About the guest: Joshua Siegel, MD, PhD is a psychiatrist & systems neuroscience at New York University. He uses functional imaging to study the effects of psychedelics and other drugs on the human brain.
Episode summary: Nick and Dr. Siegel discuss: fMRI and how it works; relationship between neural activity and blood flow; functional connectivity & the default mode network of the human brain; the functional effects of psilocybin on the brain; the role that subjective & expectancy effects in psychedelics medicine; and more.
Related episodes:
M&M #173: Psychedelics, Consciousness, Psychiatry, Psychology, Mental Health & the Entropic Brain Hypothesis
M&M #163: Anesthesia, Placebo Effects, Consciousness, Subjectivity, MDMA, Ketamine, Opioids, Psychedelics
*This content is never meant to serve as medical advice
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Joshua Siegel 1:18
First well, when did you start the podcast? It was in the within the first 10 episodes, you had Lisa montegio. Was one, for sure, yeah. And there was maybe, maybe card Harris, I can't remember. There's a couple others that, you know, I was first in pretty early stages of our research at WashU, and listened to those, and they were, like, really useful. I'm very much of a auditory learner, so I love podcasts on these people's papers. But I think hearing somebody talk about their research, you know, it brings it alive in a very different way, you know. So listening to those really, you know, help help me conceptualize how these great thinkers in the field are thinking about some of these questions,
Nick Jikomes 2:21
yeah, yeah. And what's nice about talking to someone too, is, you know, as opposed to reading an individual experimental paper or even a review paper, you know, they they bring to the whole thing the all of the contextual and historical knowledge they have. So it's a lot easier to understand particular findings and particular observations with with all of that context brought to bear, yeah,
Joshua Siegel 2:43
absolutely so, and it's probably more useful, yeah, Brian Roth, I was just checking Brian Roth was another one. Yeah,
Nick Jikomes 2:53
that was an early one I had. So I essentially started the very beginning of 2021, and so those were, yeah, those were among the first ones. Lisa with probably the first episode I did focused on ketamine. And then Brian Roth was, that was a very early episode, I think within the first 10,
Joshua Siegel 3:08
yeah, we were like, just, I just started. I was in psychiatry residency, written some small grants, like pilot grants to do psilocybin, you know, human clinical research at Wash U so we're just and then basically, depending on when it was, we got the grants, and then everything got, you know, frozen with COVID. So then I was just had some time to really immerse myself in the field.
Nick Jikomes 3:42
I see, how did you, how did you sort of get into the field? What was prompting that? Or what were you doing before?
Joshua Siegel 3:50
Well, my background is in Systems Neuroscience and and like basically fMRI and Wash U they have a particularly good, you know, program in resting state, fMRI and and fMRI cognitive neuroscience, and so I had helped build some of the tools For what, what we call precision functional mapping. And, you know, I was really, I was really interested in psychopharmacology, and that was, like the big picture plan was, I want to take these next generation human fMRI approaches and use them to understand drugs better. And it seemed like, you know, I was going into psychiatry and ketamine and psychedelics seemed like the most exciting direction to go with that. So, yeah, I saw some of the some of the card Harris initial papers, and they were, I. Exciting and tantalizing. But I was like, you know, we could take this, I think, quite a bit deeper.
Nick Jikomes 5:07
Yeah, yeah. I want to get into maybe we can start with some methodological stuff to build a base for people to understand some of the recent results you've gotten around psychedelics, so fMRI, functional magnetic resonance imaging. I want to talk about the sort of the specific precision mapping stuff that you just mentioned. But let's just start very basic here. Can you talk a little bit about the basics for how fMRI works and what exactly it's measuring and not measuring?
Joshua Siegel 5:35
Sure? Are we is this official? Oh, yeah, we're going, okay, all right. So it's a indirect measure of neural activity, right? So it's measuring changes in blood flow, and this is the most important caveat to understand about it. And so anything that changes blood flow changes fMRI signal. But the fundamental, you know, assumption, is that if a part of the brain becomes more active, there is a very well oiled machinery that increases blood flow, I mean, down to the level of, you know, a millimeter, basically, for that population of neurons, and the actual increases in oxygenation of blood. So there's this big increase of flow of oxygenated blood, right? And so what fMRI is actually measuring is blood oxygenation, which goes up when there's neural activity. And that's like the first basic thing to understand about fMRI. But then the next basic thing to understand is most of what I do, and most of what we're talking about is this idea of functional connectivity. And this is the idea that if you just look at, let's say, two parts of the brain, you know, let's say one on the left hemisphere. We'll take the visual cortex right left visual cortex and right visual cortex, and you look at the kind of resting fluctuations in this fMRI signal, and what you see is that if those parts of the brain are communicating and are basically co activating, you have a very correlated, You know, up and down fluctuation of this fMRI signal, and that's the two area example. But you can scale that up all the way to the level of the entire brain, and come up with these pretty intricate maps of brain networks, you know. So you scale that up, and you get the visual system, scale it up further, and you have attention systems, motor systems, and then these kind of executive function and default mode network has been one of the big sort of revelations that's come out of this resting state fMRI approach, you know. And so it's a, so it's a powerful Systems Neuroscience tool for understanding, you know, large scale brain in humans, what's going on when you're you know, in under different disease conditions, what's going on under different drug conditions.
Nick Jikomes 8:10
So, so fMRI is measuring, it's not measuring neural activity per se, but the idea is, you know, neurons become more or less active in response to what an organism is doing. So if a neuron starts firing more this is a very energetically expensive process. It requires a lot of ATP, and therefore, when a chunk of tissue becomes more active in the brain, blood flow has to increase to that chunk of tissue in order to reinvigorate the tissue with oxygen and nutrients and all the stuff that's going to sustain that very metabolically expensive process, the information transmission mechanisms of what neurons do. But what we're actually measuring with fMRI is not directly the neural activity, it's the change in blood flow to different areas, which we assume or know to some extent or another, is going to correlate highly with neural activity. That's
Joshua Siegel 9:01
right, yeah, yeah, that's right, if you really want to get into the weeds, which you probably don't. But you know, there's a magnetic pulse that aligns the electrons. And the rate at which deoxygenated blood, the electrons and deoxygenated blood relaxes, versus oxygenated blood relaxes differs, and that's what kind of creates the fundamental contrast of fMRI.
Nick Jikomes 9:24
Are there any are there any ways that the FMRI signal can start to mislead us if we rely too heavily on the assumption of a one to one correlation between blood flow and neural activity? So for example, are there any known examples where you can have more or less purely or largely vascular changes that are actually not so well correlated with underlying neural activity. Yes,
Joshua Siegel 9:49
There absolutely are. And this is one of the, I mean, this was one of the fundamental things that when we, when I started doing psychedelics research. One of the fundamental questions was, these studies have been coming out showing, you know, some cool changes in functional connectivity, let's say some cool changes in, you know, evoked brain activity with fMRI and but at the same time, if you dig into the neurobiology of the five HT to a receptor. This is a receptor that's actually expressed on vasculature as well, and we know that at high doses, psychedelics can be vasoconstrictive, and they can change basal blood flow. They can also maybe change the relationship. What's less known is whether they change the relationship between neural activity and blood flow. But that was, yeah, that was, for sure, one of the big questions. And then, actually, that's been a side project. We have a paper that's under review at Nature Neuroscience right now, which gives a very compelling answer to this by simultaneously measuring fMRI and neural activity.
Nick Jikomes 11:01
Interesting. So, so the so called psychedelic receptor, the serotonin two a receptor which is very important for the effects of serotonergic psychedelics. This is not this receptor is not only located on neurons, it's also located on blood vessels themselves. And so a psychedelic could bind to this receptor on blood vessels and induce changes that you would pick up in an fMRI signal that may not have anything to do with the neural activity in that pixel of the FMRI image.
