw closing in on one, was obviously a disastrous mistake which was doomed to complete failure and immense human suffering. So I saw the end of the '60s that the only way really out of the taboo, to overcome the taboo, was undertaking the very best scientific research to demonstrate the advantages they had.

- [Steve] For those years during prohibition, you must have felt like this lone voice in the wilderness. No one wanted to do these studies.

- [Amanda] No, no one wanted to.

- [Steve] No one wanted to pay for the studies-

- [Amanda] And the danger is your children, 'cause then I had two children, you know, parents wouldn't necessarily want their children to play with people, et cetera, et cetera, and bank managers wouldn't give you a overdraft. One was considered a weirdo, and maybe a dangerous weirdo. And the "Daily Mail" later called me Lady Mindbender and, you know, things like that, which I wasn't at all, you know, at it, .

- [Steve] When did that change for you?

- [Amanda] Very slowly. I was compelled to follow this because I felt it was true. To begin with, I tried to do it through finding scientists and doctors to work with. For 30 years, it was a long time, from '66 to '96, I did it trying to influence influencers or do research with scientists or do it through artworks, 'cause I was an artist. And then I thought as a conceptual artwork, I need to become a foundation. Because as a single female without letters after my name, how can I change global drug policy and open the doors for psychedelic research? But suddenly I got the idea, well, if I become a foundation, which in England is relatively easy, it costs 1,000 pounds. And I like the word foundation. I didn't know you were meant to have money if you were a foundation, but, so I became a foundation.

- [Steve] Which she named the Beckley Foundation, a charitable trust that has promoted scientific research on psychedelics for more than two decades.

- [Amanda] As a child, my dream was to water the desert. Then I realized that the desert is the human brain. Thank you.

- [Steve] Listening to Amanda Feilding, it struck me that the psychedelic renaissance is usually told as an American story, revolving around people like Gordon Wasson and Timothy Leary, and more recently, Roland Griffiths. But some of the pioneering research has also been done in the UK, and a lot of it funded by Amanda Feilding's foundation. For example, one of her scientific collaborators is another guy at this conference, David Nutt.

- [David] So I think I'd be useful to start with the beginnings of neuroscience, and that goes back to the writings of people like William James.

- [Steve] David Nutt is the neuropsychopharmacologist who led the Centre for Psychedelic Research at Imperial College London. He sees his work as part of a long lineage of scientists who've studied psychoactive substances.

- [David] And he took mescaline and he took nitrous oxide. In fact, I actually think understanding consciousness is as challenging as understanding the origins of the universe.

- [Steve] In 2009, Nutt created an uproar when he told an interviewer that LSD and ecstasy are less dangerous than alcohol.

- [David] If you tell them that ecstasy is a Class A drug and very harmful when everyone knows it isn't, then why should you trust the government on anything?

- [Steve] Not surprisingly, that got him fired from his post as the British government's chief drug advisor, but it gives you a sense of his commitment to this research.

- [David] So I use drugs to explore brain function, and I've probably given more different kinds of drugs to human beings than anyone alive. I don't think there's a class of drug that is used either legally or illegally that I haven't studied in humans. We started off, and this was Amanda's theory, that psychedelics would increase brain blood flow. And the first study we did showed that they didn't, in fact, they decreased blood flow, but in one or two specific regions in the brain, which we now know to be part of the default mode network, and it was completely paradoxical. How could people have these wonderful visions, have these experiences of floating out of the scanner, going to another dimension, going to God, how could that happen without the brain being turned on? In fact, we were so bemused by that first result that we repeated the whole thing, got exactly the same results, and then realized we'd actually discovered something really important. That these drugs don't turn on the brain, they actually turn off the brain, but they turn off the parts of the brain which keep the brain doing what it's always done. And you turn those bits of the brain off, the brain can run free, it can do its own thing. It's like taking the conductor away from an orchestra or taking a school teacher away from a class of kids, and they all do their own thing. And from that, some interesting observations emerged.

- [Steve] You're basically saying you're shutting off certain parts of the brain so you can access other parts.

