In this episode of the Psychedelic Podcast, scientist Manesh Girn emphasizes that psychedelics affect the entire brain, not just the default mode network (DMN).
Girn advocates for a personalized approach to psychedelic research that considers individual brain characteristics, mental health conditions, and environment in order to truly understand their effects. He challenges the misconception that psychedelics are inherently beneficial and highlights the importance of positive inputs for positive outcomes. This compelling conversation further explores the influence of set and setting, the interdisciplinary nature of psychedelics, and their potential to shape self-identity.
Manesh and Paul F. Austin uncover profound insights into the neuroscience of psychedelics and the need for personalized, comprehensive research.
Manesh Girn is in the latter stages of obtaining his Ph.D. in Neuroscience at McGill University and has been the lead or co-author on over a dozen scientific publications and book chapters on topics including psychedelics and the default mode network.
He is currently researching the brain mechanisms underlying psychedelic drugs in collaboration with Dr. Robin Carhart-Harris and other leaders in psychedelic science. As a postdoctoral psychedelic neuroscientist, he will join Dr. Carhart-Harris at UCSF in August 2023. Manesh is also Chief Research Officer at the Canadian psychedelic bioscience company EntheoTech Bioscience. He runs a YouTube channel and Instagram page called The Psychedelic Scientist, where he discusses the latest research in an easy-to-understand but non-superficial form.
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0:00:00.4 Paul Austin: Welcome back to the Psychedelic Podcast by Third Wave. Today I am speaking with Manesh Girn, the Psychedelic Scientist.
0:00:11.0 Manesh Girn: You can't just focus on a single network in understanding Psychedelics effects on the brain. Psychedelics fundamentally affect the way the entire brain functions and they effect of variety of networks beyond the Default Mode Network. And so one way to kind of in a more nuanced fashion, relate to the brain to Psychedelic effects is to ask the question, how do Psychedelics change fundamental ways that the brain processes information?
0:00:38.5 Paul Austin: Welcome to the Psychedelic Podcast by Third Wave, audio mycelium, connecting you to the luminaries and thought leaders of the psychedelic renaissance. We bring you illuminating conversations with scientists, therapists, entrepreneurs, coaches, doctors, and shamanic practitioners, exploring how we can best use psychedelic medicine to accelerate personal healing, peak performance and collective transformation.
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0:04:25.1 Paul Austin: Hey, listeners, I'm so excited to have Manesh Girn on the podcast. Today we talk about Brain Coherence and how complex systems, complex science applies to the basically application of Psychedelics within the brain. So as many of us know the Default Mode Network, the DMN is the most commonly talked about phrase or term as it relates to why Psychedelics are helpful and impactful on brain. We hear things like by interrupting the Default Mode Network, we become more present. We step out of rigidity, we step out of stories, etcetera, etcetera. We brought Manesh on today to talk about the most recent context on Psychedelic Neuroscience and talk about while the DMN is a great model, the impact of Psychedelics on brain action is so much more complex than just the Default Mode Network. So we get a little technical, but as always, I managed to bring the conversation back into understandable terms for you. I think you are really going to enjoy this episode on Psychedelics And Brain Action.
0:05:35.8 Paul Austin: Manesh Girn is a Psychedelic Neuroscientist with feet in both academic and industry. His interest in Psychedelics has led him to develop extensive expertise on the Neurobiology and Psychology of these substances, and he applies this knowledge as both the Chief Research Officer at EntheoTech Bioscience and also as part of his process of obtaining his PhD in Neuroscience at McGill University. Without further ado, here's my conversation with Manesh Girn, the Psychedelic Scientist.
0:06:12.3 Paul Austin: Hey, listeners, welcome back to the Psychedelic Podcast. Today we have Manesh Girn, the Psychedelic Scientist. Manesh, welcome to the show. It's good to have you on.
0:06:22.5 Manesh Girn: Thanks, Paul. Super excited to talk with you.
0:06:25.2 Paul Austin: Let's talk about your YouTube channel. To start off with, I think that's how I first heard about your work through a mutual friend of ours, Nick Vassov. You started a YouTube channel, I think almost two years ago now, two and a half years ago now, called The Psychedelic Scientist, which I love. It's bold, it's quite the claim, and you've done a lot of work and research in this space. So I'd love just to hear sort of the origin story about why start a YouTube channel talking about Psychedelic Neuroscience.
0:06:52.2 Manesh Girn: Yeah, definitely. So psychedelics have been an interest of mine for a long time and it's been interesting to see them emerge as such a popular topic in the past few years, really. And I, looking at the media landscape and the type of reporting that was out there, it's like obvious there's a lot of sensationalist news reporting, a lot of simplistic narratives taking hold. And like a lot of things that scientists working in the field would kind of cringe at and this is still the case. And so, this was during the pandemic as well. I found myself with extra time and I was like, huh, why don't I just use some of this extra time to contribute to the landscape?