Joshua Siegel 11:30
Yeah, that's exactly right. I mean, it's, it's expressed in a lot of places, so astrocytes, which they are indirectly related to, you know, vascular responses also have now somewhat lower than the level that the five HT to a receptor is expressed in in kind of pyramidal neurons, which are the primary excitatory neurons in the cortex, but it is expressed in astrocytes, and it has all these different functions. And you know, like a fun thing to keep in mind is that serotonin, so it's, it's a serotonin receptor, right? And then the name serotonin is actually combination of serum and tone, because the way it was first discovered is the fact that it exists in blood and it increases the tone of blood vessels. So, in other words, blood vessels to constrict. So this is like, you know, this is critical information if you're trying to study what psychedelics do, particularly if you're trying to use changes in blood flow and infer that those are representing changes in neural activity.
Nick Jikomes 12:35
And so how do you understand and parse those two things? Is, are the studies that you're referring to the type of work that you mentioned. Is it animal work, where you can simultaneous, you can do both fMRI imaging and direct measurements neural activity using electrodes or things like that.
Joshua Siegel 12:53
Yeah. Well, we have one. So I worked with some, some a group, Adam Bowers, the PI but they have, you know, animal imaging facility, and they can do simultaneous, you know, calcium channel imaging, where you get basically fluorescence anytime a pyramidal cell depolarizes and and blood flow imagery at the same time. So you can get both the neural activity and the blood flow and actually map out the relationship between the neural activity and the blood flow, which you know, like we said, under typical conditions, is very consistent and stable. And so we did some studies assessing if and how that changes with a psychedelic that's like, you know, that's like, step one. If you're going to use fMRI to try to make assertions about how psychedelics are changing brain networks or brain connectivity, you have to know that. You know, Are you, are you looking at changes in blood flow, or are you looking at changes in neural activity?
Nick Jikomes 14:08
And so when you do functional mapping using fMRI, you're using this blood flow signal that's a proxy for neural activity. And you know, when a human is engaged in something, a visual task, or whatever, this will induce different chunks of tissue in the brain to become more or less active, and there'll be, like, a systematic pattern to this, and so you can sort of infer. The idea is that you can infer patterns of literal like anatomical connectivity, essentially from the correlated change of signal in different parts of the
Joshua Siegel 14:41
brain. Yeah, that's right. So, you know, the fundamental idea of functional connectivity is that you can look at resting fluctuations in activity, and from that you can infer patterns of you know, you can infer brain networks. You can infer patterns of connectivity. But then the next step for that. Right is that you know, if you want to understand how a drug is changing brain networks, you can look at how those patterns change in response to the drug, and infer how that drug is altering. And of course, that's, you know, that's the big question with psychedelics. Or a big question is, is, what is causing this very unique, subjective experience that psychedelics produce. And
Nick Jikomes 15:24
one of the things that you you read a lot about in the literature, the FMRI literature, is networks that arise under situations where there's task engagement versus no task engagement. So for example, you know, obviously if you engage someone any visual tasks, they have to look at things and use their eyeballs and their visual system. The visual system is going to sort of light up and be engaged in ways that it wouldn't otherwise be. If you instead give them a task that's an auditory task, obviously, the visual and the auditory systems are going to have different levels of activity reflecting the use of the auditory channel versus the visual channel and so forth. But even if you give someone nothing to do and they're just sitting in the scanner at baseline, there's still patterns of activity there that reflect this non engagement in a task. And that's where you start to think about things like the so called default mode network. So what exactly is the default mode network? How is it discovered? And what is it really
Joshua Siegel 16:21
well, yeah, so, so just to I'm going to start by building off of the first thing that you were describing, because I think it's, it all fits together, right? Which is this idea that even, you know, free of, like, a specific task or a specific, let's say, function, the brain is always, you know, the brain is always active, right? And, for example, when somebody is at rest and not doing anything externally, versus the most demanding cognitive task is maybe, you know, like a 1% difference in actual metabolic and hemodynamic activity in the brain, right? So, the brain is always active, okay? And the the fundamental like way that that the brain is active is that you have fluctuations in, you know, you have collections of neurons that form kind of big circuit, and those neurons are always working together and commuting together, communicating together, and they are fluctuating, you know, in terms of their activity. And they're kind of fluctuating between active local states and and deactivated local states. And so that's the kind of fundamental unit is a collection of, we'll say, 100,000 neurons that are typically very synchronized and CO activating. And then you take multiple units, or multiple brain areas, and they're also, if they are working together normally, for example, you know, the visual system or the motor system, they're going to activate and deactivate and Synchron and so this is this kind of understanding, and the ability that you can measure this with fMRI to a pretty reasonable degree is what has led to us to be able to do kind of a full parcellation of the whole brain and say, What networks are there? What are they doing? And one of the things that's emerged from this, which has been really influential in our thinking about what the brain does and how it works, is the default mode network, and this idea that there's a collection of brain areas. You know, we will stay away from the neuroanatomy. I'm happy to go into it, but we'll just say across both hemispheres and across, you know, from the more anterior and more posterior parts of the brain, collection of areas that are more active by default when you're not engaged in any in any sort of external attention demanding task, which is why it's called the default one over And this collection of areas. And then, when you I mean, the way it was first discovered is that when you had somebody get in an MRI scanner and do whatever you know task, the experimenter told them to do this collection of brain areas actually deactivated and decreased in their activity. But what we what we've now learned, is that what these brain areas are doing is seems to be critical to creating your sense of self, okay? So these, these brain areas, are like defining you know who you are and and allowing you to think about yourself in relation to your environment. So, for example, if you, if you ask somebody, if you give somebody a list of words and ask them which words describe you okay, the when they are picking out words that describe themselves, the default mode network is actually more active. So, you know, this has been a, I mean, why has this been a fundamental discovery? Partly because it looks like many psychiatric illnesses, and probably some, you know, neurodegenerative illnesses really. The fundamentally are illnesses of the default mode network, which fits into a lot of more psychological theories about kind of the role of self and pathology of the sense of self and depression, and, you know, in other psychiatric illnesses, schizophrenia. So
Nick Jikomes 20:17
what would be a sort of an example there? So you know, something that comes to mind for me is when you look at clinical descriptions of what major depression is, things that you know it's often characterized by things like rumination. People are constantly thinking about themselves, and what's wrong with them is, is that kind of the idea here that the system is involved in yourself, your sense of self, thinking about yourself, attributes that apply to you. And if, essentially, if it becomes too overactive or active in certain ways, this results in pathologies where you're, you know, say, negatively ruminating about yourself. And we call that depression. Yeah,
Joshua Siegel 20:57
that's exactly right. Nick and there's, you know, there's been studies showing that in people with depression, who are, you know, ruminators, they are, they have more active Default Mode Network, and they have a more difficult time turning off their default mode network in order to engage in an external task. So, yeah, that's exactly it. The nails on the head, yeah.
Nick Jikomes 21:17
And I would imagine, too, like, on an intuitive level. You know, I think everyone basically knows, or can, can know through introspection, that, if you're just sitting around, it's really easy to think about yourself and your life and this and that, but if you're the more you're engaged in a task, the harder it is to retain that narrative around you and yourself. You know, if you're playing a championship basketball game, you're not really thinking about yourself. You're thinking of, you know, just engage in the sort of sensory motor activity of trying to get that ball into the hoop. Yeah,
Joshua Siegel 21:50
I found that to be interesting to think about, like, when exactly. So, you know, you talk about the flow state. What is the flow state? In a large part, the flow state is like the quieting of the sense of self, right? And so that attention can be completely focused on engaging with your environment. And by contrast, turns out that the majority of time that somebody is mind wandering or daydreaming, the contents of that is deeply related to sense of self, either in the present, in the past or in the future, right? And so that's why just you let somebody mind want, let somebody daydream and their minds wondering, the default mode network is probably going to be more active.
Nick Jikomes 22:40
And so let's walk people through what, what was sort of known in the literature, leading up to some of the work that you've recently done with respect to how psychedelics affect the brain in general, in terms of what we know from functional imaging, but the default mode network in particular, what, what's sort of, what's, what's the field, what are the results in the field that we think are relatively solid there?