- [David] Yeah, you're switching off the control centers of the brain so that the brain can do other things, 'cause the brain is an extremely efficient organ. It's 10 times more efficient than any known computer, and that efficiency comes at a cost. It comes at the cost of actually being repetitive rather than flexible. And what psychedelics do is they break down the processes that keep you doing the same thing, thinking the same things, and allow connections to be made that haven't been allowed since you were a baby, really. And those connections allow you to see things that you've forgotten and to come up with solutions to problems that you've not been able to solve and think differently about yourself and your life and your family. As it turns out, when you use them in people with depression, people can come out with a different perspective on their past and a new way of thinking about the future, which is much more positive than it used to be.

- [Steve] So, wonder drugs is what you're describing here. I mean, is that fair to say?

- [David] Well, I think the use of psilocybin in resistant depression is a wonder. I mean, our study showed a single dose of psilocybin is the most powerful, beneficial effect in resistant depression of any treatment that's ever been given, certainly a single dose. It's equivalent to three or four weeks of ECT. So it is truly wonderful the impact that these drugs can have, particularly on people who've failed on more conventional treatments.

- [Steve] So it seems like there's some big mysteries as to why psilocybin is so effective therapeutically. I mean, is it changing the brain in some way, rewiring? Is it the experience, this remarkable experience that then people reflect on and somehow it changes them?

- [David] Yeah, I think all of the above. If you're a depressed patient who's been locked in a set of ruminations about your worthlessness and your hopelessness and there's no hope for the future, a trip that can show you your brain can change in itself can be empowering, because you realize you are capable of change. That's the first thing. But I think there's more to it than that. I think for some people, they do get to understand why they're depressed. One of the things we're beginning to get clearer is that a lot of depressive thinking is about trying to stop you dealing with the event. It's kind of filling your mind so you don't have to confront the problem. You've been abused by your father, but you don't wanna confront that, so you keep thinking about yourself as being a bad person. I, you know, vividly remember one of our patients who said, you know, during his trip, he suddenly realized why he was depressed, 'cause he saw his father abusing him, and it all made sense.

- [Steve] Why would the trip kick in that memory or that realization?

- [David] Because he has been suppressing that, or repress. You cannot push things back under a psychedelic, 'cause the bits of the brain which do the pushing back are not working so well. So you can access thoughts, memories, facts that you couldn't access. So those kind of insights as to why people are depressed can be really useful in helping people move on, because they can get closure.

- [Steve] Can you put the current psychedelic renaissance in some historical perspective? I mean, how does this compare to what we had in the '60s? I mean, are we on the brink of a psychedelic revolution here?

- [David] No, I think we are on the brink of a revolution in terms of therapy. This is the biggest innovation. It is the most important new wave of therapy in psychiatry in the last 50 years. Up till now, everything we've done has been using drugs which are modifications of drugs which were discovered in the '50s, so it's hugely important for psychiatry. And it's even more important now than most people might hope for, because most traditional pharmaceutical companies have given up on the brain. They've said it's too hard to find new treatments. So it's exciting that there is hope for patients who aren't getting better from traditional meds, and that's up to about a third of patients. But of course, the science has moved on enormously, and science is gonna understand altered consciousness. I don't think you can understand altered consciousness without psychedelics. So that's a whole new dimension of what psychedelics are bringing, not just to therapeutics, but the consciousness research.

- [Steve] That's David Nutt, professor of neuropsychopharmacology at Imperial College London and president of the European Brain Council.

- [Anne] So we've heard from some of the pioneers who helped launch the psychedelic renaissance. But if you noticed, we began with a question that we still haven't answered. For all the research, all the therapeutic promise, what exactly happens in the brain when it's tripping?

- [Steve] In a minute, British researcher Robin Carhart-Harris explains his theory of the entropic brain. You're listening to "Luminous," our series on the history and philosophy of psychedelics. I'm Steve Paulson.

- [Anne] And I'm Anne Strainchamps. And you'll find more interviews in our "Luminous" podcast feed and on our website at ttbook.org/luminous. As "To The Best Of Our Knowledge," from Wisconsin Public Radio and PRX.

- [Steve] We asked a question at the beginning of this hour, can neuroscience explain what happens in a psychedelic experience? I mean, if you could somehow peel back the skull and look at someone's brain while they're on acid or mushrooms, could you watch the trip happening in real time? The answer is yes. That's what British neuroscientist Robin Carhart-Harris has been doing for the past 15 years. He got into psychedelic science after meeting Amanda Feilding, who introduced him to David Nutt at Imperial College London. And since then, Robin has done pioneering studies of psilocybin using brain imaging, which is pretty remarkable when you think about it. I'm just trying to imagine your test subjects in an fMRI machine. I mean, you have to be absolutely still, and they're having this mind-blowing experience as you are looking at what's happening in their brain while all this is going on. It sounds crazy!

