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Episode 51: Robin Carhart-Harris: The promise of psychedelics
258 Plays1 year ago
Joe and Rolf talk to psychedelic researcher Robin Carhart-Harris. Robin is at the cutting edge of research on the therapeutic benefits of psychedelics such as psilocybin (magic mushrooms), LSD, and DMT. He discusses psychotherapy and the unconscious mind, models of what psychedelics are doing in the brain, and many other topics. A really fascinating and in-depth conversation.
You can find links to his published research as well as a series of videos on harm reduction at the following link:
https://www.carhartharrislab.com/
Special Guest: Robin Carhart-Harris.
Recommended
Transcript
Introduction to Hosts and Guest
00:00:07
Speaker
Welcome to Cognation. I'm your host, Ralph Nelson. And I'm Joe Hardy. Our guest on this episode is Dr. Robin Carhart-Harris.
Dr. Carhart-Harris' Research Focus and Role
00:00:17
Speaker
Dr. Carhart-Harris is the Ralph Metzner Distinguished Professor of Neurology and Psychiatry at the University of California, San Francisco, where he heads up a lab that focuses on human neuroscience and psychopharmacology.
00:00:30
Speaker
Robin is best known for his groundbreaking research on how psychedelic substances affect the brain and how they could be used as treatments for mental health issues such as depression. And for my money, Robin is simply the world's leading expert on the effects of psychedelics on the mind and brain. Robin, thanks for coming on the show.
Early Academic Journey and Influences
00:00:50
Speaker
Well, thanks for having me on, Joe. Yeah, good to be with you guys.
00:00:54
Speaker
Robin, we wanted to start off by asking you a little bit about your background in terms of what you studied in school and how you got interested in the area that you're focused on now. Sure, gosh, school. Yeah, well, let's see now. I wasn't particularly studious at school, but when I discovered psychology, apart from physical education and
00:01:22
Speaker
Yeah, that was a topic, and I guess science as well, in my teens that I really felt drawn to for the first time, a topic that I actually enjoyed learning about. In the UK, it'd be A levels, pre-university. One of those was psychology, the other one, sociology, and then chemistry. You might see a certain combination there and how it might make sense.
00:01:52
Speaker
But yeah, I was deeply drawn to wanting to understand the mind and then in time drawn to understanding the brain. And even though there are a few missteps here and there, I was initially enrolled to do a degree in biochemistry that just didn't quite do it for me. I really wanted to be learning about the brain
00:02:21
Speaker
The things just didn't really fall in my favor and I led towards doing that biochemistry degree I dropped out of and then was lucky enough to go again and did a psychology degree. And after that, I'd long been interested in depth psychology, so psychoanalysis, the likes of Sigmund Freud and later Carl Jung and others. And so I was enrolled to do a master's in
00:02:50
Speaker
I think experimental psychology or applied psychology and went to the first lecture and it wasn't fun. It was stats heavy and I was really, you know, drawn towards the blood and guts of human nature. And I noticed that there was another master's program in psychoanalysis. So,
00:03:18
Speaker
I inquired about that, I went to the first lecture, it was on totem and taboo, Freud's totem and taboo, fascinating paper on the origin of human consciousness, hypothesis about that. And I was sold and so I changed my masters to psychoanalysis.
Discovery of Psychedelics and Academic Pursuit
00:03:37
Speaker
And during studying psychoanalysis, I was in a seminar one day and was, the topic of the seminar was
00:03:47
Speaker
ways to access the unconscious mind. And so we went through dreaming and bungled action, slips of the tongue, free association, even the pressure technique that Freud used early on, you know, touching the forehead now you'll remember kind of thing. Talk about priming. Or inducing maybe false memory, I don't know. But anyway,
00:04:14
Speaker
When you're left with those options, they just seem deeply flawed and limited. And so it helped explain, in a sense, why psychoanalysis was so fringe and not generally regarded as science. And so I asked, what about a drug? If this thing exists, and we're all here because maybe we have a hunch that it does exist, meaning the unconscious mind, then we need something better than dreams is the royal road,
00:04:44
Speaker
You know, I think we can do a little better given, you know, errors in recollection or the dream reports come after you wake up and memories are vague and so on. So what about a drug? And so this, you know, the seminar leader was like, oh, how interesting. And I was like, OK, what next? And so it sort of lingered as a thought. And as soon as I got back to my on campus room,
00:05:13
Speaker
I looked this up and found Stan Groff's book, Realms of the Human Unconscious. That was a pivotal, I would say life moment, was, oh my goodness, there is this. And the subtitle of that book, Realms of the Human Unconscious, Studies with LSD, I think it is, or Human Studies with LSD. And I was just like, oh, wow. And then I got that book out of the library
00:05:42
Speaker
I devoured it, probably scribbled all over it, which is what I tend to do. And yeah, and which has got me banned from from libraries before, but not something to be proud of. But yeah, that was my that that was that was a life that was a pivotal moment. And then, you know, discovering that literature, I then became very single minded, like a mono mania in a sense. And I
00:06:12
Speaker
I went looking for somewhere in the UK to do a PhD on psychedelics. And through some Google searching, I found two names that seem promising. One was David Nutt at the University of Bristol running a psychopharmacology unit. And the other one was a lady, literally a lady, you know, sort of aristocracy.
00:06:42
Speaker
Amanda Fielding of the Beckley Foundation and write to them both and things came together. And I did get my foot in the door to do a PhD with David and his group. It wasn't strictly sort of entirely focused on psychedelics. It was actually focused on MDMA and its impact on the brain, on serotonin functioning, using sleep as an index of that.
00:07:11
Speaker
But it was said to me sort of implicitly that this was about me getting my foot in the door. And if I bided my time, then maybe I could get to do what I really wanted to do, which was human functional brain imaging with psychedelics.
Personal Experiences with Psychedelics?
00:07:31
Speaker
That's how it all started.
00:07:34
Speaker
Interesting. So in that context of that work, if you don't mind me asking, did you have personal experiences with psychedelics? And how did that impact, if at all, your interest and study of the topic? Well, it did. I left that out. And my policy is to be intentionally vague on it. So if it's all right with you, I'll be intentionally vague and say I had some experiences. I was a curious
00:08:03
Speaker
curious young man, curious teenager, and that curiosity, you know, drew me into an interest in the mind and these compounds, yeah. We won't force your hand on this one. That's all good. That was vague, so it sort of works, and you don't have to edit that out.
00:08:24
Speaker
And I want to get to a lot of evidence that you found for effectiveness of these drugs. But first, I'm really interested in the idea that your study was in the area of psychotherapy at first. So that sort of laid some groundwork for the way that you think about these things. I wonder if you could say something about how you conceptualize what the unconscious mind is.
00:08:52
Speaker
Do you think of it as an active agent in the sense that Freud thinks about the mind repressing and having certain defense mechanisms? Do you think about it as the accumulation of all of the biases that we have in everyday life? Or what's your conception of the unconscious? And how does that play into the way that psychedelics might access it?
00:09:23
Speaker
Yeah, I mean,
Unpacking the Unconscious Mind
00:09:24
Speaker
I'd say the unconscious is an umbrella construct. So that means a lot falls under it, which means that it's going to have a few different aspects. And will, you know, with that umbrella qualifier, that it's abstract. So it's not as concrete and pinned down as as other, you know, constructs and phenomena in the world.
00:09:53
Speaker
And maybe with that specific term, the unconscious, it's created a bit of a problem for people in terms of understanding what it is, because it's very hard and specific in saying it's about things that you're not fully conscious of. If that was true, absolutely, then we could never get to know it, and we just have to give up. So it's not that.
00:10:18
Speaker
It's not as strict as that because the unconscious can become conscious and can impact on our thinking and behaviour in ways that sure, we're often unconscious of and so that influence is implicit. And yes, you brought up repression in psychanalysis, that would be the dynamic unconscious, the sort of pushing out of conscious awareness
00:10:47
Speaker
things that, again, psychoanalytic, maybe ego-distonic or unwelcome to the ego, to the conscious mind and self-schema, you know, how we think of ourselves. Maybe injuries and adverse experiences, psychological injuries and adverse experiences that we've had in our life.
00:11:17
Speaker
are the kind of things that can get pushed down, pushed out of conscious awareness, so repressed. So the unconscious, I tend to think of as a system, and this is where we start to focus in and get a bit more specific and more specific to the question, how do I think of it? As a system, and in Freud's work, you see this evolution into him referring to it as the system unconscious, the system unconscious,
00:11:46
Speaker
that later became what he called the it. And then in the English translation, that. It's not it. Yeah, it's not ID. It's
Psychedelics and the Mind
00:11:58
Speaker
ID. Yeah, it's the it does. Let's see. That's S in German, as distinct from Das ich. So the I. So Freud never used the words ego. Is that maybe Greek, ancient Greek?
00:12:15
Speaker
and id, he used the it and the I, I, the letter for self, the personal pronoun, I. And so people say, you know, Freud has more poetry in German and it was a little more, you could say specific and less sort of abstract. So that system unconscious became the it.
00:12:40
Speaker
And that's how I think of it. I think of it as a primitive mode of consciousness, a system, you know, governed by dependent on a primitive mode of brain function that as we evolved, as a species became, it remains core to who we are and what we are.
00:13:08
Speaker
became overridden by this hyper associative and analytical mode of mind that comes with what we now refer to as ego and the capacity to self reference, to have a sense of self, to have a quality of consciousness that is distinct from other species. I could commit to that claim.
00:13:37
Speaker
you know, underneath that is this more primitive mode that I would associate with the system unconscious, the functioning of that system. So there are other terms in psychoanalytic psychology, and more specifically Freudian meta psychology that are relevant. And one of them is primary process thinking, which Freud associated with
00:14:07
Speaker
uh, with the dream state and other altered states. Um, and, and that mode of thinking of cognition is what he would associate with the system unconscious. Um, so, you know, this is where I, this is probably my favorite aspect. I like a lot about psychoanalysis. I like the poetry, but I also like how Freud was thinking mechanistically. He was trained as a neurologist.