Joshua Siegel 23:06
Well, yes, so, you know, there was the idea that psychedelics are in particular, targeting the default mode network. And you know, Rob McCart Harris, who you've had on maybe a couple times as a guest. He both had some empirical evidence for this with some of the first fMRI studies that he did, you know now, going back 10 years at Imperial College. And also built it out as a, you know, as a psychological theory, theory. And this comes to some of these, you know, the entropic brain hypothesis, and some of the, you know, writing that he's done in terms of thinking, putting together, what is the idea that psychedelics are altering the default mode network? And, you know, should we be thinking about how these drugs working? I think at an intuitive level, it makes sense that, you know, they're disrupting a sense of self. And, you know, people report, obviously, ego dissolution and, and that's a core part of the experience. And so connecting that with the default mode network, I think, you know, he laid some of the groundwork for some of those ideas.
Nick Jikomes 24:24
So then, is there any, is there any worry with that pre existing literature? So if we, if we riff on what you were saying earlier about fMRI being it's a, it's a blood flow signal that we're measuring, blood flow is going to correlate quite tightly with neural activity most of the time, but not always completely. And you do have this additional potential problem here with the psychedelics in particular, which is that the vascular system, the blood vessels in the brain itself, are sensitive to psychedelics because they express the five, HG, two, a receptor. Is there any worry that some. The results from the pre existing literature might have some confounds there
Joshua Siegel 25:06
that was certainly a concern, that was certainly a concern. And you know, we did a number of things to test out that idea, including some things that we did in the human study, you know, and also with this particular animal setup where we're simultaneously measuring neural and and blood flow fluctuations. And you know, I think there's two sides to this. One is that there are consistent changes to the impulse response function between neural activity and blood flow on a psychedelic, but they are relatively small. You know, if you look at the sort of shape of the impulse response function, actually it's not even what I expected. It's weird. It's a little quicker after taking a psychedelic, which I don't even know what that means, or how to necessarily think that. Think about it, but it is surprisingly consistent between mice and humans. So you have a slightly faster blood flow response to a change in neural activity. You know, I mean, it's a it's relatively, like I said, Not a huge is maybe a few percent faster and also more transient, so you don't get this longer lasting increase of blood flow. So there's a little shift, and it may account for part of the changes that that we saw in humans, but one of the things that we did in, you know, in the human study, which, you know, I can, I'm jumping at a little bit, I can tell you more about, you know, how the study was laid out. But we actually had people doing some tasks while they were on psychedelics, so we could specifically, you know, show, look, you still get a blood flow response to neural activity. It looks relatively similar to off of drug, and it looks basically like we would expect, and we can actually account for some of the changes to blood flow and still see that there's pretty dramatic shifts in functional connectivity, and you know, in the signal in general.
Nick Jikomes 27:20
What? Are Yeah, that makes sense. What? So before diving into some of the work, the specific work here, I think it's worth mentioning walking people through a little bit when we talk about the default mode network, what are some of the major hubs in that network? We don't necessarily need to go through all of them in complete detail, but what are some of the major hubs, and how do we normally think about the function of these, these different hubs of the network? Hubs of the network?
Joshua Siegel 27:44
Sure. I mean, one of the big ones that's really been of interest in psychiatry and in emotion is the medial prefrontal cortex. And you know, so this is a part of the brain that that seems to be a critical link for one thing between the limbic system, so the, you know, hippocampus, amygdala, which are these sort of emotional and memory hubs of the brain, and the cortex, which is the, you know, higher cognitive thinking. And so a lot of you know, there's a lot of sort of both theories and and empirical evidence about how the you know, cortex relates to these emotional structures, but a lot of that connection is through the ventromedial prefrontal cortex. So that's, you know, that's a hub of the default mode network, and it seems to be, you know, intimately involved in in reacting to emotion seems and processing emotion seems to be intimately involved in empathizing with the emotion of others, for example, and and then you know, other parts of the brain, posterior cingulate and some parts of The Angular Gyrus, which are also have pretty strong links to or pretty strong associations with interpreting, you know, theory of mind, so thinking about what someone else is thinking about, or understanding someone else's actions in relation to your own
Nick Jikomes 29:19
and So, so you published a paper recently in nature looking at the effects of psilocybin on the human brain using fMRI. Can you set this up for us both, sort of conceptually in terms of the types of questions that were motivating this work, and then methodologically, how you went about
Joshua Siegel 29:36
it? Sure. So this was started about, you know, the kind of conceptualization for this study goes back around five, six years now, and you know, at that time, the idea of precision, functional mapping is. Was really emerging from the imaging group that that I had been collaborating with at Wash U and I think that, honestly, that's really the central critical advance to the work. And that's, you know, to put it simply, this is the idea that the way most fMRI studies are done, you're averaging across a group of people, let's say, in condition A, and looking at, you know, how does the brain respond to some variable in condition A, and then how does the brain respond to some variable in condition B? So you take everybody, you know, you take the data from maybe everybody in the first group who's exposed to condition A, and you average it together. And you take the data from everybody in the second group who's exposed to condition B, and you average it together. And the fundamental problem here is that everyone's brain is different and and it might sound silly, almost, but even you know, the best possible technology and techniques that we have for for registering brains together to a common space are still far from adequate, and you know the particular shape of the area in your brain that responds, let's say, to a face, right? You know, you have this well defined fusiform face area, but it's not going to be well aligned to the part of the brain that responds to a face in my brain. So
Nick Jikomes 31:31
you want to align things functionally, but there's not going to be a one to one anatomical correspondence in terms of where these functional parts of the brain are in one brain versus another,
Joshua Siegel 31:41
exactly, right? Yeah. And so precision functional mapping is the idea of essentially doing all of your neuroscience and all of your analysis within the single individual, and only then kind of after you've looked at the effect of intervention comparing Is it consistent between individuals. And so that includes getting much more data on a single subject and following them kind of longitudinally, and mapping out, you know, their connectome fingerprint and their brain areas, you know, in my example, mapping out their fusiform face area, right, and then saying, what is the effect of my intervention within this person. And then comparing to your fusiform face area, you know, is the effect of the intervention the same for you? Does that make sense?
Nick Jikomes 32:33
Yeah, so I would imagine, you know, say, say, if I'm reading an old paper on psychedelics in the default mode network, what you have to do for each individual that's going into that study is you have to map out functionally where exactly their default mode network is, where the boundaries and links between all these hubs are. Then you have to measure the effect of something like a drug, like a psychedelic, on their individual default mode network. And they have to do it for all of the other individuals, but you have to do the mapping separately and specific to them, because everyone's going to be a little bit different in terms of where that network is and what it looks like. And then you aggregate the results together and give average, average depictions or visualizations of what's happening. And that's, that's typically what we're looking at in a paper.
Joshua Siegel 33:14
Yeah, that's right. And the way, you know, I mean some, most of the Psychedelic Studies, and most studies in general that have been done, you average brains together first, and what you see is, let's say the effect of a psychedelic is, is this very fuzzy, blurry change in, you know, default mode connectivity, or maybe fuzzy, blurry change in connectivity and association cortex. But by actually mapping these systems within an individual with a high precision, you can get much more detailed answers about which particular sub circuits, you know. I mean, this has been it's kind of amazing how just by sort of flipping this idea on its head, and looking at things within a single subject, we've been able to define very nuanced and reliable subcortical networks in the thalamus and the basal ganglia and the cerebellum, and just has made fMRI a lot more powerful. So
Nick Jikomes 34:21
you're able to detect things that would otherwise basically kind of get smeared away in the process of analyzing this data. Yeah,
Joshua Siegel 34:29
exactly. So, you know, the fundamental question was, I think, was two things, actually. One is, can we get a more detailed picture of what, FM, of what, not from what psilocybin is doing that's producing the very unique subjective experience, what is doing in the brain, in the words, that's predict, producing the unique subjective psychological experience. And then the second was, what is the lasting effects after the. Has worn off. And, you know, by getting these much more high resolution images, can we actually see changes that are lasting in the weeks afterwards? And part of the, you know, part of the story there is that there's been all this fascinating data showing, you know, we're talking about Lisa monteji earlier, and her and some others have shown that there's these lasting plasticity effects with ketamine and with psychedelics, which last for days weeks afterwards. So the question is, you know, what's that doing at the level of brain networks and kind of Systems Neuroscience?