- [Robin] Well, it does! But it can be quite a thrill, and, you know, we're safeguarding against anyone freaking out having their first psychedelic experience and then having it in such a-

- [Steve] A confined environment.

- [Robin] Yeah, yeah. And so it worked.

- [Steve] So were there any big surprises as you started looking at this brain imaging?

- [Robin] Yes, because there wasn't much to go on at that time. There'd been some early positron emission tomography, I know that's a fancy term, PET imaging, but not much. And the methods were kind of crude. So we would inject in our psilocybin with the scanner running. We would subsequently look at changes in their brain blood flow and see that it was dropping.

- It was dropping?

- It was dropping.

- [Steve] So there was actually reduced brain activity?

- [Robin] There was reduced brain blood flow, because it isn't quite a one-to-one relationship between blood flow and brain activity. I know it sounds like a detail, but it's not really a minor one, it's actually quite important.

- [Steve] Hmm. So is one way to think about this is the way our prefrontal cortex works, it kind of acts like a filter in a way, so it blocks out certain things that we might otherwise sense from our unconscious. And I know there's this phrase, the executive function. The cortex is what allows us to move around in the world and sort of act out. And I guess the question is, what happens when that system is knocked out?

- [Robin] Yeah. It's not entirely knocked out, but it is dysregulated, sort of scrambled in its functioning. It is reasonable what you say, the locus of this is cortex and it's high level cortex, and the prefrontal cortex is typically a part of the brain that we think of as massively expanded in humans. People have a certain clarity of vision under psychedelics. Is sort of suggests that maybe humans have overshot and we do too much analytical thinking, and if you just relax that there can be this broader, clearer vision.

- [Steve] Now, you've come up with this theory, what you call the entropic brain, that psychedelics sort of activates this tendency towards I guess what you call less regulation, more disorder, is it fair to say?

- [Robin] Yeah. Psychedelics seem to increase the already very complex quality of brain activity during normal waking consciousness. They lift it up. And so another synonym for entropy, these are all synonyms, complexity, diversity, richness even, is information.

- [Steve] Hmm, more information.

- [Robin] More information.

- Which is fascinating.

- Yeah.

- [Steve] Because you would think that, again, going back to the cortex, you'd think that this very analytical part of the brain that that's the information processing part, but you're saying actually maybe that keeps out information?

- Yeah. It sort of suggests that although our information processing during normal waking consciousness seems very impressive and our analytical skills are impressive, there can be a sort of compression of other aspects of information held within the system. Things like memory, emotion. I'm referring to these things because these are the things that seem to arise and emerge under a psychedelic, that people have insights, emotional insights, personal insights, remember things sometimes very remote into their childhood.

- [Steve] You've described this as a reset, like the brain gets jumbled up, it's knocked out of its old way of thinking and it's, I don't know, new neural pathways are opened up?

- [Robin] Yeah. There's pretty good evidence for that now, concrete evidence in terms of anatomy of the sprouting of new components of neuronal communication via exposure to psychedelics, something referred to as synaptogenesis.

- [Steve] Is the brain actually getting rewired then?

- [Robin] Yes, it likely is. At least there's an opportunity for rewiring. And there is this paradox around plasticity, that in and of itself it's not necessarily a good thing. You could use that window of malleability or plasticity for sort of ethically questionable ends. We could think of things like the history of military, use of psychedelics around things like mind control. But in psychedelic therapy, it's about opening, well, creating this openness, this opportunity for realization, self-realization done in a very nurturing context.

- [Steve] Now, there's some fascinating evolutionary questions here. I mean, one is just why would the human brain even respond to psychedelic substances, let's say mushrooms laced with psilocybin we find in nature. I mean, did these co-evolve, the human brain with mushrooms? Was this just an accident that our ancient ancestors happened to eat these and they had these remarkable experiences? Do you think about that kind of thing?

- [Robin] Yeah, I do a bit, and there are theories about it. Terence McKenna most famously had the so-called stoned ape theory of consciousness and the evolution of consciousness.