0:07:27.8 Manesh Girn: And so I thought about it and originally it was gonna be a written blog, but then like, people don't really have attention spans these days. You need video content. And so I decided to make a YouTube channel around that just to provide like rigorous, reliable, scientific information about psychedelics that is also layperson friendly and accessible. And so that was basically the motivation there.
0:07:46.6 Paul Austin: What is your most popular video so far that you've recorded, the one that's gotten the most views or traffic or whatever?
0:07:53.7 Manesh Girn: So I think a couple of the most popular ones, the first one I think is How to prepare for your trip, which is classic 'cause people want practical information. And then another one is, it was either on the neuroscience of ego dissolution or my breakdown of what ego dissolution is in terms of philosophy and also the psychology assessments that they use in research.
0:08:13.3 Paul Austin: Okay. So that's a good lead in, what is the neuroscience of ego dissolution?
0:08:19.7 Manesh Girn: Right, it's complex, yeah.
0:08:21.0 Paul Austin: Here we go.
0:08:22.1 Manesh Girn: A lot of people link it straight to the Default Mode Network, and can you hear a lot of people saying basically equating default mode disintegration with ego dissolution. And it's really not that simple. There are studies that have shown that yes, like a couple of them, but there are several that haven't, they just haven't found it. And then there's some that have found other correlates of ego dissolution. And so I think what I kinda mentioned in this video and I've talked about before is that we have to stop and ask yourselves what is ego dissolution?
0:08:51.9 Manesh Girn: Is it really something we expect to have one correlate in the brain? 'Cause what I talk about in that video is how very broadly you can even separate the experience of ego dissolution into two things, which are usually grouped together and conflated. So one is an alteration of our sense of being located in our body, of like, this is where my arm ends and this is where the couch starts or whatever. It's like that sense of bodily representation of where we are in space physically.
0:09:22.1 Manesh Girn: And then the other part of it is like our sense of identity. Who we are in terms of the stories and concepts and memories. I am Manesh, I have this history in the past, this is my projected future, this is my traits, these are my traits. And in certain cases you can be totally dissolved physically, but your mind is still there. You still know who you are, right? And that could be described by some people as an ego dissolution experience. But then some other people might have an experience where they completely forget who they are. They forget all concept of reality and they're just dissolved with everything. And they might be calling that ego dissolution experience. And so then when you try to link all this to the brain, you're linking these distinct types of experiences under one header. And so therefore it's gonna be hard to parse out something clear.
0:10:11.3 Paul Austin: Tell us a little bit more, so the Default Mode Network the DMN, you know, Robin Carhart-Harris is probably best known for popularizing this through Michael Pollan's book, "How to Change Your Mind." And I remember when we started, I started a legal Psilocybin Retreat Center a few years back. We had have a lot of people who came to that after reading Michael Pollan's book, basically saying, Hey, I wanna dissolve my DMN, you know, so they had this sort of linguistic context they were primed to think that their Default Mode Network was the thing that was actually responsible for their challenges, their issues, their stuckness, their stagnation, whatever it is.
0:10:46.8 Paul Austin: So I'd love for you to just further flesh that out because I think as part of this conversation, what we're gonna do is sort of poke holes in that hypothesis that the DMN is sort of the predominant way of or the predominant model of perceiving ego dissolution in psychedelic experiences. But before we can do that, we just need to better understand what is the Default Mode Network, why is it relevant? And from your lens, from your perspective, why did it become sort of the most widely talked about model for psychedelic neuroscience?
0:11:18.9 Manesh Girn: Yeah, totally. So we'll start with what is the Default Mode Network? And broadly speaking, if we start from the basics, if you understand the brain, you can understand it as a set of different brain regions which interact and then subsets of those regions interact more with each other than with the rest of the brain. And we call those distinct networks. Now in a very popular kind of way of separating the brain into networks, there are seven networks. One of them is like the visual network. One is somato-motor related to our sense of touch in our motor commands or movement. And then one of these is a Default Mode Network. And the thing with the Default Mode Network is it's actually composed of regions that span a lot of the brain. It's not just located in one spot. And these are parts of the brain that are the most developed in humans compared to primates.
0:12:04.2 Manesh Girn: So they're arguably the regions that make us uniquely human. And related to that as you expect therefore they're related in a lot of cognitive processes and aspects of our experience that differentiate us from other animals. For example, as humans we seem to have a pretty unique ability to be able to abstract from the present moment and think about things that are not here. We're able to kind of extricate us from the limitations of our immediate sensory inputs. And the research tells us this is what the Default Mode Network fundamentally does. It's an abstraction network that allows us to draw on internal representation, stored knowledge in terms of experience and concepts, to think about things that are not here, and also recombine those things in new ways as in imagination or future planning.