Nick Jikomes 35:40
Interesting. Okay, so, so begin to walk us through the recent paper. So you did this precision mapping. You looked at psilocybin, what? What were some of the or some of the questions you were asking that were new here, that was building on the previous literature?
Joshua Siegel 35:59
Well, yeah. So one was, what is changing in the brain when you take a high dose of psilocybin, both immediately and in the weeks after what's a high dose here? So it's 25 milligrams. But this is 25 milligrams of synthetic psilocybin, which, as I understand it, is probably close to five milligrams of psilocybin mushroom, dried psilocybin mushrooms, five milligrams or grams. I'm sorry, did I say milligrams, five grams? So that's, yeah, that's, that's big, yeah, and that's the dose. I mean, that's been the dose that that, I think all of the companies that are that are in later phase clinical trials are using as their kind of full therapeutic dose.
Nick Jikomes 36:50
Yeah. I mean, well, I mean, you know, Terence McKenna famously said that the heroic dose was five dried grams in silent darkness. And yeah, I can tell you that five grams. I don't think I've ever taken five grams. Five grams, that's a lot. Yeah,
Joshua Siegel 37:03
yeah. So for one thing, it's miraculous that folks were able to tolerate being in a scanner for two hours while they were on five grams of mushrooms.
Nick Jikomes 37:12
Were they? Were they previously experienced with psilocybin? Yeah, we,
Joshua Siegel 37:17
we decided to make it a criteria that they have to have had a psychedelic. And, you know, have had a relatively good experience at some time in the past, but we kind of walked in terrible because we also said they we don't want them to have taken a psychedelic within the last year. Okay, they had all had an experience with a psychedelic.
Nick Jikomes 37:41
Okay, so, so what are some of the initial results here? So I believe, for this study, you did many scans per individual, and only, you know, only a couple scans or so are with psilocybin. You did a lot of baseline measurements as well, I think,
Joshua Siegel 37:53
yeah, and by the way, that you know, so we did a lot of baseline measurements, which partly was so that we could get this very detailed connectome, you know, individual connectome fingerprint for each subject. But one of the unintended, unintended consequences of that was, I think it actually made it a lot easier for people to tolerate being on this hero dose while
Nick Jikomes 38:14
they were in a, you know, loud bang scanner. It wasn't the first or second time in there
Joshua Siegel 38:19
exactly, so it was kind of a familiar environment. So actually, I mean, people did surprisingly well. And you know, for example, if you look at head motion, which is a big confound in fMRI, people actually moved less than in previous fMRI studies, which was probably because of the fact that they were, you know, fMRI Psychedelic Studies, because the fact that they were familiar with the environment. But the, you know, I'll tell you a couple of the results that I think were the most interesting from the acute drug imaging sessions. One was, you know, we we replicated the observation, and showed pretty compellingly, that, you know, there is this big change in the default mode network, which, like I mentioned, you know, there was some that was not the first time this idea was put forward, but we showed that in a pretty compelling way, that across individuals, that seems to be the area that's the most disrupted by a psychedelic and and in fact, you know, there is a sort of common change in connectivity that's pretty consistent across people, that actually very strongly correlated with some of these subjective effects, like the loss of ego, for example, and the feelings of, you know, connectedness and disruption in the sense of in the sense of space and time and self, those people's subjective report of those sorts of changes was very strongly correlated with the degree to which default. Network connectivity was altered. So that's one thing, but actually, the thing that you know, that I like the most, and this way we titled The paper psilocybin de synchronizes the human brain, is that, you know, I think that's like, maybe a first level observation is that connectivity has changed. But the second level question is, well, how is connectivity changed? What's actually going on at the level of neural activity and and when you look at neural activity and you remember little earlier I mentioned that you know this fundamental principle that you have brain areas that are highly synchronized and organized under normal conditions and and what's actually going on is that when you give a high dose of a psychedelic these brain areas, at least the parts of the brain that are particularly high in The serotonin to a receptor, they become de synchronized, okay, and and so, you know, let's say you take 100,000 neurons makes up a brain area. And under normal conditions, at any given time, you know, 90% of those neurons will be firing in very close synchrony to each other. And under a psychedelic it just becomes totally desynchronized, and all of these neurons are basically out of sync with their local field and with their neighbors. And that, you know, I think part of the reason I think that that's a interesting and important observation is because, for one thing, it fits very well with what's been observed, you know, at across very different experimental methods. So there's, there's actually, I mean, I'm talking about results from an fMRI study, but there are actually studies recording, recording from single units and from the local field, and showing that a psychedelic does this exact thing of desynchronizing single units with their local field. So I think it's, it's compelling for that reason, but I also think it it probably has very important relations, a relationship to both. You know, what is the sort of nature of the psychedelic experience, but also to why it is that psychedelics produce this lasting plasticity in these particular parts of the brain that are related to self and related to emotion.
Nick Jikomes 42:39
So one of the convenient side effects of your experimental design here, as you said, was people had to go through many sessions in the scanner, so you had more data, and you can make use of it in different ways. But also they got used to the scanner, and so they actually moved around less. And a challenge with fMRI is, right, the more someone moves their head around, the more difficult it is to actually use and work with the data. So a lack of relative lack of head movements is great because you've got less of a concern about the artifactual fMRI signals you might get from head movements. One thing I have to ask before we go to more results, just because I am a former systems neuroscientist myself, is, how do you track or deal with eye movements that might differ systematically between the psilocybin and non psilocybin condition
Joshua Siegel 43:29
here? Well, when people are in the scanner arrest, we basically just have them staring at a little crosshair in the middle of the screen, and we were recording their eyes, both to make sure they're awake and to make sure they're, you know, okay, and staring at the cross hair, so that we are relatively controlling for
Nick Jikomes 43:52
I see, so they're, they're instructed to maintain their gaze on this fixation point. And you are actually recording. You're actually able to record, to video their eyes, so that you have some sense of how much movement was there and when interesting. So so you replicated the basic result that psilocybin leads to this desynchronization and a particular type of effect on the default mode the default mode network generally gets more quiet, and that effect, more or less scales linearly with the subjective report people give for how intense the trip was.
Joshua Siegel 44:28
Yeah, I mean, I wouldn't use the term more quiet because that implies that the defammon network is deactivated. It's not deactivated really. It's just disorganized and it's not activating in a synchronized way like it normally is.
Nick Jikomes 44:48
And so this desynchronization effect. How does that compare to other drugs? I believe the control condition you guys use here is methylphenidate. How does that comparison look? Yeah,
Joshua Siegel 45:01
well, methylphenidate didn't cause desynchronization at all that I can tell you with confidence,
Nick Jikomes 45:11
you know. And this is ADHD medication, right? Ritalin, yeah, methylphenidate,
Joshua Siegel 45:14
yeah, right. So it's Ritalin, it's generic. And reason we chose that for our placebo is because we wanted to match for arousal effects of a psychedelic. So, you know, psychedelics inherently increase arousal. They increase blood pressure, and so we kind of matched the dose of methylphenidate to cause same effects in blood pressure. But it certainly did not, I mean, it didn't cause desynchronization at all, if anything, maybe slightly increased synchronization.
Nick Jikomes 45:49
And so, other than replicating, sort of the basic results that had been seen before, around the synchronization effect, did you Did you notice anything new in terms of how connectivity patterns changed, or different parts of the brain that you were able to pick up that other studies based on their design couldn't pick up, maybe because the effects were too subtle.