00:14:35
Speaker
was a physician, and, you know, trained with, with quite an eminent neurologist. So he was kind of thinking anatomically and mechanistically. And I can see that kind of undercurrent throughout his work, and I've taken quite a lot from it. Of course, you know, he was writing at the end of the 19th century, you know, into the early 1900s. So
00:15:04
Speaker
What did we know about the brain then? Not that much. We were just starting to feel our way in the dark. One of the things you mentioned too is about dreams being a way that Freud talked about accessing the unconscious or the royal road to the unconscious. And another perspective on
00:15:25
Speaker
What dreams are doing, Alan Hobson talks about dreams as being essentially the synthesis of random firings in the brain, that the origin is not an act of unconscious, but just a random process, and this gets integrated in some sort of way. Yeah, happy to comment on that. I mean, Alan Hobson, I got to know when I was
00:15:53
Speaker
In London, he befriended Carl Friston. And so I got to know him a little bit in person. And Alan Hobson was an inspiration early on for me reading popular neuroscience books. He had one called the Drug Dream Store, I think it was. Does that work? Or the Dream Drug Store? Maybe that works better. Which had some playful ideas about the action of LSD in there.
00:16:23
Speaker
and that maybe the LSD or the psychedelic state is like a waking dream. So yeah, Hobson was, in a sense, giving me some stuff, some clues, but I fundamentally disagreed with him on his view of Freudian psychology. It's a classic. And many people do, I know. It's certainly not consensus at all. No, it's not. And I don't think it will stand the test of time.
00:16:51
Speaker
Uh, you know, the dreams are random and have no, I, he even contradicts himself. He's written books on his own dreams that are very thick with, you know, emotion and personal significance. I, I just think, I mean, it's the
Challenges in Psychedelic Research
00:17:06
Speaker
classic one that, that psychoanalysis gets criticized for, which is, you know, when psychoanalysis says, oh, there's something going on in, in the domain of like denial or, um,
00:17:20
Speaker
then it's where you can't win and it's a tautology. And of course it would claim that, but I can't help but feel that a lot of that's going on with Alan. I know a little bit about his background and early on, I think some psychoanalytic interactions quite offended him personally. So I think he has a certain personal, emotional bugbear with psychosis. And I don't agree with the view that
00:17:48
Speaker
If you can identify some midbrain nuclei that are involved in the processes of rapid eye movement sleep, you can then extrapolate from that to say that all dreams are meaningless noise. It just doesn't follow.
00:18:06
Speaker
Well, I do remember I do remember it was at the Tucson Consciousness Conference one year when Alan Hobson spoke and I think it was against Mark Solms who is a Freudian inclined and they polled the audience before and after and I think they were swayed more by Solms than by Hobson. I think initially people started out with more of this neuroscientific. They felt it was more neuroscientific, but I think really were swayed a little bit more by
00:18:36
Speaker
uh by Freudian stuff surprises i remember i remember that i wasn't there but i i watched a video of that debate and uh yeah i that is how it came through and you know it's a little bit like the neuro realism sort of inferential that that sort of you know sort of cognitive fallacy in a sense that you can extrapolate from brain phenomenon to brain phenomena to mind phenomena
00:19:07
Speaker
in a one-to-one way. That route is often more problematic actually than in my mind going the other way from mind phenomena or experiential phenomena to brain phenomena. And so, yeah, Hobson took something neurophysiological and then projected it onto psychological statements. I think you'll get a lot of agreement from both Joe and I on that. Yeah, that's a tricky thing to do. Yeah.
00:19:36
Speaker
Well, thinking about getting back to psychedelics and thinking about, you know, uh, brain states and how they map to psychological states and vice versa. Um, maybe it would be good to just get your take a little bit on what are psychedelic drugs and what effects do they have on a person's psychological state? And then maybe, you know, just to tie it together a little bit about how it might be a window or a way to go that conscious to go there. Yeah. I mean, the term itself was coined in.
00:20:07
Speaker
I think 56 or 57 by Humphrey Osman, Psyche Delic, conjoining to ancient Greek words Psyche for soul and then Delic for to reveal or make manifest. And 56, 57, by that time, you know, we've got mescaline and actually the coming up with the term Psyche Delic happened through a really, well, part of the story.
00:20:35
Speaker
involved a dialogue between Otis Huxley, who had been turned on, the British author, Brave New World, had been turned on to psychedelics through, mostly through Humphrey Osmond, it seems. Osmond provided Huxley with the mescaline that Huxley took and then wrote about in the famous essay, The Doors of Perception. And
00:21:04
Speaker
So we've got mescaline, we've got foundin, you know, certain cacti, peyote, and san pedro. And then we have LSD, psychoactive properties discovered by Albert Hoffman in 1943. And we're on the cusp, I think, of the discovery of psilocybin and salicin in psilocybin mushrooms. Let's see, I think in the 50s.
00:21:32
Speaker
called Magic Mushrooms in a Life magazine article. So, you know, you have two compounds now that are thought of kind of as prototypical psychedelics, LSD, psilocybin, psilocin as the active metabolite, you know, coming on the scene at more or less the same time, very close in time to the term psychedelic being coined as psyche revealing, soul revealing, mind revealing.
00:22:02
Speaker
Um, and then yeah, sure. Mescaline's a little older, but it made famous by orders Huxley's essay again, written at a similar time. So that was a really hot period for psychedelics. I've given you some examples there of prototypical psychedelics and also the etymology of the term itself. Um, and the term itself hints at the psychological properties or phenomenology of the psychedelic experience.
00:22:31
Speaker
and also will bring us to the psychodynamics of things, you know, in terms of revealing the unconscious, because if the psyche is entirely visible, then we couldn't have a compound, an intervention, a perturbation that reveals the psyche, because it should all be revealed to us, you know. Ridiculous title book was written,
00:22:57
Speaker
in recent years called the mind is flat that basically said there's no unconscious and it's just nonsense. And I think psychedelics offer scientific tools to demonstrate that very clearly that the mind is far vaster, deeper than we otherwise realize if we only have the advantage of normal waking consciousness. So the mind certainly is not flat.
00:23:27
Speaker
But yeah, so there we have some properties, some things said that are kind of poetic. But we also have some pharmacology that we're aware of. And I guess some clarity on the pharmacology really took an advance in the 1980s when it was discovered. We knew for a while that these compounds hit the serotonin system.
00:23:56
Speaker
We just didn't quite know how precisely. But in the mid 1980s, a paper was published that plotted the relationship between the affinity of a range of different candidate psychedelics for a certain serotonin receptor. At that time, it was just called the serotonin 2 receptor. In time, we realized it was the serotonin 2A receptor, because there's also a 2B, a 2C.
00:24:26
Speaker
But it's the 2A receptor. So the stickiness, the binding potential, the affinity for this particular serotonin receptor correlated very reliably. I'm not quite sure what the correlation coefficient is, but it's like something like 80% like solid principle with the potency. And that rule for 2A has stuck as a solid cornerstone of the pharmacology of psychedelics
00:24:54
Speaker
It was added to in the 1990s in a significant way by Franz Wallenweider when he showed that using a antagonist or a blocker of that very same receptor, the serotonin-2a receptor, could abolish a trip, a psilocybin trip. And since then, similar things have been shown with other blockers and other psychedelics in humans and then
00:25:22
Speaker
in other animals where we have like a behavioral index of the animal tripping. It's a bit messy, not super reliable, but they shake their heads, rodents do when they're given a psychedelic and that's thought to be a read out of the psychedelic action. But anyway, so we have these classic psychedelics and we add that qualifier of classic really to talk to compounds like
00:25:51
Speaker
mescaline, especially LSD and psilocin that are direct agonists at the serotonin to a receptor. An agonist is a drug that stimulates the receptor as opposed to an antagonist that blocks the receptor. So I've said a few things about the psychology, the phenomenology of the psychedelic experience, revealing the psyche, revealing the soul, talked a little about
Therapeutic Mechanisms of Psychedelics
00:26:21
Speaker
a bit about the etymology, where the term itself comes from. We talked about some examples of classic psychedelics, mescaline, LSD, psilocybin, salicin, also DMT in ayahuasca, and also their pharmacology, that these are all compounds that will stimulate the serotonin to a receptor. Now, recently, people have wrongly, in my view, attempted to crisp up
00:26:47
Speaker
would dial in our definition of psychedelics by saying we can define them as serotonin to a receptor agonist. I actually think that's problematic for a few reasons. Some people think and believe they've shown that you can stimulate the to a receptor and not produce psychedelic effects. I'm entirely convinced of that yet. I think there might be more to the story that could explain some of the findings there, but even so,
00:27:16
Speaker
It's way too brain-centric. A colleague of mine said to me once, Pedro Mediano, computational scientist and polymath, that the brain is only as interesting as the mind. The brain is only interesting as the mind. It all starts with mind and experience. That's why we're interested in psychedelics, because we know that there's psychological effects. So interesting and weird.
00:27:45
Speaker
kind of unique. But if we only knew that they hit a serotonin to a receptor, you know, particular receptor, so what, so what, you know, it all really comes down to the to the experience. And so that's why I think a definition of psychedelic has to it's essential that it refers also to the phenomenology.
00:28:14
Speaker
So that the phenomenology and the neuroscience are correlated, but we take the phenomenology as being primary, or that's what we care about first, is that? Well, personally, I would use like a two-dimensional definition. I do think speaking to the brain can be helpful in terms of 2A agonism. But we also know that that produces a psychological effect.
00:28:43
Speaker
an experiential effect, a subjective effect that is captured by the term psychedelic, psyche revealing. And maybe, and I know this, this is of interest to Joe, we can, probably all of us, we can induce psychedelic states through other means. And so maybe, I'm sort of thinking on the spot, you know, should we be
00:29:14
Speaker
so committal to say that there is a principal component as really one dimension at the core and it is the phenomenology. I like that way of stating it, yeah.
00:29:26
Speaker
Great, yeah, so that's a great background on psychedelics. And I think moving that forward in time a little bit, thinking about some of the recent findings and some of the work that you've done and your colleagues and others in the field demonstrating that there can be real benefits for some psychological disorders, particularly for classic psychedelics. There's really good research now in depression.