0:12:54.0 Manesh Girn: And so Default Mode Network as a whole is this advanced network that allows these processes and under its rubric are also our ability to conceptualize ourself and create a story about who we are. This is where the link to ego dissolution comes from because it's involved in our sense of self in terms of it's the narrative around who we are or what researchers sometimes call our autobiographical self, again rooted in memory. And it's also related to our ability to think about the minds of other people. And it's very involved in our social cognition, our ability to, all the thinking that's involved in social interaction.
0:13:29.1 Manesh Girn: And people don't really know this, but if you're watching a movie, Default Mode Network is highly involved with that, and it's connecting to our visual networks because we're seeing the movie, but then we're not just watching lights on a screen, we're giving it meaning and structure and applying frameworks to it, and this application of frameworks to perception is mediate by the default mode network network... So again, you can take it a bit more broadly, whenever we're using our internal frameworks for knowledge to interact with the world or think internally in terms of day-dreaming, the default mode network is engaged. And so, psychedelics, so where this emerged with psychedelics was initially with the 2012 paper, which was the first ever paper that looked at that used fMRI Functional Magnetic Resonance Imaging to look at psilocybin. This was done by Robin Carhart-Harris and at Imperial College, London.
0:14:18.8 Manesh Girn: And so you can imagine they gave people some psilocybin and they put them in these brain scanners and you would expect the whole brain is gonna light up, it's gonna do crazy things because the psychedelic experience is so complex. What they actually found was there was only deactivations, and these were specifically in the Default Mode Network and then immediately they're like, Oh, this makes so much sense, it's turning off our conceptual filters, the things that limit our experience, and it aligns with Aldous Huxley and others talking about this reducing valve, how the brain, rather than creating our experience of the world is limiting and filtering information it's receiving to make it manageable for us, and so it really aligned with intuitions and things, and they also found a correlation between things in the Default Mode Network, and Ego dissolution in that data set, and so that inspired people's imaginations, so it just made so much intuitive sense.
0:15:07.5 Manesh Girn: And then what people don't realize is that when the 2016 paper with LSD came out, which is four years later, using the same methods but for LSD, they didn't find the same deactivations in the Default Mode Network. There were some correlations with Ego dissolution, in the Default Mode Network, but the whole concept of the brain becoming more deactivated wasn't there as much, and then a more complex picture started to emerge that researchers were turned on to, but still the public were still stuck on the Default Mode Network story. And then when Michael Pollan's book came out, I'm not sure, I don't remember when it exactly came out maybe 2016 or around there.
0:15:42.6 Paul Austin: 2018, it was made May 2018.
0:15:44.1 Manesh Girn: Okay, 2018. Then he kind of put that into that book and that just, that turned a lot of people on to psychedelics, and it just grew into this dogma almost like, "Yeah, DMN equals ego dissolution." But the reality is now, any researcher and Robin Carhart-Harris himself, like we've chatted about it many times, are no longer on board with that idea, it's just the Default Mode Network. We recognize it's much more complex. Psychedelics affects the whole brain, you can't reduce it to a single network, and there have been several studies which specifically looked at Ego dissolution and the Default Mode Network. And did not find an association. So it's no near unequivocal.
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0:18:09.9 Paul Austin: So my understanding, just to reflect some of this, with the Default Mode Network, when we talk about, its kind of the role that it plays in psychedelic healing, is that these clinical conditions, for lack of a better term, depression, addiction, OCD, anxiety, when individuals are struggling with these issues, their Default Mode Network is a lot more rigid, so to say. So there's a rigidity that is present, there's sort of a calcification, if you will, and what psychedelics do is they interrupt that process to create space, so there's more, let's say, flexibility and plasticity. So that way, these default patterns that we always find ourselves in aren't necessarily the choices that we make after a psychedelic experience. So the best known metaphor is Mendel's metaphor that was amplified in Michael Pollan's book, Mendel made the point that in the brain, with these sort of grooves, we're used to following them and then we have this fresh thing of snow that comes down, and now all of a sudden we can make new grooves in our brain. And I sense even as I'm talking about this, there is a intermingling of maybe technical terms, because even the sort of new Groves may or may not have something to do with the Default Mode Network.