Joshua Siegel 46:10
Well, yeah, I mean, there's a, you know, one thing that that came out of this that I really like was that in terms of the lasting effect of the drug in the weeks after it had worn off, you see this relatively specific change in connectivity between the default mode network and the anterior hippocampus. And so this is a circuit that is associated with kind of so hippocampus is memory. Default Mode Network is sense of self, and we think of the circuit between them as self referential memory, or the link between them as related self. And there's some interesting studies showing that this particular connection is related to self referential memory, and in the weeks after psilocybin, this connection was decreased, so you have a reset of this kind of self reference or memory circuit pretty consistently across participants. So I mean, that's one it's the first thing that comes to mind, but it's one example of, you know, by actually mapping out these systems pretty specifically in individuals, we were able to see that there's really this reliable effect. And I think
Nick Jikomes 47:28
one of the things you did here, that there hasn't been done before, it hasn't been done much before, is you weren't simply passively imaging people on and off psilocybin. There was also a task engagement portion to the study. So when people are on psilocybin, how does, how does the brain look? What are the changes that you see when they're engaged in a task compared to when they are not engaged in a task?
Joshua Siegel 47:52
Yeah, this was another cool observation. And so we had people, okay, so let me set up the design a little bit first, because we have people get in the scanner, like I was, you know, like I was saying they're, they're staring at a little plus, but basically they're letting their mind wander and, you know, having whatever psychedelic experience they're going to have. And then after maybe 15 or 20 minutes, we would say, Okay, we want you to do this task and, and this is a task they had already, you know, practiced kind of when they were in the scanner during the baseline scans. But essentially, it's a pretty easy visual matching task. So you see a picture, you hear a word, and then you make a judgment if the picture in the Word Match. Okay, so it's easy enough that you can do it when you're on a hero dose of psilocybin, but it requires you to be paying attention to your present environment. And what we saw was that when people are you know, when they switch from mind wandering to suddenly focusing on this task. Actually, the effects of the drug dramatically decreased. And this is, I love this, because there's this you know idea of grounding, right? Which is this idea, I think I first heard about it in the context of dealing with overpowering emotions that by bringing your attention to your kind of perceptual surroundings, you can take the brain out of this, you know, out of whatever internal state it's in, and re normalize, you know, brain activity renormalize emotional state. And this idea of grounding has also been certainly invoked with psychedelic therapy, that if somebody is you know, what tends to happen in a very intense psychedelic experience, maybe both positive but also negative, is that you get this like loop right where you might feel, I guess, a bad. Is probably the easiest way to, for me, at least, to conceptualize, is you start having this thought like you're going to die. Next thing you know, your body feels like you're physically dying. And this there's like, seems to be this spiral where things get more and more intense when you're just in, you know, in a psychedelic state, right? But by forcing someone's attention to their perceptual environment, you can actually clamp down the intensity of the psychedelic experience. So we saw a very nice parallel to this, where when people you know were forced to engage in this pretty easy task, the these observations. So the desynchronization, the change in default mode, network connectivity, actually got a lot smaller. So there's this nice sort of task by drug interaction.
Nick Jikomes 50:51
And this fits with what I think a lot of people who have personal experience with psilocybin or other psychedelics often find, you know, if you close your eyes while you're sitting or lying down, the trip will often become harder, or at least more intense, not necessarily harder. But then, if you engage with the external environment, you touch things, you focus on music or whatever. This brings you out of the deepest parts of the trip, usually. And
Joshua Siegel 51:16
there's a cool study I'll have to think about who the first author is, but I know it's from, you know, Robin guard Harris's lead author, where they interrupt people every minute. I think it was DMT. We have to look it up. But they give a short acting psychedelic and they interrupt people every minute throughout the experience, to ask them to report drug effects, and to ask them to, you know, answer questions. And then at the end they asked them, you know, how intense was the experience? And in the group where they interrupted people, it's a much less intense experience than in the control group, they just, you know, wait till the very end, right? They don't interrupt them, and they let them have their psychedelic experience. And then at the end they ask them about the experience. And it's less intense. It's less, you know, people use the mystical experience questionnaire, which has been a pretty good correlative therapeutic benefit. It's less of a mystical experience. So there is, you know, there's this nice, like you like you're describing, kind of this idea of grounding that fits very well with what we saw in the brain.
Nick Jikomes 52:26
And so when you do so, when you do these studies in humans, obviously we're talking about the human brain, the human experience on psychedelics. Or there's a whole, whole other world of the animal models and and using psychedelics animal models to understand things on a more mechanistic level. How? You know, this is a little bit of a vague question, but I just want to probe it a little bit. So obviously, humans and animals are different, and yet we share many commonalities. So you know, you give a laboratory rat or mouse a psychedelic like psilocybin, and they have some kind of a trip, right? They have a behavioral response you can measure. They have changes in their brain that you can measure. They have inductions of plasticity that you can measure. They have five HT to a receptors and roughly the same pattern of expression that we do. But of course, none of that is identical. And in fact, one of the things that I think is interesting is that one of the, among other things, one of the big differences between the human brain and the non human and non primate brain is that although they have five HG, two A receptors, although they respond to psychedelics in a directionally similar manner, some of the biggest differences between, say, a rodent brain and a human brain involve areas of cortex that are greatly enlarged in humans relative to rodents and other animals, and some of these have some of the highest density of five HG to a receptor expression. So I'm just wondering if you could comment a little bit about sort of how we how we should think about the extent to which the animal results translate to humans and vice versa, and where we should be particularly cautious.
Joshua Siegel 53:59
Yeah, yeah, no, I think it's a huge issue. And I think that, you know, I agree with everything you said, the ability that we can to say anything intelligent from what's a psychedelic doing in a mouse is limited. And, you know, I mean, I think a lot of the things we were talking about with the subjective psychedelic experience are very difficult. I mean, first of all, they're difficult to measure in a mouse, much less to even know that, you know, there, there is even a proxy or a parallel to the effect in a mouse. You know, it's that's totally open questions. And I think, you know, one of the reasons that it's imperative to be able to do some of these studies in humans. So, you know, I think the plasticity idea has been, has been a big influence in psychiatry. And this is just the this broader idea. That, you know, inducing plasticity is probably critically relevant to the treatment of depression and the treatment of maladaptive psychological states, and that, I think we there's enough evidence now to really believe that that's not just the case in mice. You know, it's like, it's, it's a fundamental truth across models and across species. But beyond that, you know, that still leaves a huge question about, you know, we, we've seen that when you give a mouse a psychedelic you have this activation of what's called the Neurotrophic cascade, which includes things like brain derived neurotrophic factor and all these other markers that have been, you know, measured and understood, and kind of ends with the formation of new synapses, which has also been measured in stunning detail, and, you know, in live rodents, but it's still, like, totally an open question of, what does that mean in a human? What does it mean to have Neurotrophic cascade activation or to have plasticity? And ultimately, it's, it's a those are questions that we're only going to answer with humans, just because they're, you know, there has to be a psychological consequence to these big changes, but it's not going to be possible to say what it is just from, from rodents.
Nick Jikomes 56:33
Yeah, and it's, you know, one of the challenges of trying to look at and compare and translate the human stuff from the rodent. Stuff is and the frustrating things is that, you know, we've got 1000s and 1000s of studies in rodents, mainly where, sure they they have what we call depression like behaviors and anxiety like behaviors. And you can give them drugs, you can give them antidepressants, you give them psychedelics, and you can measure what seem to be therapeutic behavioral effects and all sorts of exciting things. And yet, you know, if I'm going to caricature things a little bit here, maybe, but you know, if you just look at the past few decades of research in in psychiatry, trying to translate from rodent work to human work, and trying to come up with drugs, new drugs that do better at treating things like major depression and other psychiatric ailments in humans. We've got 1000s of studies with all kinds of stuff that look promising, and then they just don't translate to humans. And one wonders to the extent, the extent to which our animal models are truly modeling something like major depression, where someone is ruminating and thinking linguistically. And, you know, there's just, there's a lot there that the mouse brain just probably doesn't do.