00:29:56
Speaker
you know, it's maybe not obvious that you take the perspective that you were talking about from the fifties and sixties and, you know, and forward that there would be such a benefit. Uh, and so it'd be useful to kind of get your thoughts on, you know, what the evidence that you see today that, that psychedelics may have this benefit and, and maybe a little bit also we can get into. Sure. Yeah. I mean, there were bits of evidence being picked up in the fifties and sixties. It's just the methods weren't,
00:30:26
Speaker
what they are today. We used scales that weren't really scales. They were just sort of questions about degrees of improvement. And then over time, you know, we realized in a sense, the science of psychometric evaluation, standardization and construct validation, all this stuff. Where we get, you know, scales that are sort of quite well calibrated between each other
00:30:53
Speaker
And so we know how to measure something like depression and its improvements. But that's still a work in progress, absolutely. But at least we're, you know, quite a bit further along with our metrics than where we were in the 50s and 60s, where people were doing studies, they just weren't very good. And another thing that happened around the 60s, I think early 60s was that the, you know, gold standard method for assessing
00:31:23
Speaker
the efficacy of a medical treatment started to become established, the double blind randomized control trial. And it happened at a time where the potential adverse effects of psychedelics were being highlighted in the sixties and psychedelics didn't fit this testing model very well.
00:31:50
Speaker
So there was a kind of perfect storm that led to people starting to think that there wasn't a compelling evidence base for psychedelic therapy. Now, fast forward to the present day when we have better methods, better trial designs, and we started to employ those in the context of psychedelic therapy research. And
00:32:19
Speaker
Difficult to know quite where to start. There was a, we call it an open label trial done with psilocybin therapy for OCD published I think in 2006. Francesco Moreno was first author. He doesn't always get the credit he deserves because that was the first clinical trial of the modern era. We had another very impactful
00:32:47
Speaker
important study by Roland Griffiths and colleagues at Hopkins in 2006 that looked in healthy volunteers. They were theology students, I think. I think they were psychedelic naive or mostly, so they'd never had a psychedelic experience before. Given psilocybin, they have these profound mystical type experiences, rate those experiences as being among the most personally
00:33:17
Speaker
meaningful of their entire life. And that makes a big splash. And then we go into like 2011, something like that with Charlie Grove, publishing on psilocybin therapy for end of life distress. This was a placebo control study, I believe, and published in American Journal of Psychiatry. Small study.
00:33:44
Speaker
but promising with drops in depression scores and anxiety scores in this population. That gets a little glossed over as well. You tend to focus a lot on, I suppose the Hopkins work, but, you know, Francesco Moreno and Charlie Grove, very important early papers there. Let's see now, you know, I guess in my own filter bubble,
00:34:14
Speaker
at Imperial College London, we published on the first trial in depression, psilocybin therapy for depression in 2016. That was an open label trial. Open label means patients know what they're getting. There's no blinding. So design-wise, it's less rigorous than a blinded study where you don't know what you're going to get, and it could be a placebo.
00:34:43
Speaker
These can be good designs for sort of finding your feet, demonstrating feasibility, demonstrating that this is safe enough to do in a very vulnerable population. That population was, they had treatment-resistant depression, so they'd failed a bunch of different treatments for their depression. Some had very severe depression. And so, you know, while these days, it's only a few years on, 2023, but then, you know,
00:35:13
Speaker
14, 15 is when we're starting to do the work and proposing it at the time to the UK Medical Research Council as a grant proposal that we won. That's around 2012. I think it's fair to say, quite a daring thing to do and a fair degree of uncertainty about whether indeed it was safe. You could imagine all the fear
00:35:41
Speaker
around psychedelics and do they induce psychotic disorders and all these concerns about the safety. Some degree of concern in our minds very genuinely, but also serious concern in terms of IRBs, the ethics committees that need to approve the study for us to even do it.
00:36:08
Speaker
course, the Medical Research Council in the UK, which is like the UK NIH, assessing whether they want to give half a million British pounds to this study. So we managed to do it, we managed to pull it off and we published the paper in 2016, with quite a modest title around the, I think it was assessing the feasibility of psilocybin therapy in
00:36:35
Speaker
in treatment resistant depression. It might have been proof of principle or something like that. So that gave people confidence, but it was also happening at the time that Hopkins and NYU were looking at depression, depressive symptoms in end of life anxiety with two bigger studies that were placebo controlled that were also, I think published in 2016 as well, albeit a few months later,
00:37:04
Speaker
And that was a, that started to be like, you know, I always think of an auctioneer with his hammer. That was like, boom, we've got something solid now. Um, not just an open label study, but yeah, the open label study was good because of the clarity on the population. This was treatment-resistant depression. It was definitely, everyone had depression, you know, DSM diagnosed.
00:37:29
Speaker
In the end-of-life anxiety work, it was a bit smudgier because not everyone necessarily met criteria for major depressive disorder coming in. But they were very well-designed studies with the placebo control. So the combination brought a real kind of hammer blow of evidence. And since then, it's just been, in a sense, more of the same but better, bigger studies.
00:37:57
Speaker
uh, and clearer evidence. We did a trial published in 2021. Now, you know, we're getting papers into the very top journals. This is the New England Journal of Medicine, which was a double blind randomized control trial in major depressive disorders. So not as specific as treatment resistant depression, but more general, if you want bog standard depression, major depressive disorder.
00:38:22
Speaker
Let me jump in for one second. You brought up the issue of controls, and obviously it's going to be pretty easy for a participant to know whether they got a strong dose of psilocybin or nothing.
00:38:39
Speaker
How does that play out in it? And it's different, of course, than say, control for an SSRI, because it's not obvious, it may not be as obvious to the person that they got the dose. So how is that? How is that typically tackled in in this research?
Managing Expectations in Trials
00:38:55
Speaker
Well, there's a few, well, myth might be a little strong, but misconceptions, perhaps about things like an SSRI trials and the integrity of blinding.
00:39:06
Speaker
So just on that one, I think the evidence is something like 80% successful identification. Okay, so they do in a lot of those trials. I would say that's the myth is that there is blinding integrity and clinical trials in double blind clinical trials. And all of a sudden we do psychedelic ones and the blinding integrity is zero. I would say that in the psychedelic trials, the blinding integrity is very low.
00:39:33
Speaker
most people can guess, especially when they get the psychedelic, not everyone, but most. So sure, we're at, you know, very poor blinding integrity. There are a few tricks we can do to try and maintain that, but people should realize that blinding integrity is a universal problem, especially in psychiatric drug trials. So don't think that this is a special problem with psychedelics. And the other thing is that when you do, you know, double blind RCTs are a game we play,
00:40:02
Speaker
that sounds a little glib and is but it is still what it is like when you're unwell you go to your clinician and seek treatment you get the treatment and you know what it is and so it's an active part of the treatment action that you have your expectations and and there's transparency on what you're getting
00:40:28
Speaker
Now, the game we play in clinical research is to try and control for a potential confounding factor that we know is very potent, which is expectancy, positive expectancy. And you can call that the placebo response. It's really positive expectations carrying a positive response. But like I said, that's part of the naturalistic phenomenon that's always there.
00:40:56
Speaker
But in the game that we play in clinical research, we're trying to, we're acknowledging that that's a thing and then trying to tease apart, yes, but what's extra? Because if we didn't do that, you would, you could sell snake oil. You could just, you could, you know, and that feels ethically problematic. Like your treatment has to be more than just that positive expectation, even though we know the positive expectations of massive things.
00:41:24
Speaker
really potent, we still need something more than that. So that's why we play the game. Now, the question is, is the Double Blind RCT the only game in town to address that issue? I'm not sure it is. The base of all of this is demonstrating that your treatment is more than snake oil. I know I'm being very glib in the language I'm using here, but more than just
00:41:52
Speaker
the positive expectancy action. So it's a mechanistic issue, action. It's the mechanistic action that we're trying to feel more confident about, knowing that there's a mechanistic action called the placebo response. There's a thing that happens there, a process that's mechanistic that causes you to get better, even though you're getting better through the psychology of the positive expectations and
00:42:22
Speaker
that being wrapped up with, of course, biological changes that come with the, you know, circular causality between mind and brain and body. But so then when you realize it's a mechanistic question, you wonder whether yes, the Double Blind RCT is the only game in town to elucidate what
00:42:46
Speaker
the extra is to psychedelic therapy in terms of its mechanistic action and getting people better. So you can do mechanistic work. And that could be things like brain imaging. It could be pharmacological blocking studies. So that's an important point to make. The other one is that if you believe that positive expectation is a major part of any treatment, which it seems to be, then you've got to assess it. You've got to measure it. So if sometimes people get
00:43:16
Speaker
too stuck in my view on measuring the integrity of the blind, in my view, because they're very attached, in a sense, to this gold standard assessment of medical interventions, the double-blind RCT. So they assess the blinding integrity. There's a way to do that, which people haven't always done very well. But what they should also do is measure the positive expectations.
00:43:44
Speaker
We'll just measure expectations, because not all of them are positive. You can also have expectations about side effects. So you've got to do that. And I can tell you, we did that in our double-blind RCT, psilocybin therapy versus s-telepran for depression. This paper is, let's see now, has it been reviewed yet? Hasn't been reviewed, but it's being submitted. Balash Sagetti is the first author. We found, as in the authors on the paper, this was a very,
00:44:13
Speaker
hot one like there was some internal debate in the team and I think collectively this this was a fascinating paper we put together but you know in no small part because the results are fascinating so I'll try and describe them briefly we assessed patients expectations for each treatment they didn't know what they were going to get that's randomization it's a coin flip you know 50-50 chance you get psilocybin in this trial
00:44:43
Speaker
or you get acetylopram. I'm just saying it. Yeah, and acetylopram is SSRI, right? A typical standard kind of. That's right. Yeah. So some people would know it as Lexapro. It's a daily antidepressant pill that you'll take every day for, you know, X number of weeks or months to treat your depression. And in this particular trial, you took it every day for six weeks. You took a good dose of it as well.
00:45:14
Speaker
So that was one of the arms. So at the start of the trial, we asked people, what do you expect in terms of degree of improvement for solitis? Given your knowledge and expectations about that intervention, how effective do you think it will be? And they could do that. There'll be no change in my depression too. There'll be complete remission.