0:19:39.0 Paul Austin: But my whole point in saying this is the default mode network as you emphasize, is not a bad thing, just like the ego is not a bad thing, it simply is a thing that allows us to exist in reality. And the impact that psychedelics have on the default mode network or the ego or whatever it is, can be beneficial. But also it goes well beyond the default mode network. And so I'd love for you to further expand on that, right? So this comes down to a recent paper that you published, which if you want to talk through that in detail, you're more than welcome to. But talk about some of the other systems or networks or models, that neuroscientists are exploring when it comes to the efficacy in psychedelics for healing, for transformation. Maybe not even specifically ego dissolution but just generally what's happening in the brain when we work with psychedelics and why are they helpful for us as humans?
0:20:41.2 Manesh Girn: Yes, definitely. And first I wanna quickly speak to this whole thing, about the DMNs, the default mode network, centrality across mental health disorders and this idea of shaking the snow globe, or putting a fresh layer of snow on the grooves to allow for new states. A lot of that is honestly speculative storytelling and stories that are useful in a practical pragmatic sense, but not necessarily fully validated scientifically. And so then we get into... That whole... That leads into a whole discussion on the ultimate utility of these findings. For example, if somebody's able to use those metaphors and believe that that's what happens in the brain, that could be very helpful for them for their healing process. Even though strictly speaking, it might not be "objectively true". And then it's, okay, so what do we... How are we leveraging these scientific, these ostensible scientific facts? Right?
0:21:33.3 Manesh Girn: But it is the case that the default mode network is implicated in a variety disorders. And it also, it relates to our kind of spontaneous thinking, the thinking we engage in on a day-to-day basis all the time, mind wandering. And so the idea is, yeah, if you perturb the functioning of it, if you break it out of its usual patterns, then you're escaping out of those usual patterns of thought, which might be more rigid and stuck into little ruts, which, hence rumination or OCD, etcetera. And so that all makes...
0:22:00.7 Paul Austin: It sounds nice, right?
0:22:02.2 Manesh Girn: Yeah.
0:22:02.9 Paul Austin: Like it sounds like it's clean, it's tight, it's coherent, there's a good story behind it, it's easy to talk about. But what you are saying is it's science is never... It's never necessarily that simple. And a lot of these assumptions are not necessarily validated by science, by clinical trials or fMRIs or whatever else.
0:22:24.1 Manesh Girn: Yeah. Totally, totally. Anyway, yeah, it's over. It's always... The answer is always, we don't know enough, it's more complex. That's science. So if we come back to my paper then, this paper was recently published in Trends in Cognitive Sciences and the name of the paper is, "A Complex Systems Perspective on Psychedelic Brain Action." And it goes straight in line with what we've been discussing and this concept that you can't just focus on a single network in understanding psychedelics effects on the brain. Psychedelics fundamentally affect the way the entire brain functions. And they affect a variety of networks beyond the default mode network.
0:23:00.3 Manesh Girn: And so one way to, kind of in a more nuanced fashion, relate to the brain to psychedelic effects is to ask the question of, how do psychedelics change fundamental ways that the brain processes information? 'Cause intuitively it makes sense that that's what happens. You'll be in the same environment, the same light will be hitting your retina, but how it's being processed is radically different. You'll be hearing things from people, but your whole... The way that perceptual input is received by your system is radically different. And the way you think about it is radically different. It doesn't really make sense in my mind to even ask, "What is the one brain state or one region or network that does that?" It's like, how is the whole brain dynamically changing its activity over time in interaction with the external environment, whether it's people or like physical objects. And so this paper was motivated by those ideas on how to expand beyond this localized approach but also the recognition that a lot of brain imaging research with psychedelics so far, has a lot of inconsistencies.
0:24:08.2 Manesh Girn: Like sure, reduced connectivity within the default mode network, whatever it means ultimately is a pretty consistent finding. And so you do see that in most studies or basically all studies with psychedelics. But beyond that, there's a lot of inconsistencies. If you look at the other networks and how they interact, sometimes you'll get stronger effects in certain networks related to attention and how they interact with other networks, sometimes more in motor networks, sometimes more in this network. And it's with the same drug and when scanned by different research groups, are finding different things. And so it's like, why is it so different? Is it just impossible to get something consistent with psychedelics? Is there something fundamentally wrong with fMRI? How can we reconcile these inconsistencies? And what really drew my attention to how strong these inconsistencies were, was when I was looking in detail at individual people.
0:25:07.6 Manesh Girn: 'Cause when you see these studies, you're looking at averages of anywhere from 10 to 30 or more people. But as we know, everyone responds to a psychedelic very differently psychologically. So you would assume that in their brain it's not gonna be the same thing that would... This wouldn't make sense if we assume that the brain and mind are interlinked, which they seem to be. And so then looking at individual people, people had radically different responses. Sometimes opposite responses. So it's like, okay, how do we make sense of this? So then with this model we were drawing on something called Complexity Science. And so Complexity Science is a way of understanding any system of interacting parts. And usually that dynamically changes over time. For example, an ecosystem, let's say a forest, in order for that ecosystem to be in equilibrium, the jaguars need to eat the rodents and the, I don't know, the eagles have to attack the jaguars and everything has its role in place. And if you take out the jaguars, the mouse population will proliferate and they'll destroy the plants, and then the animals that eat the plants will get messed up in their diet. You see how everything's an interconnected whole.