- [Steve] Just talk about that for a moment. I mean, his theory was that actually consuming mushrooms, and maybe some other psychedelic substances, that essentially jumpstarted human consciousness, the modern human brain.

- [Robin] It's a fascinating idea. Really exciting, spine-chilling, yet I'm not sold. I just think that it's a bit too psychedelic-centric, even though it's appealing and kind of fun. I think probably what's more common is the Earth was in a particular climactic sort of state or mode that was hard, and it required some serious ability to deal with this hardship in a thoughtful and far-seeing and perhaps inventive way. And it was those early humans who managed to ride that period of high stress and challenge that have survived, and maybe they were the ones who had a bit more of the serotonin 2A receptors.

- [Steve] Which is what psychedelics activate.

- [Robin] Exactly, yeah, yeah. We know that with a high degree of confidence now, that these particular receptors that are kind of locks that sit on neurons, brain cells. And then the key comes in which could be serotonin, an important brain chemical, or it could be a drug that hijacks and mimics serotonin and works in the same way as a key, and that's what psychedelics seem to do. They're a kind of magic in the broad sense key that comes in and turns the lock.

- [Steve] Why are psychedelics so powerful? Why can one trip just literally change someone's life?

- [Robin] So to answer that, I would appeal again to the serotonin system and these magic locks, the 2A receptors. I think that they're special receptors. Humans have a lot of them. They are disproportionately expressed in cortex that humans have so much of. And these 2A receptors are especially prevalent at the highest level of the already high level aspect of brain, the cortex. And so they're in these regions of brain associated with consciousness and species-specific functions like self-reflection, self-consciousness. Why are they there is a really crucial question, and that can help us understand why psychedelics are so profound in their action. And my feeling is that they're there for profundity in a sense. They're there for fundamental shifts in perspective. And it's only really with fundamental shifts in perspective that you can have fundamental shifts in behavior. I think that's why they're there.

- That's neuroscientist Robin Carhart-Harris, previously at Imperial College London, and now director of the Psychedelics Division at UC San Francisco. So after I'd done all these interviews, I thought I had a pretty good sense of the latest thinking about the neuroscience of psychedelics, and then I started looking into the work of Gul Dolen, a neuroscientist at Johns Hopkins University, and it turns out she has a very different idea of how psychedelics change the brain.

- [Gul] I don't wanna blow off the entire field of neuroimaging, but, you know, just to nail it down, what the problem is with pointing to a brain region and saying, "Oh, well this lights up when we give psychedelics. Now we understand that this brain region or this set of brain regions is responsible for the psychedelic experience." I think the main problem with that is revealed by the octopus studies that we did.

- [Steve] Okay.

- [Gul] So here's an organism that doesn't have a default mode network. It doesn't have a hypothalamus, it doesn't have an amygdala, it doesn't have any of those brain regions. And yet when you give them MDMA, it produces the same pro-social behaviors as when you give it to a human or a mouse, right? And so what that's telling us is that there is a serotonin transporter in an octopus brain, and that serotonin's function as a encoder of sociality is so old that even though our last common ancestor with an octopus was, like, 650 million years ago, right? Like, we are more closely related to a starfish than we are to an octopus. And yet, all you need to do this remarkable MDMA pro-social psychedelic thing is that same binding site, which comes down to the molecular level.

- [Steve] So many questions, right? She gave MDMA to an octopus?

- [Anne] What is an octopus on ecstasy even like? Eight arms and a lot of hugging?

- [Steve] Well, you'll have to wait to find out, because that's in an upcoming episode in our podcast feed.

- [Anne] You're listening to "Luminous," Steve's series on the science and philosophy of psychedelics. And while we're waiting for the lowdown on octopuses, there is more online at ttbook.org/luminous.

- [Steve] "To The Best Of Our Knowledge" is produced in Madison, Wisconsin by Shannon Henry Kleiber, Charles Monroe-Kane, Angelo Bautista, and Mark Riechers.

- [Anne] Our technical director and sound designer is Joe Hardtke, with help from Sarah Hopefl. Additional music this week comes from Kai Engel, Nctrnm, Psychadelik Pedestrian, and Arvo Part. Additional footage courtesy of ITN News and Amanda Feilding.

- [Steve] I'm Steve Paulson.

- [Anne] And I'm Anne Strainchamps. Thanks for listening.

- [Announcer] PRX.