Entropic Brain and Mental Health
00:45:39
Speaker
And they do exactly the same for acetalapra, because they don't know what arm they're going to go into. We don't know what arm. It's before the coin flip. So they do it for both treatments. Then, of course, the coin gets flipped, and they go into one of the arms. And then at the end of the trial, we can assess how well they've done. And we can also track back, now knowing what treatment they had, and look at their expectations for that treatment, and see if there's a relationship.
00:46:09
Speaker
maybe if you have really high expectations for psilocybin, you're the kind of person who's done fantastically well having received psilocybin. What we found was that that wasn't true. These are the results now. So there was no relationship whatsoever. In fact, directionally, it was the inverse of the usual relationship. So no relationship between positive expectations of
00:46:38
Speaker
efficacy or how well the treatment's going to do. We're focusing on psilocybin here, positive expectations for psilocybin and actually how well you did. Like I said, directionally, it was actually in the inverse direction to what you would typically expect. So meaning inflated expectations for psilocybin associated with slightly worse response. That relationship wasn't statistically significant, but it directionally, again,
00:47:06
Speaker
Repeating myself, it was the opposite of what we're used to. Now with acetalopragm, it was exactly what we're used to. Higher expectations, better response, solid across the board for all the measures. So it was a fascinating finding because this has been a spectre that sort of hangs over psychedelic therapy, which is people saying things like, oh, they're super placebos.
00:47:33
Speaker
It's all placebo response. There's no integrity to the blinding. Well, there may be very poor blinding integrity, but now I'm sort of willing to say, do you really think it's compelling that psychedelics are snake oil, that there's no active action to this treatment in improving people's core pathology? I don't buy it. I don't buy it.
00:48:02
Speaker
compelling evidence to suggest that and this particular result supports that.
00:48:08
Speaker
Now, in terms of expectations, of course, if you've never had psilocybin before, your expectations might be based on who knows what, right? Media exposure or something like that. Yeah, Michael Pollan's book. Right, Michael Pollan's book, right, exactly, how to change your mind, yeah. But then you might have, I guess, you might have different expectations, maybe this is hard to say, but you might have different expectations after taking the drug, right?
00:48:35
Speaker
Your expectations about what's happening might be different than I guess you had expected. So after taking the drug, you might think, oh, initially I didn't expect anything, but now I do expect there to have something to have happened. Does it matter that it's just an expectation before ever taking the drug?
00:48:55
Speaker
And I guess another thing might be if people are more familiar with it, repeat users might have different expectations because they have something more realistic to ground it to. I think that's a good point. And it's that expectation is a dynamic thing. It's also locked in a process. So you have expectation prior to any intervention, but then you receive it and all of a sudden you have an action and you're attributing your
00:49:25
Speaker
there's this complex causal interaction between changing expectations, actual effects that you're perceiving. So it's just difficult to tease apart the causation once you start having some actual action as well. So I guess the cleanest way to do that is you've got expectations pre any intervention. And that's the result I was reporting.
00:49:53
Speaker
It is tricky stuff. But also, I think also, I mean, one of the things speaking in favor is, I think, as you sort of mentioned, the effect sizes, that you're seeing pretty large effect sizes on a lot of these, and even especially compared to standard SSRIs. Yeah. I think that matters. We could talk that through a little bit.
00:50:19
Speaker
If you have absolute outcomes, and you know, absolute outcomes is just something like how many people in your population that you had in your trial are now in remission. Let's imagine an extreme scenario, everyone's in remission. You did an open label trial, everyone knew what they were getting, and now everyone has zero on their depressive symptom severity rating scales.
00:50:47
Speaker
If you're being really strict and faithful to the double-blind RCT, you would say you can't infer that the intervention in your trial caused everyone to have absolutely zero depression now. This is a toy example. We don't have an example of something quite like this, but it's an extreme example to make the point. If you had fantastic absolute outcomes, do you not still have fantastic absolute outcomes?
00:51:16
Speaker
I mean, you could be left saying, well, this is just an example of the super snake oil effect. But another part of you would be like, well, we're not used to seeing everyone hit remission. These outcomes are really exceptional. And there aren't many treatments out there that can work as well as this. So that kind of way of thinking has come into this.
00:51:45
Speaker
because we do look at absolute outcomes. We say things about electroconvulsive therapy, very controversial intervention over the time and wrapped up with cultural associations through things like one flew over the cuckoo's nest. But if you look at absolute outcomes, very effective for reducing depressive symptoms severity, electroconvulsive therapy.
00:52:15
Speaker
And so you are left with people making statements in psychiatry like ECT is, you know, one, if not the most effective interventions for depression. You don't say it's the best because people don't like it. It's you into a seizure and all the, you know, um, other sort of side effect issues in terms of like, you know, cognitive, um, negative impact on cognitive functioning and, and, um, yeah, some other things.
00:52:47
Speaker
But what I'm trying to say is that we do make inferences on absolute outcomes. And can we do that with psychedelics? Well, if we do it about ECT and we do it about other things, then maybe we can make those inferences. And so what kind of things can we say about the absolute outcomes? Well, there have been three investigator-led studies in major depressive disorder that have found 70% response rates
00:53:15
Speaker
with one or two interventions at the primary endpoint, at the place where you stick your flag and say, this is the main time since intervention that I'll assess how effective it is. Imperial, Hopkins, and Yale have all done psilocybin therapy studies in major depressive disorder that have found 70% plus or minus a few. This is in people with somewhat intractable depression, really difficult cases.
00:53:45
Speaker
Uh, just bog standard depression. So it's not treatment resistant pressure. And this is major depressive disorder, but typically to do a trial like this, you do have entry criteria of, of at least moderate severity depression coming in. So I think the, the fairest thing to say is this is sort of a generalized, quite a general quality of depression. Um, and then 70% response where responses are halving at least a halving
00:54:15
Speaker
of your baseline scores at that primary endpoint, where you stuck your flag, say, six weeks or three weeks or four weeks after the intervention.
Psychedelics in Treating Depression
00:54:25
Speaker
This is where I'll assess, 70%. Now, that's good as an absolute outcome. It's quite a bit better, maybe about 20% better than what we're used to with SSRI trials in depression. And it's close to what you see with ECT, actually.
00:54:45
Speaker
So that's, that's one thing now investigator led trials are, um, well, they don't have industry bias because the investigator led as opposed to like industry sponsored. So these are all people like me designing a study, yes, get, getting a drug from somewhere, but not being pressured in any particular way by the drug company, just doing your science. So those are the investigative studies that I'm talking about now, drug.
00:55:13
Speaker
Company-sponsored trials have been done in depression as well. You have Compass Pathways have done a Phase IIb study in treatment-resistant depression. So that's the more intractable depression. And then you have Usona, who are an interesting sort of not-for-profit, that have published on psilocybin therapy for major depressive disorder, but not a small investigator-led study, a multi-site study,
00:55:43
Speaker
something like 100 patients in that trial. Though they had different assessment criteria stricter than the ones I've been telling you about, their assessment of response, this is a little granular, maybe too much for your listeners, but their assessment of response required that halving of your score at every single assessment time point up to the primary end point. So it was quite strict.
00:56:11
Speaker
And when they did it in that stricter way, it dropped down to 50% response rates, but it's sort of, you know, what do they say? Apples and Pairs or Apples and Oranges wasn't quite the same test. So it's harder to compare that one. Compass, the efficacy rates were not as impressive as the investigator-led studies, maybe because it was a tougher population, maybe the
00:56:40
Speaker
know the quality of the therapy wasn't as good as in the investigator-led trials, maybe its quantity was a little less, and they only had one single dosing session. So there's a few reasons why I think the response and remission rates in the Compass trial were quite as impressive.
00:57:01
Speaker
Just a brief pause to say that if you're enjoying the podcast, please spread the word to your friends and rate us on Apple Podcasts or whatever you're listening on. You can contact us at cognationpodcast.gmail.com or you can check out our new YouTube channel. Just look up Cognation on YouTube. Thanks for listening.
00:57:22
Speaker
So if we get a little bit out of the weeds of some of the studies, it seems like, I mean, it's been fairly well established by now. And I think we've cataloged a few different psychedelics, psilocybin, LSD, DMT. And there seems to be fairly compelling evidence by now. And I think a lot, thanks to your lab and some of the associated labs.
00:57:52
Speaker
jump in if it's all right. All of the studies I was referring to was psilocybin. And yeah, it was a bunch of people. I mean, we did two trials there in depression. And I guess the fairest thing and the most conservative and sober thing would be to say that the early results look promising rather than rather than compelling. Depends who you ask. You know, the public think it's super compelling.
00:58:26
Speaker
Yeah, sorry. If we leave, I think that's good. I think that's a very measured response. I think, yeah, you obviously don't want to get ahead of anything. But I think by now there's some general consensus that there is something going on. Absolutely. So I think the next step is to talk, I mean, you've done quite a bit of thinking about the mechanisms and thinking about models that might explain what's going on. So maybe you want to get into how effectiveness of these
00:58:46
Speaker
I think it's very promising.
00:58:56
Speaker
psychedelics is working. Yeah, sure, happy to. And this is, of all the topics, well, this is a really juicy one. I mean, there's a few favorites, but the actual action, how does this work, is probably my favorite topic and the thing that I think about most. And just to give an example as to why it's important, and it kind of comes back to that whole kind of snake oil thing a little bit.
00:59:26
Speaker
you know, people use examples like smallpox and, you know, we were able to develop a effective vaccine that eradicated smallpox, at least in the West, through understanding its action. And so that's why action matters. When we understand what something is, like imagine if
00:59:54
Speaker
COVID had happened and we didn't know what the hell it was, then, gosh, the number of deaths would have been way greater than they were, I think it's fair to say. If you look at past pandemics with other viruses and how they wiped out even vaster populations. But by understanding what it is, you can then come in with a targeted intervention.