0:26:16.3 Manesh Girn: And so in this paper, we're applying that same kind of thinking to the brain. It's like every brain region plays a role, but in synergistic interaction and complementary interaction with each other. And so if you perturb one part of the brain, it's gonna propagate throughout the brain. So how can we understand this propagation? And so we drew on a whole bunch of fMRI findings, and also findings about how the brain functions independent of psychedelics to make the argument that psychedelics, what they're doing is inducing a different state of whole brain functioning. They're changing the way the entire ecology functions of the brain. And in particular it's making the brain, making the whole ecology and making the whole brain more integrated. So information is able to propagate throughout the network more easily. It's making it more flexible. So it's patterns of interaction change more over time and it's making it more adaptive and sensitive to inputs that come in.
0:27:12.3 Manesh Girn: So if the ecology of the brain is receiving an input, let's say information into the eyes or verbal information, it's much more sensitive to it. It's able to incorporate it into its functioning in a much more sensitive way, such that it's able to respond many different ways in response to the same stimulus. So there's a greater flexibility and adaptivity of response to stimuli. And, that this kind of change in functioning, depending on what stimuli it's receiving, is gonna manifest very differently. If the brain is processing information differently in a fundamental way, where the brain is gonna go is dependent on the interaction between the information it's receiving and that new mode of functioning. And so for one person, you might take a psychedelic in one particular environment and given their past psychological history, their traits, all these things are encoded in the brain and that's gonna interact with the drug as well as the inputs you're taking in environmentally and send you along a different, you could say, trajectory or path of states in the brain and mental states.
0:28:20.1 Manesh Girn: And that's your unique psychedelic journey. Somebody else in the same context is gonna have a very different experience because their brain's different or they're in a different environment. And so this framework tells us how it's more, the psychedelic effects are more abstract. They affect the way the brain processes information and the way that... The goal can be very different for different people. And this is actually consistent with several findings, in the field as well.
0:28:42.9 Paul Austin: Okay. So I wanna, I wanna do my best to land this. So what I'm hearing, and correct me within this, 'cause I think it'll be helpful for a listener understanding as well, is the brain when working with psychedelics, will have, it will be impacted differently depending on the type of psychedelic, depending on the environment in which you are taking that psychedelic, depending on the amount of psychedelic that you are doing, their... Depending on one's trauma path, history in terms of what's already been encoded in the brain. And that, and I love the metaphor of like ecology, that our brain is interconnected, like you said, complex systems, complex science, all of these things are working together. And that when we do a psychedelic, it activates certain parts of the brain, that helps to facilitate greater coherence between all elements of the brain, which means the way that I feel is I feel more centered, I feel more present, I maybe feel outside of time, I'm not as stuck in stories of the past or stories of the future.
0:30:03.4 Paul Austin: And I'd love potentially, I'm now extrapolating kind of from what you're talking about. And I would love for you to maybe discuss a little bit about like, what parts of the brain are usually not that activated, that become activated through psychedelic use that lead to some level of healing, some level of insight. For example, is it the prefrontal cortex, is it the hippocampus? Is it the cerebellum? Is it kind of what's going on from that lens and that perspective in terms of these different physiological parts of the actual brain?
0:30:41.2 Manesh Girn: Yes, for sure. First I wanna say that, you know, it's, although yes, this change of functioning can translate into a more balanced centered state that's conducive for healing, as we both know it doesn't have to be that. It's not necessarily gonna be that. And I think it depends on the inputs you're receiving and all these things I was telling, which is gonna interact with the effects.
0:30:58.9 Paul Austin: For sure.
0:31:00.3 Manesh Girn: And so the whole thing about set and setting and proper prep and all these things is to be able to kind of control what inputs, what information is interacting with the drug to produce a particular experience. And so if you feel safe, ready to surrender with close friends, no surprises, no crazy things going around you that's creating a set of information or stimuli or inputs which interact with the drug to produce a positive experience. Right? So that's an important part. Like I think what I wanna emphasize with this paper is that it's neutral. It's changing the way the brain functions. If you put in garbage, the garbage is gonna come out. If you put in good things, you're more likely to have good things come out. And in terms of specific regions, so, I'm kind of hesitant to answer, that because I think even there's a movement towards conceptualizing things like depression and other disorders as whole brain phenomena, right? It's like what is their brain as a whole doing differently?