Joshua Siegel 57:47
Yeah, completely agree. I think one of the, you know, the this whole Neurotrophic hypothesis, just to come back to that for a second, like one of the big goals, and to me, like a holy grail of sort of modern psychiatry and psychiatry theories, is to be able to measure plasticity in humans and to actually, and which we've done, you know, we've achieved it 100 times in mice, but to actually measure it in the human brain for exactly that reason, because, you know, if we know, and know is probably a strong word, but we can assert that drugs that or treatments that make the sort of this core machinery that's related to depression more adaptable and more plastic are going to be therapeutic. And you know, like you're saying, we've now found 1000 drugs that do this in mice, but it's much harder to determine if those drugs are going to have that effect in humans. And if we could give a drug to, let's say, four people, and say, with confidence, yes, this drug is taking these circuits that are related to mood, you know, and, and just to back up here, I mean, like, you know, we have this, this, this idea of the of the cognitive behavioral model, which is The idea that, you know, you have emotion, behavior and and thoughts or cognition are in this kind of self perpetuating loop. And when you're in depression, this self perpetuating loop is is in a very negative state, right? And the consequences you don't want to get out of bed, you have, you know, a pessimistic view of the world, and you feel lousy, right? And you seem to be stuck in that state. And so, you know, I think it's pretty well understood now that one of the core pieces of treating depression is putting the brain into a more adaptable state. So. It can get out of those thoughts, right, those maladaptive thoughts. And one of the, you know, I think, like holy grails of of modern neuroscience related to psychiatry, is to actually be able to measure the degree to which a drug puts the brain into a more plastic and adaptable state, and there's this great and we don't have a we don't have a tool to do that yet, which is actually surprising, because it's been harder than you might have thought. Because, you know, like I said, there's so many ways to do it in mice, but you would think there would be an easy, let's say, PET imaging biomarker that would say, you know, here's how much BDNF is in your brain, or here's how how quickly your brain is forming new synapses. But it's been pretty elusive, but there is cool studies, for example, in pigs. So at least pigs are probably a lot closer to humans than than mice and and you, you give a pig a high dose of psilocybin, and you actually get like, a 10% increase in in synaptic density in the hippocampus, which is wild to me. That's, yeah, that's pretty big effect, I think, yeah, yeah. And something in the order of, you know, 6% increase in synaptic density in the medial prefrontal cortex. So that's getting at least a little closer, but this is all still like, you know, post mortem studies, so not exactly techniques that could easily be scaled up to humans.
Nick Jikomes 1:01:39
And remind me so you have training in psychiatry as well, right?
Joshua Siegel 1:01:41
Yeah, so of MD, PhD and did residency in
Nick Jikomes 1:01:47
psychiatry. So as someone with that sort of dual background in functional imaging, human systems, neuroscience and psychiatry, when you think about taking this stuff from the laboratory to the clinic. When you think about the nature, the inherently subjective and powerfully subjective nature of these drugs, and you think about things like the procedural requirement to have placebo control groups when you're trying to do clinical trials to get things approved by the FDA, what do you think about so maybe we'll just take the maps studies that the FDA didn't approve recently. I believe one of the key things there for the FDA was that you didn't have what they consider to be a, you know, a true placebo control group, given the given the nature of these things with when it comes to subjectivity and the subjective effects and your psychiatric background. How do you sort of think about doing placebo control studies, or whether we need to rethink that, perhaps, when it comes to thinking about whether to take these things to the clinic and start using them on a larger scale?
Joshua Siegel 1:02:58
Yeah, that's been a big, big issue, and I like, I can't even decide how to respond, because I totally appreciate both sides of the argument. So let me, let me like, build both sides very quickly of the argument, and then we can pick which side we like. So on the one side, and I really like depends what day you ask me, I believe both things on the one side. It's like a ridiculous idea that I should be able to control for this powerful, transformational experience. Because what does that even mean? Like, it is fundamentally the combination of the of expecting that you're going to have a powerful transformation, transformational experience, uh, plus having a very salient, very powerful experience that are that enables healing and enables somebody to, you know, I think both of those are like important parts of recovering from a psychedelic treatment or with a psychedelic treatment and and to label like that, to label that a placebo effect, it's almost like, Well, okay, fine, if you want to, but it works, right? So, so who cares if you label it a placebo effect?
Nick Jikomes 1:04:12
Yeah, I think one thing that's worth pointing out here, at least for me, is what we might call an orthodox sort of clinical view. Would be that, well, there if, if we're talking about the brain and securing someone's depression or something like that, is going to involve triggering a certain pattern of brain activity that makes them better. What I'm just going to call the the Orthodox clinical view might be something like, well, we need to have a placebo control group to show that it's not merely or largely someone's expectation or desire to get better that is actually making them better. But what's problematic about that is the effect of the drug, coupled with things like your desires and your expectations will actually induce a different pattern of brain activity. Right? Which so someone with who wants to get better and expects to from the drug is going to have that expectation coupled to the drug effect. That's going to induce one pattern of activity. And if I'm highly skeptical or I'm just rigid, and I don't necessarily have the motivation to get better than the other person does, that's going to mix together with the drug effect and give a different overall pattern of brain activity, which itself. I mean, if we're talking about patterns of brain activity, that is sort of the the medicine here, in some sense, yeah,
Joshua Siegel 1:05:26
and there's a, I'm thinking. His name is Stan. He's an anesthesiologist at Stanford. Kim Boris. Heifetz, thank you. Heifetz, yeah, he he uses this great example of this in, you know, I heard him give a talk at ACMP conference last year, and she described this study that's, you know, I think it was like from the 1940s 50s, maybe, where they just give epinephrine, and then in one group they, you know, basically prime them to believe it's going to be a very positive, joyful experience. And in the other group, they prime them to believe it's going to be a very negative and, you know, sympathetically activating angering experience. And you get those exact effects. So they use, it's kind of a fun design, because they use a, what do you call it? They put someone in the room who as a Confederate, who's, you know, who's in on the experiment, right? And have them react in different ways to the drug and but the point that he's making is that, you know, is just what you're saying, which is that the expectation of the effect of the treatment can dramatically influence the effect of the treatment. And then there's another side to that with psychedelics that is an equally big issue, I think, which is that, if you, you know, let's say I'm recruiting for my psychedelic clinical trial, who's, who's coming to, you know, seek out my trial. Well, some portion of them is going to be people who have heard that psychedelics are a great treatment for depression, or who have had an experience with psychedelics before that led them to believe, personally, that it might be a promising treatment. And then you take those people, and now half of them are randomized to receive a placebo. And so you have also this kind of effect where they are going to be disappointed and, you know, have a worse reaction than they might because of the, you know, the actual, the expectation that they were going to benefit from a psychedelic is actually causing them to do even worse on a placebo than they would if you had never given them the expectation that they were going To get a psychedelic in the first place. So the fact that we're so bad at blinding in psychedelic clinical trials is like a double hit because of, you know, because of the way that it's affecting the arm that gets the psychedelic, and because of the way that it's affecting the arm that gets the placebo, right. So that's the other side of the
Nick Jikomes 1:07:58
Yeah. So it can actually sort of exaggerate the difference between the two groups, yeah, yeah, on both sides, interesting, yeah. But it's like, so, like, I
Joshua Siegel 1:08:09
mean, just to, just to bring it back to this point of, of, maybe we shouldn't be so obsessed with this is there's nothing wrong with, I mean, one of the fundamental principles of psychotherapy is setting the expectation that this treatment is going to help you get better. So you have to use the placebo effect, and it's effective, it's it's huge in psychiatry. And so why would you not use it, right? Why would you not set the expectancy that a treatment is going to help
Nick Jikomes 1:08:41
you? Yeah, yeah. But, and again, you know, for from my perspective, you know, setting that expectation, it's not as you're saying, you know, it can be used as a tool intentionally, and the setting of that expectation is going to change the functional brain context in which the drug acts, which will result in a different pattern of functional stuff happening in the brain than taking the drug in the absence of that expectation. And it's, I think it's entirely reasonable and plausible to suppose that, to a large extent, the the dual combination of a drug and an expectation might be necessary for therapeutic value to actually emerge
Joshua Siegel 1:09:21
totally. And there's some, there's some good examples of this too, with, you know, if you know the history of psychedelics, with like MK Ultra right, and nefarious ways that psychedelics have been used. And when you use psychedelics in nefarious ways, you tend to get nefarious outcomes. So, you know, I mean, the the basic idea was, like, if you the expectation was that a psychedelic produces psychosis, and lo and behold, when you, you know, tie someone down to a bed and inject them with LSD, and, you know, put them in a padded room,
Nick Jikomes 1:09:58
and all they've probably heard. Is that they are, yeah,
Joshua Siegel 1:10:02
you're about to get a drug that's going to cause you to lose your mind. Lo and behold, it's a pretty awful experience, and a lot of people you know, have psychotic effects from it.