01:00:24
Speaker
So that's why it's so essential. And then you develop an intervention that is as on-target as it can be with the least amount of off-target action, where off-target can bring in side effects and not bring the desired remediating action. So that's why it's really essential in the context of psychedelic therapy, because you need to know what's doing it. And if you don't,
01:00:54
Speaker
you're going to be sloppy and have a lot of off-target action. Maybe some of that off-target action is expensive, or maybe it brings side effects. So it's all about being able to dial in your medical intervention so that it really does what you want it to do with minimal, not what you want it to do. So that's why it matters. Then we have a few ways to look at this.
01:01:22
Speaker
And this is where the hypotheses come in. And I'll share some of mine that I think is shared by a lot of people in this space, not everyone, but a lot. Most of the people doing the human research and who have done the human research in recent years share these assumptions that I'm going to share with you, which probably the main one is that this isn't about just a drug, a drug action. And the clue is in the name, psychedelic therapy.
01:01:52
Speaker
Some people go as far as to call it psychedelic assisted therapy or even psychedelic assisted psychotherapy.
Plasticity and Change through Psychedelics
01:02:00
Speaker
In my view, that puts a little bit too much weight on the other component and sort of says you just have the drug that's pushing along the psychotherapy. I get that, but I think it's probably better, better principle to think of a synergy.
01:02:22
Speaker
the one plus one equals three in this context. It's not an additive thing, but a multiplicative thing. Maybe three plus three. It's not three plus three equals six, but three times three equals nine kind of thing. You know, you're getting more by bringing these things together. You have a drug that opens up the mind and the brain and it's functioning in their functioning in such a way that gives you a window of opportunity, but then adding in
01:02:51
Speaker
therapy thing, we can call it psychotherapy if you want, we could call it contextual manipulation, because is, for example, music listening, which has happened throughout all of the trials, is that psychotherapy? Well, we do have music therapy, but a bit of a stretch to say listening to music is psychotherapy. So let's call it therapy because it's less committal to, you know, to one component of it, psychotherapy, sure, very important, we assume, but
01:03:21
Speaker
too much emphasis. Psychedelic therapy, that combination where making the mind and the brain more supple, more sensitive, we can bring in plasticity here. And I would encourage people to go with a definition of plasticity, which is very generalised, which is close, if not right on the dictionary definition of plasticity.
01:03:48
Speaker
which if you were to look it up would read something like the ability to be shaped or molded, which is more or less synonymous with malleability. So the ability to change, not change itself, but the ability to change is plasticity. We increase the ability to change, and we marry that with contextual manipulation that is trying to do a few things. It's trying to coax emotional responses.
01:04:19
Speaker
perhaps Coke, Coke's emotional responses with some sensory experiences like visions, sense of wonderment and awe and exploration, confrontation. And we're marrying that, yes, with good solid psychological support, we could call that psychotherapy if you want, and it'll be there
01:04:45
Speaker
It will be there ahead of time to help prep and prime people for the right kind of attitude and willingness to explore, go into the experience. And then we have that psychological support to hold the individual, give them a sense of trust and safety in the experience itself. And then have some aftercare, which is giving space and time
01:05:14
Speaker
for integrating what's come up during the experience so that people can make sense of it, start to plan healthy behavioral changes. Yeah, so it's that combination and the assumptions that we hold at the moment are that it's a synergistic combination. It's not just additive. There's a bit of evidence out there that you get a bit of an additive improvement
01:05:43
Speaker
say a course of SSRIs in depression plus some evidence-based psychotherapy like CBT, cognitive behavioral therapy, you'll get a slightly higher improvement bar or a slightly lower decrease in symptom severity bar if you add the two. It's an additive thing, a little bit more. But with psychedelic therapy, we're assuming we're hypothesizing that you get a lot more when you put these two things in combination.
01:06:12
Speaker
And that's why we think it's potentially quite an advance on current treatments. Now there's a lot more I could say about markers of say that plastic action. Most of the markers that we think of in terms of neuroplasticity come from rodent work and sort of bench work, looking at cells in dishes and sometimes looking in living animals with optical imaging and so on.
01:06:42
Speaker
Very, very interesting, very important. The markers in humans are less nailed down. I can share that we have some promising markers, some functional in terms of changes in brain activity that we're now seeing can predict improvements in mental health outcomes downstream. See the change in activity acutely under drug using recording devices like EEG.
01:07:09
Speaker
You see that effect and then the bigger the magnitude of that effect, the bigger the improvements in mental health outcomes downstream. That particular metric I'm referring to is a measure of signal complexity or entropy. It's the randomness or statistical complexity of the signal across time and in space. So the more complex that signal, the richer that signal,
01:07:39
Speaker
the harder to predict that signal, the bigger is the effect. And that correlates with the intensity of the actual experience, the bigger the trip. And now we're seeing also the bigger the improvements downstream, albeit in healthy volunteers so far. And yes, unpublished, but a work in progress. I call that the entropic brain because the signal complexity
01:08:09
Speaker
is more or less, well, it is synonymous with entropy in the informational or statistical sense as the, it's easy to say random, the randomness of the signal, but perhaps a better way, more accurate way to say is that we're uncertain about the signal or the phenomenon if it's more entropic.
01:08:37
Speaker
it's harder to predict across space and time. In some sense, it's related to information as well, right? So yeah, how much? Because if you've got a single coin with, you know, two sides, that will give you very little potential information because it can only either be a heads or tails. But if you have a system with a huge, you know, repertoire of potential states or sub states, then
01:09:05
Speaker
The potential information that you can get from decoding that system is way faster than a simple coin with two sides. So yes, it's very closely related to the potential information.
01:09:20
Speaker
I think we've talked about this on a podcast before in relation to the idea of criticality too, that as you approach criticality, you're increasing the information and increasing and approaching more chaos at that certain inflection point too. Yeah.
01:09:40
Speaker
Yeah. And I think that your theoretical work on this, Robin, is so interesting because it brings together these domains of complexity theory, some of these neuroscientific measures, EEG, fMRI, and then at the intersection of psychedelics and psychopathology. So it's bringing together a lot of really interesting, exciting pieces of what's the current state of the art in neuroscience right now. I hope so. Yeah.
01:10:10
Speaker
I mean, you know, people have said that maybe information is sort of the most fundamental thing, you know, physicists have said this in the universe that underneath, you know, matter or energy or is the most basic it's it's sort of information or, you know, in meaning in the statistical sense, bits of information.
01:10:38
Speaker
Yeah, and just thinking about how in your work, particularly your paper on canalization and plasticity and psychopathology, you posit this notion of a single factor for psychopathology. In other words, that you can kind of reduce down how psychopathology develops into a single factor
01:11:01
Speaker
And it would be great to hear from you like how you think about that and how that relates to the action of psychedelics and the entropic brain, as you say. And, you know, because I think it's maybe not obvious to someone coming from the outside that, you know,
01:11:17
Speaker
increasing the entropy on it or the randomness or complexity of brain function would actually lead to benefit. Maybe that sounds like something you might associate with actually a negative outcome, but I think your theory pulls it together in a really interesting way. I hope so. I hope it's useful. Yeah, I mean, you think of an entropic mind or brain.
01:11:41
Speaker
And you might think psychosis, you might think chaos in the mind and the brain, that sounds like madness. And I wouldn't walk that back, I would say, well, it may well be that during an acute psychotic episode in a florid psychotic episode, you would see an increase in brain entropy. Yeah, yeah. But is a psychotic disorder like schizophrenia always, does it always look like that? Or does it often look like someone
01:12:12
Speaker
you know, who's retreated from the world, who's developed some fixed illusions, who in a sense rather than being in a hot state is in a very cold state. And so it's very state-specific psychotic disorders, I think. And so, yeah, so there's that. Something like depression is more obviously a cold state. And yeah, I am using the analogy of temperature here, but it sort of works.
01:12:41
Speaker
You know, you get frozen in a sub-state, again, retreat from the world, retreat from things that used to give some pleasure or engage some interest, and sort of stuck. And this stuckness is what's at the heart of this canalization idea, where canalization was a term introduced to me through Carl Friston,
01:13:10
Speaker
the neuroscientist and then I went down the rabbit hole of looking into this thing and found Comrade Waddington's work on energy on the epigenetic landscape where he presented this famous, now famous, at least in science, Waddington landscape
01:13:41
Speaker
which looks like a kind of, you know, descending sort of mountain scape with valleys and then you have balls that get stuck in the valleys and that's the canalization. But there's actually an even more interesting geeky history here where the origin is Henri Bergson of Elon Vital and other interesting ideas who introduced the analogy of the canal. The canal is cut
01:14:10
Speaker
is something cut into the earth, where the dynamics in that system are all one way. There's no freedom. All the waters got to move in this particular direction, enforced by the constraints. Now, it was Norman Whitehead, the philosopher, also talked about canalization, inspired by Henri Bergson. But Waddington picked it up in the context of genetics and epigenetics,
01:14:39
Speaker
you know, phenotypic development where it was basically saying, you know, properties of an organism, phenotypes, can get stamped in into our genome in such a way that they don't change from, you know, generation to generation. We typically have, you know, two arms and two legs and so on.
01:15:03
Speaker
And that's an example of certain properties that get canalized, that get stamped in. Canalization formally is the inverse of plasticity. So rather than being
Personal Perception and Psychedelics
01:15:17
Speaker
the ability to be shaped or molded or to change, and how that is going to interact with environmental pressures, where if you're
01:15:29
Speaker
very changeable or very malleable, what's happening in your environment is going to have a more exaggerated influence on you. That's plasticity. Canalization is a resistance to change. Now things have become entrenched and stamped in where whatever happens in the environment, you're going to have two arms and two legs or what have you. So I use that theme. Carl put me onto it.
01:15:55
Speaker
I can't quite remember what the original seed was that he gave me. He certainly gave me the term to then go and look up. But I could see that that could apply to psychopathology and a lot of it, whether it's depression where you get stuck in a negative cognitive bias, you retreat from the world very generally, retreat into your head.