0:32:03.1 Manesh Girn: Because again, it's like, if you were to quote unquote like, or disintegrate the default mode network, that's gonna have ramifications throughout the brain, it's like, okay, so then can you really just look at the default mode network and ignore what's happening in the rest? And there's this movement in psychiatry, you know, it's biological psychiatry is all the rage these days. So they're trying to find what are the biomarkers associated with different disorders, right? And so usually that's in terms of training a machine learning classifier on people's whole brain and doing it for like 100 sorry, like over a 1000 people. And then that classifier will find regions or networks across the entire brain and different patterns of them and how they relate to different subtypes or types of a given disorder.
0:32:41.1 Manesh Girn: And so for example, one subtype might be focused on default mode network, one subtype might be more focused on attention networks. And then you can make the argument that what each of those people need might be different because their depression or whatever is taking a radically different manifestation in their brain. And so, I think similarly psychedelics are gonna affect different regions more for different people and that's gonna have relevance for different disorders in a more of an individual specific way. So I think what's interesting here is the movement towards more of a precision medicine approach where we look in more detail an individual person, what's their unique brain like? What's their unique presentation of something like depression in their brain? And how can we make inferences about, for example, which psychedelic or which environment might be better for them based on an idea of what psychedelic-induced brain states will counter the pathophysiology brain states of depression, the negative brain states associated with that?
0:33:44.8 Manesh Girn: And for some people, maybe you need more prefrontal cortex connectivity with other regions, with the amygdala, what have you in order to increase your ability to regulate through emotions or regulate through a thought stream or for someone else it might be, I don't know, related to their insula, which is a region involved in your body awareness and connectivity with your bodily signals. Maybe it needs to be more somatic for them or it could be really anything. And so, I think what regions are most important in terms of your experience and also clinically is gonna be different based on the person. But again, it's like you have to take into account the whole brain context to make these inferences.
0:34:24.6 Paul Austin: Now, what comes up as you're talking about this is neurofeedback. I have done some neurofeedback. I've worked with a practitioner out here in San Diego who's a world-class practitioner. He did a brain scan prior to the neurofeedback, identified certain parts of my brain that maybe weren't as hooked up or connected. Kind of showed it to me on a map, said, "Okay, now with neurofeedback we're gonna tie these together and create greater connectivity between these two." And then we did three days of neurofeedback with some sort of core intentions. And what I found to be true with neurofeedback is neurofeedback felt much more... It felt like a precision modality. In other words, it felt like sort of my brain was an instrument and we were going in with neurofeedback and we were tuning the brain to facilitate different states. And whenever I would talk about my experience with neurofeedback, I would compare it with psychedelics where psychedelics felt more like a volcano.
0:35:23.3 Paul Austin: It felt more like it was catalytic, where it was... There was less of a capacity to be precise about the application of that for certain indications. And so, I'm curious from your lens, how can we make psychedelics more precise in this way? What needs to happen? What research has to be done? What... Yeah, 'cause I just feel like there's a gap right now. It's like, I can smoke 5-MeO-DMT and even the same friend of mine, he did brain scans with another friend before and after 5-MeO. And it was incredible what 5-MeO did in terms of what it activated and what it opened up. But there wasn't any sort of like oh... Like precision. Like, okay. Now you smoked the 5-MeO and we're gonna know that it's gonna do X, Y, and Z. There wasn't that ability necessarily. And so, I'm curious from your lens... I know this probably has something to do with the type of medicine. This probably has something to do with the amount of medicine and this also has something to do obviously with the set and setting and when you're doing it. But I'd just be curious kinda from your lens, how could we make psychedelics more precise as medicines for the brain?
0:36:34.2 Manesh Girn: Yes. Yeah, it's a great question. And one interesting thing here, 'cause you mentioned 5-MeO, is that 5-MeO actually works very differently than things like psilocybin or N, N-DMT or LSD and that it mainly works with the serotonin 1A receptor rather than the 2A. And the thing is, the 1A is more predominantly located in different set of regions such as actually the hippocampus and stress and memory related regions. And so, the neuroplasticity boost through 5-MeO seem to be predominantly located in different areas than the other psychedelics. And that would have ramifications for the therapeutic effects as well.
0:37:08.2 Paul Austin: Which it's interesting because it's a tryptamine still, so the assumption would be that it would be similar to N, N-DMT because it's a tryptamine or that it would be... Why is it different? Any sort of insight into that?
0:37:21.1 Manesh Girn: Yeah, it's hard to know unless, maybe certain chemists might know the relationship between the chemical structure and what receptors. But for whatever reason it's quite differently. Whereas the other ones like psilocybin or N, N-DMT, you give a serotonin 2A receptor blocker, you're basically blocking all effects. Not necessarily the case with 5-MeO, there seem to be... Well, to make it sound as intense as it is, the affinity of 5-MeO for serotonin 1A, how much it is drawn to it compared to 2A, is somewhere around 300 to a thousand times more. So it really goes there. And you only get strong serotonin 2A receptor activation at higher doses of 5-MeO. So you still get it, it just takes more.