Nick Jikomes 1:10:16
What is your gen, you know, given your back? You know, and I asked some of the same questions to a lot of people, because, you know, people have different backgrounds. People, you know, focus on the cellular biology, the level of animals. Other people are purely clinical. And then, you know, you're sort of in this, I guess I'll call it middle, middle place, where you've got the Latvia, sort of the research side, the non clinical research side, and your clinical background, where, where do you what's your current perspective on sort of the hot button issue in this field, which is whether or not we'll likely be able to engineer what people often sort of cheekily refer to as non psychedelic, psychedelics, non hallucinogenic, psychedelic derivatives, which will, some hope, have all of The therapeutic benefits we want on the psychiatry side without the what some people call side effect of a trip.
Joshua Siegel 1:11:09
I heard you ask Robin this question, and and I think he gave a persuasive answer, which probably is pretty similar to the way that I think about it, which is that it's not likely. I mean, what does that mean? It's not likely that you're going to get as big of a you know, these dramatic, transformational experiences that that you sometimes see in psychedelic clinical trials. Is it possible that, you know, we will be able to engineer another antidepressant that works, kind of like Prozac, and kind of, you know, as well as Prozac, it's very possible, but there is no, you know, There's no question that the experience is part of therapeutic effect of a psychedelic And fundamentally, to me, I think it's, it's probably, there's, there's two things happening here, and one of them is, is this plasticity phenomenon, you know, this idea that I've been riffing on, that these drugs are putting the brain in a more plastic state, right? That's the one thing, and maybe you can find a drug. In fact, we know that there are some drugs that don't produce the same degree of, you know, altered consciousness, but that they put the brain in a more plastic state. But then the other thing that's happening is that you're causing this experience that many people find to be mystical, that many people find to be deeply meaningful and transformational. And and you look at that experience and, and now it's like very clear that if you look at the lasting therapeutic benefits, they are pretty strongly and specifically correlated with how people rate that mystical experience, okay? And, and the way that I think you should think about this is the first thing that I talked about, the Neurotrophic effect that is a precursor to change, right? But what is the change? Is the change? So making the brain more adaptable to change, just like we were just talking about, you know, it could cause somebody to become psychotic, it could cause any of a number of consequences, but you combine that with the specific sort of experience that people have with a psychedelic particularly when you combine it with good therapy, and you reliably now are changing people's sort of sense of self and their habits in a way that tends to recover from, you know, maladaptive behavior. So actually, so one last thing I'm gonna say about this, which is that a colleague of mine here at NYU Petros now has this very nice analysis looking at addiction data with, you know, we did this big study here with with psilocybin for alcohol use disorder and and what they did in this, in This data set, is there's all these effects of psychedelics, right? They cause visual, you know, imagery. They cause they can cause anxiety, they can cause nausea, and then they can cause the mystical experience. And what he shows is that all of those things are substantially increased with a psychedelic but it is only the mystical experience that is predictive of lasting therapeutic benefit. So now you're separating, you know, because it when you're just showing a correlation, you can say, well, that's correlation, not causation, but now you're actually showing that there's specificity, and it is this particular sort of experience that people are having that is predicting long term benefit.
Nick Jikomes 1:14:59
Yeah, and I. There's probably the magnitude and the power of the subjective effects could be some kind of like, I almost think of it as, like a sensory, Confirmative evidence that your expectation has actually been met. So I'm just, I'm riffing a little here, and I have a head cold, so hopefully this is a coherent idea. But when we think about things that are reliably transformational to people across times and cultures, very often, what people point to in their own lives are certain developmental transitions, many of these having many ritual behaviors that are part of their culture. As part of it, you know, think about the birth of a child or a marriage, for example, everyone goes into a marriage, you know, expecting it to be transformational, and you get a lot of sensory feedback that confirms that expectation in the ritual itself. That is part, part of the whole process. People are clapping, they're cheering, they're dancing. If you somehow could concoct a situation where someone went into a marriage ritual with all of those expectations and all of their friends and family didn't clap or cheer stand up, it might have different effects because they don't have a sensory confirmation of their expectations in the moment. And again, I just wonder if the subjective effects of psychedelics are serving that kind of function for people, expectation does matter, and the trip does matter, and the so called Pure pharmacological effects of the drug do matter. It's, it's sort of the the cons, the combination of all these things that leads to a maximum benefit or to a certain type of brain activity that isn't present without any one of them.
Joshua Siegel 1:16:36
Yeah, yeah. I think it's funny, like the it's such a powerful experience in and of itself that it demands some sort of ritual around it to recognize its power also, which, I don't know if there's exactly the same thing that you're saying, but it's but it's been a funny thing to think about on the clinical Trial side of things, because, you know, we're very like, we're very conservative, and how we approach sort of rituals, and how we approach there's obviously all these, you know, shamanic, longer histories of the use of plant medicines and and there's various associations of psychedelics with certain religious practices, and there's always this like intuition that, oh, we shouldn't, shouldn't go there because we want to be open to any, you know, any participant. We don't want to buy into one particular cultural or religious practice. But there has to be a way to recognize the power of the effect of the drug, because you need to construct this sort of narrative for people that we are going to create this transformational experience for you, you know, like, just like you're describing. And this is an important experience and a powerful experience, and you're going to go through it, and when you come out of it, you're going to be able to change in some way, right? So you need to, like, make a context for that
Nick Jikomes 1:18:12
on the the human functional imaging side of things, what are you guys working on now? What's coming next? Or just more generally, what do you think are the biggest questions that we need to answer that can be answered in the near term, meaning the next few years? Say,
Joshua Siegel 1:18:31
Well, I will say, despite my skepticism about non hallucinogenic, psychedelic analogs, I would love to do some studies with them to actually try to hammer out and objectively answer some of those big questions. So hoping to do that. That's so I just started it at NYU a few months ago. So it's not like the first thing on the agenda trying to get set up here and trying to, you know, make sure we have good, good tools for brain imaging and good tools for doing acute drug studies, which is not easy, but longer term. I do want to, I would love to play with some of the non hallucinogenic psychedelic analogs, and actually be able to do direct comparisons to psychedelics to understand how is the brain changing. What's the subjective effects of these drugs? I think that would be very useful. But the shorter the shorter term, the first order thing that I'm doing is is there is some folks here who are really world leaders on the clinical side of psychedelic therapy. So Michael Bogan shoots and Stephen Ross, I mean, I think at this point they're like, you know, two of the most well funded NIH, well NIH funded psychedelics researchers. So they both have big NIH grants and have really exciting. Studies going on with end of, you know, with cancer recurrence for Stephen Ross and and, and using psychedelics to cancer recurrence. Yes, so he, so Stephen Ross had this, this awesome study. It was, it was a two site study, or, I guess it was parallel studies at Hopkins at NYU, right, and Roland Griffith at Hopkins and Stephen Roth said NYU that was looking at terminal illness, and, you know, end of life anxiety and individuals with kind of a terminal cancer diagnosis and using psychedelics as a tool to aid with, basically, coping with end of life issues and and that had pretty incredible results. But one of the next phases of that is looking at individuals with cancer, with cancer either in remission, who have fear of cancer recurrence, or people who have had cancer recurrence, and understanding, you know, how psychedelic can be used in those individuals to basically cope with sort of these, these existential distress, and, you know, anxiety about physical illness. So that's, that's one study that's going on here right now and then, and then, Michael Bogan shoots has been more on the addiction side, and, you know, has had this really very impressive result with using psilocybin in alcohol use disorder To after the acute detox phase, doing psychedelic therapy has a pretty dramatic benefit on reducing remission, and so he's carrying that research forward. And also, you know, has a big grant starting up, or study starting up with opioid addiction, and people who are, you know, on methadone treatment for opioid use disorder. And so my big goal, one of the things that I'm doing in the short term, is helping with biomarkers in those studies. So understanding, you know, some of the things we've been talking about, can we actually link them to therapeutic benefit? Right? Because a lot of the you know, the work I was doing at Wash U was in healthy, non psychiatrically ill folks. And you know, a lot of these observations, we think that they're pretty important to the therapeutic benefits. But you know, coming here, I view it as a good chance to actually clearly understand. How does this relate to the clinical benefit of psychedelics?