01:16:18
Speaker
or eating disorders, anorexia, the caloric control, you get stuck on that, obsessive about that. Or addictions where you get stuck on some objects of relief, a drug, for example, and there's craving for that thing. And so your repertoire of potential state space is now constrained into, I just need to gamble,
01:16:49
Speaker
get the drug or get a drink to let's see obsessive compulsive disorder where these intrusive thoughts I just need to clean my hands or you know it's it's just it's it's compulsive to specific anxiety disorders you know I guess social is quite general but if it's a phobia it's very specific
01:17:18
Speaker
And so again, there's a constraining of the state space around whenever I encounter whatever it is, it's just an overwhelming terror. So all these things are characterized in a sense by an over-learning. And this is, I think, an important twist because when we're taught in neuroscience, we're often taught about the Hebbian plasticity, the associative plasticity, and how it's the cornerstone of learning.
01:17:48
Speaker
And we tend to think, oh, well, that's a good thing. That's a good thing. More of that. And we measure that. We can measure that. We can show development in certain synaptic properties through these associative processes. But it's an interesting pivot to say that actually might be ill health in terms of psychiatric disorders, where there's an excess, there's an overshoot
01:18:17
Speaker
heavy and mechanisms for whatever reasons. And we could go there. Why does it happen? But I think it happens. And then we entrench in certain ways of thinking and behaving. And that becomes the problem. And that's the problem in, I would say, most of psychiatric disorder, not all of it. You know, earlier on, we talked about the hot state of a Florida psychotic episode.
01:18:45
Speaker
You know, there might be some other examples of exceptions to the rule, but, you know, all rules are rules. They're models. They're not necessarily true, absolutely. They're just models that are designed to capture something, not everything. And so I think this, that's what I proposed in that paper is that the principal component of mental illness is the entrenchment of certain ways of thinking.
01:19:14
Speaker
and behaving, the canalization of thought and all that.
01:19:17
Speaker
Yeah, so that's really intuitive, I think, from my perspective, that you get stuck in certain ways of thinking, reacting to stimuli that become over-learned. We had, back in 2006, I think it was, when we were doing cognitive training research, Michael Mersnick and Henry Manka and others, including myself, wrote about negative plasticity, this idea that you can
01:19:47
Speaker
really is fundamentally a Hebbian type of learning, which for those who aren't familiar with Hebbian learning, it's basically the idea that when there's associative learning in the nervous system, when two neurons are active at the same time, they tend to become associated, you know,
01:20:05
Speaker
Further associated in subsequent firing. So the colloquial phrases, neurons that fire together, wire together. So that's the Hebbian process. The idea that through this process of what might be in a certain moment, adaptive response over time gets rutted into your, to use your term, canalized into a negative overall response. And it becomes very difficult to
01:20:33
Speaker
dig your way out of that. So our approach was to try to step by step through inverting that with positive plasticity, using more of a Hebbian approach, more of a learning approach, try to dig your way out of that. And there's some interesting research in schizophrenia, for example, using that approach, which has been shown to be somewhat effective.
01:20:54
Speaker
But the approach of psychedelics is rather different. And the plasticity that is implied by that is quite different. I guess in a psychotherapy like cognitive behavioral therapy, it might be something like, weaken this bad association, strengthen this association. And so it's still maybe somewhat hebbian
01:21:22
Speaker
you're trying to depotensiate the negative thing and potentiate a different positive thing. I just say self-esteem, how to look at yourself. Depotensiate the negative way of looking at yourself and potentiate a positive way. I guess psychedelics are very generalized in their action on plasticity. It's a very generalized pro-plasticity effect is how I see it, where it's all about the potential for change.
01:21:51
Speaker
And then you realize why it matters what you twin with that window of elevated potential for change. It's like essentially important. So this is a great point. So the idea, so just the pure idea that what psychedelics are doing is increasing plasticity. What are the parameters around something like that?
01:22:20
Speaker
because I don't think you would want to take LSD and then go work on your tennis game, right? Because there are probably certain things that it's useful for changing, for decanalization or whatever, flattening out some of those canals or reshaping that landscape a little bit.
01:22:42
Speaker
But also, if you're on LSD, you're probably not in a state of mind to be changing just any random thing. It's a very particular state. So what are the parameters around plasticity here? What sorts of things is the mind ready to change and learn? Well, it's a great question. I think the first thing to go to is dose.
01:23:10
Speaker
And it's possible, at least it's theoretically possible that you could take a low dose and work on your tennis game or some other habit. And I'm sure that's the promise for people who are microdosing is the idea that you can gain some of this brain plasticity without being interfered with mentally. Yeah. And I think as a colleague of mine, Adam Ghazali, said,
01:23:38
Speaker
He used the analogy of steroids. You don't just take the steroids and expect to get big, you know, you take the stories and twin it with the training. And it's a similar thing with microdosing. I think it then dawned on me that absolutely that's so true. It would be, it's sort of a training opportunity. And that's still theory. It hasn't been tested, but that's what rings true in my mind. You could take the low dose. The dose would be not so high that it knocks out function in a generalized way.
01:24:07
Speaker
and you get that generalized deficit compound where you just can't function because you're tripping balls. But if it's a little bit, maybe you could feel more in your body when you do your golf or your tennis and start picking up on some of the skills that you were picking up on, but now with a little bit more malleability in the body and the mind and the learning apparatus. And so it's a very juicy idea. And let's see where it goes, but I
01:24:37
Speaker
I would love to do a trial there. Of course, all these things are funding dependent. And I can't do that right now, but someone should and will do a trial around microdosing and training. But thinking about, you know, you were talking about microdosing, but back to macrodosing in the context of a therapeutic setting.
01:24:58
Speaker
you have this model that you're talking about called temp. And it would be, I think it's very interesting, you know, the relationship between
01:25:10
Speaker
you know, taking a moderate to high dose of psychedelics, and how, and this notion of entropy, and then how that relates to this landscape, you know, this, this, this landscape that, and sort of, yeah, flattening of that landscape. Yeah, and to call it temp was intentional, because it sounds like short for temperature. And in fact, the tea is temperature by entropy mediated plasticity, I think it is.
01:25:39
Speaker
where it is using that analogy of heating something up so that you increase the energy in the system such that you can go from, say, a solid state to a more liquid state. And that's the idea with the macrodosing. It's a more dramatic liquefying in the sense of the system such that everything's uncertain now.
01:26:08
Speaker
even the very core sort of model or assumption that we have in our minds during normal waking consciousness, as exemplified by use of the personal pronoun, I, that starts to break down to and that's ego dissolution. So in a sense, it all breaks down and everything is uncertain. And, you know, in that chaos,
01:26:36
Speaker
really capturing part of the essence of the psychedelic experience of these macrodose ranges and those are the doses that we're using in the psychedelic therapy and sure that sounds a bit like madness that sounds like some kind of delirium that doesn't sound nice and it doesn't sound good I think often it's not nice you know these drugs aren't self-administered by animals they're not classic hedonic drugs
01:27:05
Speaker
people don't take them because they feel really good in some simple way. Like they generally feel good if they have a drink or, you know, they would have something like a stimulant or an opiate. It has that sort of valence bias that it tends to feel good. I don't think so necessarily with psychedelics. I think they're quite valence non-specific. And if anything, more aversive than hedonic drugs.
01:27:33
Speaker
But yeah, so that said, everything's breaking down. Everything's breaking down. And there lies, you know, there starts opening up some uncertainty in my mind, to be honest, about, you know, the next frontier in understanding action. The entropic brain was characterizing that breakdown of stuff, you know, introduced this thing called relaxed beliefs under psychedelics or rebust.
01:28:01
Speaker
which is again about the breakdown of stuff. It's about our confidence in our assumptions breaking down. And it says that goes hand in hand with the entropic effect. Entropic effect happens and that looks like this drop in our confidence, you know, and to use the language of Bayesian
01:28:30
Speaker
inference, it's the precision waiting of the priors, which is a fancy way of saying something which is way more accessible, it's our confidence in our beliefs. And that confidence decreases, so relax beliefs under psychedelics, just an effort to make it more understandable to more people. It's the same principle. So these are breaking down things, you know, but there's that very interesting question of, is that all
01:28:59
Speaker
the psychedelic state is. Or as Carl Jung says it, you know, in all chaos, there is cosmos in all disorder, a secret, in all disorder, a secret order. You know, that's him being very poetic about his principle as things break down, stuff can come up. And, you know, again, I don't think we call
01:29:27
Speaker
we'd have a different name for these compounds than psychedelic, psyche revealing. If all it was, was, you know, the breakdown of stuff, it would be more like psyche, you know, dissolving, but we don't call them that, you know? So yeah, the cosmos in the chaos is the thing that I'm, I'm fascinated about how we might capture that. You know, we measure, I think we measure aspects of this in,
01:29:56
Speaker
some subjective ratings around things like psychological insight, where scores on psychological insight rating scales now seem to predict improvements in mental health outcomes downstream. But in the brain, in the dynamics of the brain, what is that cosmos? What's that secret order that comes in?
01:30:26
Speaker
alongside the disorder. One thing that occurs to me as we're talking about this now is, you know, there's another analogy that we sometimes use, which is like shaking the snow globe, which, you know, is that same idea of like creating this chaos in the brain and reducing your beliefs, making, you know, making manifest the notion that you don't really know what things like what you are, like what the world is and what your relationship between you and the world.
01:30:53
Speaker
I mean, to me, that was the thing that when I discovered psychedelics and, well, at least certainly when I did LSD for the first time.
01:31:01
Speaker
what I discovered about myself was that my understanding of the world was mediated through my senses. Simple thing, like Newton says, the rays to speak properly are not colored. Kant speaks about this as like, you can't know the thing in itself. But that realization was so imminent for me that it completely opened my mind to the world around me as being
01:31:31
Speaker
to question my assumptions about the world around me and particularly the negative assumptions, but just in general made me more curious and open. So I wonder about this concept of openness to experience as being like an opening. And this is something as I've been talking with a lot of people in interviews recently about
01:31:51
Speaker
their moves towards better approaching their mortality and thinking about that. This idea of being more open to the possibilities as being actually profoundly comforting in a way. And so maybe there's something in that as a linking principle, this idea of how it can
01:32:14
Speaker
can tend to be positive, although we can obviously also see in this conversation that it doesn't necessarily need to be positive, right? It can definitely be negative. Well, there's a lot in that. There's so much. It's hard to know now where to go. But yeah, that principle of our experience of the world being generated. Where did that quote come from? Sorry, was it?