0:38:07.0 Manesh Girn: And again, this has ramifications for neuroplasticity that we really just don't even know yet, 'cause the research is still in its infancy. And especially with 5-MeO, there's not that much neuroplasticity research actually specifically with that. In terms of how to make psychedelics more precise, I think it's really about, one, understanding more about where these drugs... Kind of the selective differences and what regions these different drugs target neuroplasticity-wise, for example. And then also really just on the therapeutic support side. It's like, right now it's the Wild West in terms of what is the therapy and psychedelic assisted therapy? So people say, "Oh, CBT is the way to go, or ACT, or somatic therapy, or you just gotta shut up and let the inner healer do it all." And so there's really... It's unclear on which one is ideal, if we can even say one is ideal or the best, or which ones are better for specific applications. People have their own intuitive understanding of that, and a lot of practitioners who have been doing it for many decades or what have you have an idea of that. But in terms of the literature and scientific medical context, we really don't know.
0:39:17.9 Manesh Girn: And so I think in order to try to make more specific targeted interventions with psychedelics, it needs to be informed by a greater degree of knowledge on the neuro-pharmacology side but then also in terms of the interaction between different therapeutic frameworks and the effects of psychedelics, and what interventions should be coupled with it, and also what environments. Like, we haven't even looked at the efficacy of taking psilocybin in a forest versus in the standard, I don't know, comfortable living room type environment. We don't even know that yet. We don't even know the effects of set and setting, really. It's just assumed since, Leary, that that's a thing. And we assume somewhat that our medicalized lying on the couch with two therapists is the best way, but maybe at the beach, for some people. Maybe in a forest. Maybe... Wherever.
0:40:09.6 Manesh Girn: Yeah, so a lot of the times, it's a very shotgun approach with psychedelics, as you're saying. It's like... I heard this analogy, or whatever it is, if it's not an analogy, recently of shooting a cannon at a rabbit. It's like [chuckle] kind of blasting the whole thing in order to try to get something might be a bit more specific. And that's just what we have right now. But with everything I just described, or even the creation of second, third generation psychedelics, which are somehow more targeted as well, might be the way to go. But all this stuff is years away, I think. We're still really in the early stages exploring this stuff.
0:40:42.6 Paul Austin: Yeah. And in some ways, it... I've been hosting this podcast for six and a half years, and I have been talking about personalized medicine for about that length of time. So it's always been a thought, an idea, something that's on the cutting edge, something that we feel like we're on the precipice of leaning into. And yet still here in 2023, the vast majority of people don't necessarily have access to what we would consider personalized medicine. A lot of it, what I found, comes down to intuition and mentorship. So in other words, like if I've done X, Y, and Z and I have a friend or a colleague or whoever who reaches out to me and they give me a little bit of context and background about their story, then I might be able to make a recommendation based on that. It's why we at Third Wave are investing so much in our training program for coaches, because there's a lot of, I think, insight and wisdom that just can't yet be captured by modern technology because it's simply not accessible to the degree that we would want it accessible for.
0:41:43.1 Paul Austin: Because not only is it a matter of, "Okay, everyone could... Like, it'd be so cool if there was a technology that made it easy where I could... I could go on Amazon, I could buy a brain scanning tool for a hundred bucks. I could scan my brain every morning to see how it's changing. And then based on that scan, I could submit it to a coach and they would tell me, "Okay, take this microdose or take this psychedelic." Maybe I also submit my Oura Ring data and they go, "Okay, I'm seeing sleep here. I see... "
0:42:10.8 Paul Austin: But the interpretation of that data itself is quite difficult anyway. So training and education and bringing all the people into this is quite a lift. So for the time being, my sense is this, like for any listeners who are at home, who are joining us, kind of having an intuitive sense of where you're at, talking with people that you trust, who have maybe walked that path before you, and then simply experimenting to some degree with different medicines, with different amounts of medicines. Always ideally with the support of either a trained therapist, a coach, or at least a good friend, feels like the... Like you said, we're still in the Wild West to some degree. And I'm not sure... Because of all the bureaucracy, because of all the red tape, I'm not sure when that inflection point will hit. I feel like we've been building up to it, we've been building up to it, but we haven't reached that inflection point where all of a sudden this personalized approach is widely accessible and people can easily utilize it. I know it will happen at some point. It just continues to be unclear as to when that might be the case. Any thoughts on that? I know you're...