Nick Jikomes 1:22:47
Are there any final thoughts you want to leave people with, or anything you want to reiterate based on anything that we talked about or the work that you're doing?
Unknown Speaker 1:23:01
Well,
Joshua Siegel 1:23:08
nothing that immediately comes to mind, but
Nick Jikomes 1:23:12
it sounds like we've got some stuff to look forward to in the pretty near term, in terms of your work.
Joshua Siegel 1:23:19
Yeah, I think there's, there's two directions that that my work is, is going, and I told you about one of them, and the other is continuing to build out this idea of, you know, precision, individual brain mapping as a tool, not just to study psychedelics, but to understand drugs in general, and and to be honest with you, equally excited about that, because I think you know it's going to, it's going to be a powerful tool for a lot of reasons, one of which is because we now have, you know, these increasingly intricate ways of like, stimulating the brain, right? And if you're going to start stimulating people's brains in a targeted way, then an important precursor is knowing exactly where you're hitting in their brain, right? So, so that's another direction that I'm going with my work and excited to see unfold in the future.
Nick Jikomes 1:24:18
All right. Well, Josh Siegel, uh, fascinating stuff. I really liked reading your work in the past few weeks when I when I first started seeing it come out. Yeah, I look forward to seeing what else you come up with in the near term. And the research is coming out, and at some point, I'm sure I'll talk to you again.
Joshua Siegel 1:24:35
Thank you very much for having me, Nick,
Unknown Speaker 1:24:36
thank you. Hey, there
Joshua Siegel 1:24:38
is another thing that occurred to me, which probably isn't that important. I don't know if you want to include in the podcast or not, what's up? I just remembered that when you were having this conversation, I listened to recently with Robin, and you guys actually looked at a figure in my paper in this with this decent grade. Effect, oh yes. And you guys were debating about it, yes. And I was like, I want to chime in, because I can give them a clear answer to that. Oh, well,
Nick Jikomes 1:25:08
well, let's just, let's do that. I've got, I've got time. I'm going to share the screen here. I believe you're talking about figure four, yeah, task, performance, functional, yeah, all right, let's bring that up. We'll describe it verbally as best we can for people, but obviously, for just listening, there's going to be an image in the video version. Okay, share.
Unknown Speaker 1:25:38
Okay. Can you see?
Joshua Siegel 1:25:43
Yeah, all
Nick Jikomes 1:25:44
right, so we'll set this. Set this up for us. What are we looking at
Joshua Siegel 1:25:49
here? So this comes back to this, you know, context dependence, grounding effect, where the effect of the psychedelic seems to be dampened down when you have people engage their attention to a visual task. And my, I'll try to, you know, give you my recollection of what the question was when you all were talking about this. So on the on the left side, this is the effect of, you know, this is showing this sort of task by drug interaction, in terms of functional connectivity change, and you can see that at rest, functional connectivity is altered when you're on psilocybin, but when you're engaged in a task, functional connectivity is much less altered by psilocybin, right? But I think the question was about the right side, where we show the same interaction, but now it's looking at this desynchronization measure. And the fundamental point here, or the fundamental issue that I think was causing confusion, is that if you look just at baseline, the desynchronization measure is actually much higher during task than at rest. Yes, this one right here. Okay, and this is not a new right. This is not a new observation. This has been shown numerous times in numerous different ways, that when you when the brain engages in a in a task, actually, many parts of the brain become desynchronized, okay, and so just at rest, fluctuations are much more synchronized and organized. And then you know, when you start engaging in a complex task, different parts of the brain are activating in relation to the task and become desynchronized. Does
Nick Jikomes 1:27:45
that make sense so far? Yeah, so task engagement tends to boost desynchronization. Yes,
Joshua Siegel 1:27:50
yeah. And like I said, this is not a new observation. This is like, you know, this has been shown since the, you know, since early neural recordings, but then the effect of psychedelic, the effect of psilocybin, if you look just at rest, you get an increase in desynchronization, yeah. So
Nick Jikomes 1:28:09
basically, this bar here, the white bar, and this condition is higher than this one, yeah.
Joshua Siegel 1:28:15
And then when you look at the effect of psilocybin, when someone's performing a task, there is much less of an increase compared to performing the task at baseline.
Nick Jikomes 1:28:27
Yeah. So the dark bar here is bigger than the white bar in both cases, but the delta is much less over here,
Joshua Siegel 1:28:33
right? And so, and then there's still this interaction. So now what you have is both doing a task and taking psilocybin globally desynchronize the brain, although where they de synchronize the brain actually turns out to be a little bit different, but globally, both of those interventions de synchronize the brain. But I see
Nick Jikomes 1:28:54
so the reason, the reason the psilocybin bar here is higher, but not that much higher, is essentially that both of these lead to some level of desynchronization measured globally across the brain. And in essence, you're basically hitting a ceiling, maybe,
Joshua Siegel 1:29:08
well, maybe, or maybe it's the same thing that's going on in the left which is that doing the task actually decreases the effect of psilocybin, I mean, or maybe those are saying the same thing, I don't know, right? But the point is, you have this interaction where task, or doing this task on psilocybin, kind of has dampened effects, dampens the effects of psilocybin. I see interesting. There's definitely I'm framing. Does that make sense? Yeah. I
Nick Jikomes 1:29:37
think that makes sense. Yeah? So yeah, both, yeah. I think that one of the keys here is to understand that task engagement itself can lead to desynchronization measured globally, although there's, there's probably important caveats there in terms of, like, exactly how that manifests in different parts
Joshua Siegel 1:29:53
of the brain. Yeah, it's, I mean, there's good examples, like with the visual system, for example. That when you're just looking, when you have no visual stimulus, your visual system is much more synchronized, and then when you start stimulating the visual system, it comes out, it goes out of synchrony. Yeah, and I think
Nick Jikomes 1:30:10
that's a pretty general finding in neuroscience, right? Task engagement tends to de synchronize activity in the chunk of tissue you're recording from. That's task relevant? Yeah, yeah. All right, I
Joshua Siegel 1:30:22
remember you guys had argued about that. So
Nick Jikomes 1:30:24
yes, yes. Probably should have brought that up. I have to admit, because of my illness, I didn't prepare quite as much for this one. But yeah, if people go back to the robin Carhart Harris episode, which I did not so long ago, we kind of go through this paper figure by figure, at least for some of the figures, and then at one point, I had a question about this figure that me and Robin discussed but didn't necessarily resolve. And then, if you watch that, and then this chunk, those will hopefully, hopefully answer some questions there. Yes, sir. All right. Well, Dr, Josh Siegel, thanks again for your time, and I look forward to chatting
Joshua Siegel 1:31:02
again. Thank you very much. Pleasure.
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