01:32:42
Speaker
Yeah, it was new to, uh, so sir, Isaac Newton. Uh, so I, my, my background is in color science and Ralph also did color perception. So we always go back to that one, but yeah. Yeah. Colors depend on our perceptual apparatus and the, yeah, I guess the wavelength of the light and all that kind of thing. And it's, uh, in, in and of itself, they don't have that intrinsic property. It's all dependent on the how it's received by the perceptual apparatus. So.
01:33:09
Speaker
Yeah. And the, you know, the hierarchical predictive processing model, this model of the brain and the mind as generating our experience of the world, rather than receiving the world, we generate it actively. The so-called generative model is the same kind of thing. And another sort of simple way to put it is that in this
01:33:38
Speaker
handshake between world and brain. Brain is dominating or the top down is dominating. Again, to that principle that we're generating our experience of the world, we don't realize it until that generative mechanism breaks down in some way. And then when that happens, it's like, wow, I didn't even know I was blind to that one. You know, talk about a blind spot. And I guess that's the
01:34:09
Speaker
systemic development or transformation that can come with psychedelics. It's like, it's like a knowledge that maybe you always knew, but you were blind to. And it's like insight through things coming down, rather than things coming up, like, you know, an earthquake knocking down a cluding structure so that you can see more. So that might be a part of the clue as like, you know, the cosmos in the chaos is like, oh,
01:34:39
Speaker
with things coming down, there's like a flattening and an opening up. There's an opening up now. Um, and, uh, you know, so I think, I think it may well be that. And then the opening up becomes, yes, it's a broader scope now. It's a broader scope. Now it's less pinned down. We think of things like it's less entrenched. Um, and, uh,
01:35:09
Speaker
And it's more, it's like an open playing field or a blank slate. I mean, there is this intriguing thing, you know, I once heard it called by Dennis McKenna as the paradox of ego dissolution, which is that, you know, these drugs psychedelics can cause ego dissolution on the drug, but then it comes back with a vengeance. He was talking about like jumped up egos and, and,
01:35:39
Speaker
that he was noticing actually in the psychedelic community. And so coined this term, the paradox of ego dissolution, I think is quite good. So there's one system that, well, yeah, sure, it breaks down under psychedelics, dose-dependently. And it's hard to find many interventions that can do that as robustly and reliably as psychedelics.
01:36:08
Speaker
It's a lot of training and expertise to achieve that with meditation, for example. But even with meditation, you know, Jack Cornfield says this nicely, there are no enlightened people. There's one of his books, maybe After the Ecstasy, the Laundry, such a powerful statement that he opens the book, there are no enlightened people, only enlightened states. So you can achieve that opening and the
01:36:37
Speaker
uh cleansing of the doors of perception but you come down and they come back you better watch out yeah and i think that's especially true of the ego just recently i was listening actually to a podcast by the santa fe institute the complexity science institute very good podcast i think it's just finished um uh but uh
01:37:05
Speaker
The host was saying something very interesting about systems with memory and systems with nodes that have a long memory or a deep memory are more stubborn and resistant to change. And it just made me think of the ego and the paradox of ego dissolution that that system is so deep. I tend to think that I think a bit anatomically about the ego as well.
01:37:34
Speaker
neuroscientists will be able to follow me on this, like the default mode network into the limbic system, into the medial temporal regions. And like, that's a lot of the brain. And it's not just a lot of the brain in terms of brain mass in humans, but in evolution as well. That's like, yes, you know, human brain into mammalian brain. That's a deep system. That's a deep system. So to think you're going to change that thing, dissolve that thing and it not come back
Set, Setting, and Sustaining Practices
01:38:04
Speaker
Well, you start to realize, of course, it's going to come back and find itself. And maybe we should be glad that it doesn't. Otherwise, what are we left with? Maybe it's not sustainable. It's not healthy to inhabit a state of permanent ego dissolution or something. That does sound horrible. It does sound horrible to me.
01:38:34
Speaker
Well, Rolf and I have an ongoing discussion about this, our views on our own ego, and whether we'd like it or not. I'm all for it. I want to keep my ego. And getting rid of it. But Rolf is at the bottom with his. I really appreciate my ego. I'm not kidding with it.
01:38:51
Speaker
But I think this gets into a couple other very interesting directions, both related to how psychedelics are impactful in the treatment of psychopathology. One is, I think it's just not really mentioned much in the literature, which is how much prior experience a person has with psychedelics and how efficacious the therapy will be. Oh, I could think to some naturalistic research we've done where we
01:39:19
Speaker
We use prospective surveying, so like just online questionnaires to track people before and after psychedelic use. And when we've done that, we have found that experienced people tend to have nicer trips, more positive trips. In terms of improvement, it's tricky because you get the ceiling effect where there's less scope for improvement if someone's wellbeing is already high. But we have found that they have
01:39:48
Speaker
more positive trips, more experienced people. So I don't know. We have done studies in entirely psychedelic naive people. We have seen, yes, we see some challenging experiences, but we have seen the big improvements in mental health outcomes. And actually, we've also seen some brain changes that are really exciting, even anatomic
01:40:16
Speaker
potential anatomical brain changes, which would be quite remarkable. That's a draft that we're working on at the moment. Paper's gone through review. Major revisions, we're coming out the other side, feeling good about it. They could be microstructural changes in the white matter, in the cabling of the brain that happen after your first ever psychedelic experience, high dose psychedelic experience.
01:40:47
Speaker
Yeah, I guess the naive brain and mind is fresher, maybe more sensitive to the impact of psychedelics. Well, I think it also speaks to this idea that we were just talking about of if there's this insight that this veil is lifted, now you can see something real about the world that you didn't know before. Once you've seen it,
01:41:13
Speaker
Now you know it. And like, and you know, so, you know, you talk about Roland Griffith's work and his finding that this is the most, one of the most impactful experiences of someone's life, most impactful spiritual experiences of one's life. That's not going to, I just, I would posit that that's not going to be the case the 12th time they do it. Yeah. Maybe they might inch up a rank if it was a really big experience. But yeah, sure. There's less scope. There is absolutely less scope in it.
01:41:43
Speaker
You know, it reminds me of the Alan Watts statement, once you get the message, hang up the phone. And yeah, the thing is you do forget. And this comes in in spiritual practice as well. Like you might, you might hit something like a, you know, enlightenment like state with some profound meditation and some insights. But then you go back to ordinary samsara, you know, waking consciousness and start falling into the old patterns and so on.
01:42:13
Speaker
Even though, sure, you might have the vision, it is very easy to forget. In spiritual practice, it's more obvious that it requires a practice for the sustaining, for the maintenance of the healthy changes or realizations that have come about through the experience. I have heard that term used in the context of psychedelics as well as psychedelic practice.
Challenges in Accessibility and Affordability
01:42:42
Speaker
I guess the danger is
01:42:43
Speaker
that becomes psychedelic abuse or overuse, but it doesn't have to, you know, it might just be quite sparing use of psychedelics when you fall into that forgetting state, or let's put it into the more concrete space of psychopathology, you know, when you relapse into say depression or back to the addiction, you know, it then makes sense to, in a sense, have the reminder of another psychedelic therapy session.
01:43:14
Speaker
Yeah, I think we're sort of, we're sort of orbiting around this principle of, which maybe takes us full circle back to psychedelic and the definition psyche revealing, that there's something of this action, and of this therapeutic action when it's psychedelic therapy, that is in, that could be characterized as epistemic, like it's an understanding, it's a knowledge thing. And that's maybe where the benefit
01:43:46
Speaker
Yeah, and then we guess the other related question then is around therapy. So, you know, we often talk about this idea of set and setting. And then, of course, within the context of a lot of these studies, there will be one or two therapists present during a dosing, and there will be
01:44:08
Speaker
you know, some kind of a therapeutic process associated with that. How do you think about that process in terms of, I mean, in some ways, if we think about the science of psychedelics as, you know, a psychological intervention, you know, we, there's certainly there's work to be done on the molecules themselves. And there is a lot of work being done there, but it seems like a much, uh,
01:44:36
Speaker
easier place to start, if you will, or yeah, I mean, another place to start would be what, how can we optimize the therapies? And does your work or your theorizing give you any directional sense of where to take that? It's a great point. And there are some ideas that we'll explore. Um, and it brings in some of the practical considerations in a sense, you know, the, the harsh reality of, um,
01:45:05
Speaker
medical interventions, and the medical system, and even more concretely, you know, the cost, the cost of medical care, because we could imagine a kind of Four Seasons model, where, yeah, and you get the drug, but on top of the drug, you, you overlay this, like, paradisiacal scenario, like, I don't know, whatever it is, the most heavenly sort of context that just is really enriched and is,
01:45:35
Speaker
not just there for the session, but extended in time. And you can have as many interventions as you want and as much psychotherapy as you want. But, you know, that's really the private payer model. That's the Four Seasons model that most people can't afford and can only dream about. And that's the harsh reality here because in healthcare systems, whether it's an insurance based one or a public healthcare system, you have someone's got to foot the bill.
01:46:05
Speaker
someone's got to pay for the treatment. And, and so the treatment has to be affordable enough. Otherwise they ain't going to cover it. And that's the reality. Like insurers won't cover psychedelic therapy. That's a very real concern at the moment. So, you know, all, all the work could be done by your maps or your compass or you sign or what have you. They get a license and then insurance companies don't cover it because they just can't see how the
01:46:34
Speaker
Some can work up to make this affordable and coverable. Whereas SSRIs are really cheap and yeah, easy to cover the cost to those. You don't need any psychotherapy, you don't need any professional staff time. So it's a real reality bite for this space. And what do you do with that? So sure, you can get creative and think of the Four Seasons model. And I've been doing that with some colleagues at UCSF,
01:47:04
Speaker
more specifically Neuroscape likes of Adam Ghazali, we developed this really exciting nature immersion project with Louis Schwartzberg and his amazing nature footage and then East Forest and his beautiful nature inspired music and sounds and that combination is really beautiful and yeah we you know that that doesn't have to be expensive it's an audio visual
01:47:31
Speaker
thing that you can deliver through some medium, you know, a decent enough sound system. But that's only going to be, you know, say at the start and at the end of a psychedelic experience. But let's see now. Because of the cost and the harsh reality, technology could come in to help us there.
01:47:56
Speaker
And this is where there's a really interesting tension going forwards, which is that the purists, and I know this having had a bit of a background in psychoanalysis, proponents of psychoanalysis think that we all need, we do, I don't know, need is a strong word, but regular psychoanalytic psychotherapy for many years to be a well enough functioning human being.
01:48:25
Speaker
But of course, very, very few people can afford that luxury. So we don't have that. Instead, within a medical system, we have six weeks of CBT. And even that is a bit challenging to roll out at any scale and make available to large numbers of people. Hence, there's often long waiting lists to have even that kind of evidence-based psychotherapy through your insurance or through a public health care system.
01:48:56
Speaker
So we've got a challenge here, and how could tech help us? Well, I think there are some daring creative ideas around things like machine learning and VR, and providing an alternative to, I guess, an expensive human being. And there are many hours.
01:49:26
Speaker
And this is where we're going. This is where we are going, whether we like it or not, you know, it's similar with say vehicles. I mean, in terms of self-driving cars, they could massively improve road safety matters, you know, deaths and accidents on the road. But the thought of all the vehicles on the road being essentially like machine driven or robot driven,
01:49:55
Speaker
is very frightening for many people. But is there space for some kind of, you know, machine intelligence coming into the psychotherapy space to help us out in terms of the cost of the cost problem with psychedelic therapy going forward?
01:50:15
Speaker
I mean, the other, the other piece of psychedelic therapy cost has to do with, you know, in the model that is being developed now is that it is being done in a medical setting and this, the setting itself is expensive. Uh, you know, so like, for example, a therapist, you know,
01:50:34
Speaker
depending on what kind of therapist it is, maybe not that expensive, actually, you know, like compared to other things that we're doing. But if you do it, especially in a hospital, or even in a, you know, in that kind of a setting, and then you've got all the constraints around that. Yeah, that is, that is part of it. But then, you know, these places for healthcare do exist. And it wouldn't necessarily be expensive for them to retrofit around
01:51:04
Speaker
psychedelic therapy. Yeah, you know, you still go to a hospital or a clinic to, I don't know, have a vaccine or have a lot of
01:51:16
Speaker
Yeah, I guess where I'm going is you've got this approach that's being done more underground, which is, you know, especially, you know, group based, um, you know, kind of experiences where people come together around a ceremony and you know, that is still not cheap, but it's potentially, I just wonder in a regulated system, whether you could have that, but you still go to a license place.
01:51:44
Speaker
It's just within a regulated system, you're, you bring in the regulations because you want a safeguard and the checks and balances can be, you can feel more confident about them. They're not going to be watertight and things can still go awry and that can be bad practice, but at least you have the regulation. You can be, you know, struck off as a provider. There is some oversight of this.
01:52:13
Speaker
Otherwise, if you leave it to Wild West, I think it's quite reasonable to expect that there'll be more cases of sort of bad practice. And so the take home psychedelic model is a very, very challenging one in terms of thinking how that could really happen in a system of scale. I am a little skeptical that that's a real possibility going forward.
01:52:43
Speaker
But people who think that that's the way we need to go with this intervention are the ones who are thinking of stripping away the trip. Let's see how successful they're going to be. I'm a little skeptical on that. Both for its efficacy and even if they get the efficacy, is there still a bit of the trip? Is that really going to be safe to take home? Are there subtleties around microdosing?
01:53:12
Speaker
if you think you could strip away any kind of care. Earlier on, we were talking of like microdosing time, some kind of training. So can you actually get around the fact that you still need to twin the drug with something to get the right kind of safety and efficacy or benefit? Yeah, well, I mean, yeah, as you're talking about that, it makes me think, you know, CBT, for example, cognitive behavioral therapy, which can be quite manualized
01:53:41
Speaker
and delivered with an app, for example, maybe an interesting twin for an ongoing kind of therapy. And of course, in recent years, catalyzed by the pandemic, we have this now. We do so much of our communication remotely. And so maybe some kind of video type therapy could be another workaround
01:54:11
Speaker
I think there'll be a lot of these kind of compromises where, yeah, it might not be the extreme of take-home psychedelics or certainly not take-home macrodized psychedelics. People will still do that anyway. They'll skirt around the system and do what they want to do as they're doing right now. But at any kind of scale within any kind of structured system, I don't see that happening easily.
01:54:39
Speaker
unless people go around the system. Well, we want to be mindful of your time here, and we've been talking for quite a while, which has been fantastic. But I want to make sure that we get to a question that we usually ask our guests, which is, what are you excited about? What's coming up down the pike that you're excited to see experiment-wise or regulation-wise or anything? Sure. Well, I'm excited about a lot.
Harm Reduction and Future Research
01:55:10
Speaker
I've got a few exciting things going on. I've just launched my lab and a website for it, kahaharrislab.com. Nice to get that out. It's something I felt I had to do for a while. So it's not the best website in all. But it's something. And I'll get a bit of help and I'll improve it and enrich the content. It's very informative. I've been on it. It's super informative.
01:55:38
Speaker
Well, I like that I put these harm reduction videos on there, you know, for another project, I created those a few years ago, a couple of years ago, at least, and they hadn't got into the public domain. So I'm pleased to have gotten them in and knowing that psychedelics, you know, do you want to say, do you want to say something about the harm reduction videos? Yeah, they're intended as sort of psycho education around psychedelics. And
01:56:05
Speaker
Knowing that some tragic cases have happened recently with people procuring psychedelics themselves illegally, having experiences, getting into trouble, sometimes tragic cases, loss of life, and suicide as a cause, it really, really tragic. So learning of some of these cases and then just thinking these could have been avoided with better education.
01:56:33
Speaker
Um, that was a strong motivation to just get these things out. Um, even though it's vulnerable when you stick yourself out there, you know, some people could easily be like, Oh, what, why is he an expert on that? You know, I thought he was a neuroscientist. There's different things like that. And so I don't want to over claim on, on the videos. Most of it's borrowed from other people. Um, you know, whether psychedelic therapists like Bill Richards mentored, um,
01:57:03
Speaker
me early on and our team doing the depression work and then I've had other mentorship as well. And then just borrowing from like wise people in spiritual practice. There's a lot of Thich Nhat Hanh in there and Jack Kornfield, Stephen Batchelor, sort of secular, I guess with the exception of those who are a little bit more religious maybe with Buddhism, it's generally quite secular.
01:57:34
Speaker
Yeah, and sort of wisdom teachings inspired. So it's there, it's, you know, take it or leave it. I don't over claim it's just there. And maybe it could be helpful for some people who want to learn about psychedelics and how to mitigate. Well, certainly put some links up on this on with the show notes for that. Thanks. That's great. Thank you. Yeah, and I just completed a book proposal, which is going out, just signed
01:58:03
Speaker
this morning for that, which is nice. Beyond some of my theoretical work on psychedelics and mental health, the canalization model, more or less everything is going to be, I'm going to try and condense it into this. We'll be on the lookout for that. It's probably a few years away from actually publishing and being out there for the world, but it's happening. And the other things, well, I'm doing a study now dosing people
01:58:33
Speaker
Deep fMRI study, what does that mean? It means doing a lot of scanning within the same person and not a lot of people were going deep within given individuals, deep fMRI. We call it insight two, there was an insight one. So there's a giveaway there in that we're interested in the mechanisms of insight. And we're trying to capture sub-states that arise within a psychedelic experience.
01:59:02
Speaker
The psychedelic experience was never one thing. It has many different faces and some quite starkly different faces as captured by the doors of perception, heaven and hell. So this could be quite an advance. As things stand right now, we don't have a handle on questions like, what's a bad trick? What's going on in your brain and body
01:59:32
Speaker
when you're having one of those compared to like surfing heaven on a psychedelic. So I'm excited about that. I've also recently just yesterday connected with someone who's created a, a sort of large language type model for fMRI data, brain LM. It's only just come out as a preprint, but I've reached out and I'm excited about having that call to see if we can
02:00:00
Speaker
use that training essentially to scrutinize our psychedelic data and to see what it'll say or see when it looks at those data. It may well say, I suspect this is weird. I'm not used to this. This is novel. I actually, you know, I felt that that's a thing that we'll come to for a while. And it's psychiatry embrace psychedelics in this
02:00:30
Speaker
so-called renaissance of the last couple of decades, psychedelic renaissance. Psychiatry was pretty quick on picking up on this and publishing it in top medical journals. Cognitive neuroscience has been slower for whatever reason. But I think what might change things is will be the novelty of the action, in a sense, the novelty of the data.
02:00:56
Speaker
Once people start realizing that you see things under psychedelics that are really unusual, you don't typically see that in human brain function. I think that's where there'll be a pivot and there'll be even more interest in the scientific community and psychedelics as scientific tools. And they'll start to realize why they're so important in consciousness science, for example. So yeah, excited about that study. Another study that
02:01:23
Speaker
It's underfunded, but it's an ambitious study to test the assumption that I was talking about earlier that psychedelic therapy is a synergistic thing. It's more than the sum of the parts. And so to test that, you need a certain kind of design that will test for the synergy. And more specifically, you need forearms. You need to control for drug, drug versus placebo.
02:01:51
Speaker
And you need to control for, in a sense, the therapy, therapy, no therapy, or enriched, unenriched. Enriched set and setting, unenriched set and setting. So you need those components to show that when you add in the drug and the enriched, it's a sort of multiplicative additive effect. It's a big change on drug versus enriched versus unenriched. Whereas on placebo, it's more or less kind of the same, not much change. So.
02:02:20
Speaker
to do that you need big numbers and unfortunately it's expensive and we've got work to do there but that's a good way through the approval process so it's fast-tracked we'd be able to start quite soon but yeah we need to raise some money to do it so these things excite me i love being at UCSF it's ideal for me now i love living in the bay area so yeah life's pretty good to be honest yeah i'm very lucky to
02:02:50
Speaker
Well, Robin Carhart-Harris, thanks so much for joining us here. It's been a great conversation. We appreciate you spending so much time with us today. It's been my pleasure.
02:03:23
Speaker
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