0:43:21.2 Paul Austin: So one thing I was gonna mention is you're joining Robin Carhart-Harris as a postdoc. He's working with Adam Gazzaley, who we've had in the podcast before. Adam is attempting to pioneer a lot of these things. When you think about precision medicine, when you think about neuroscience, when you're looking at the research, where are we at in that process? Are we actually reasonably close? Does it feel like we're potentially many years off? What are your thoughts on this whole precision medicine, neuroscience psychedelic overlap?
0:43:51.0 Manesh Girn: Yes, for sure. I think a large... Well, the main issue with psychedelics is the cost of collecting data. So for precision medicine and to be able to predict based on, let's say a combination of biometrics and neuroimaging and psychological measures, if we bring all that together and try to predict what drug they need or what treatment is better for them, etcetera, essentially, at the end of the day, you need these machine learning models. You need the algorithms which are able to take all that data and parse out some structure and map that onto things you want to map it onto, and that requires lots of data, like probably thousands of people to make it accurate, usually. 'Cause mental health is so complex, it takes various forms, etcetera. And so the thing with psychedelics is it's so costly to have somebody take psilocybin and then you have to look after them for 6-8 hours, and then you pay for a therapist time, you pay for a physician time, you pay for the technology. That adds up. And scale that to 100 people, it's already a lot of money. Then you need thousands. It's kind of crazy. Especially when federal funding and these things are starting to trickle in for psychedelics, but historically, they haven't been there this last decade. And so data is a major thing there. But I think there's a lot of promise in the precision medicine, as you're saying. We just need better models and more data.
0:45:08.4 Manesh Girn: And partially what they're doing at Neuroscape, which is where I'll be working with Robin and also Adam, is trying to incorporate more of these multimodal biometrics and seeing how they change with psychedelics to get a sense of how they're affecting more basic things like heart rate variability, like in our sleep patterns and a variety of other physiological metrics and how they relate to the psychological ones, etcetera. The ideal, I think right now, and this is kind of what some of the projects are aimed at, you want to be able to know based on baseline or immediately after their first experience, what's your likelihood this is gonna be a long-term benefit? Is it more likely they're gonna need another experience in three weeks, in a month, in six months? And all these other different concerns that they might have of, is it safe for this person to go off their medication or not, and are they showing markers suggestive of a strong relapse into suicidal ideation? And I think the more data we collect and the more multimodal it is spanning psychology, the brain and also physiology, the more accurate our models will be. And we're definitely moving towards that. But as you said, we've been moving towards that for quite some time. And I think good-quality, reliable data is largely the bottleneck.
0:46:22.1 Paul Austin: Yeah, and like I said, I sense we're building up. There's a lot of building, there's a lot of building. There's clearly people who are at the cutting edge. There's early pioneers. I would consider myself to be one of them. I think I would consider you to be one of them as well. But we haven't yet reached a point where it has hit that inflection point. And all of a sudden, we all have Oura Rings, and we're all getting blood tests, and we're all doing our own brain scans and looking at how we dial in. I think that has to be the future of medicine. That's sort of decentralized, democratized accessible approach. So people can really own their own data, they can own their own choices and decisions and see what the actual impact of those choices and decisions are. But right now, the vast majority of people are not anywhere near getting behind this.
0:47:09.4 Paul Austin: Slight transition. Although you were just touching on this. Robin Carhart-Harris, Robin is one of probably the most prominent psychedelic neuroscientist currently alive today. I think last year or the year before, he was mentioned in Times Top 100 People To Watch. He was at Imperial for a very long time. He was one of the original Three Musketeers with Ben Sessa and David Nutt. And he is now at UCSF with the Ralph Metzner Distinguished Fellowship Professorship or something like that with Adam Gazzaley, and they're doing some really dope shit. Tell us a little bit about your relationship with Robin and why you were choosing to join him as a postdoc at UCSF.
0:47:54.1 Manesh Girn: Yeah, for sure. So I've been collaborating and working with Robin since around 2017, something like this. And me, as a young researcher, obviously, I saw his papers in the news, in the media. I'm like, "Oh, how can I get linked to this guy?" And he's kind of this high... This figure who's way up there. Everyone puts him on a pedestal, etcetera. And around then, 2017, I came up with an idea to analyze some of their LSD data in relation to creativity and in relation to research I had been doing at the University of British Columbia in a cognitive neuroscience lab. And long story short, I ended up publishing a paper on... A partial review, a partial experimental paper on psychedelics and creativity, and that came out 2018, I believe, and that forged a collaborative relationship between me and Robin. And since then, we've published... We've been on three other additional papers together, including the one I was talking about before. He's on that paper. A lot of those ideas were born out of discussions I had had with Robin over Zoom, etcetera. And so now, we talk quite often and get along very well. He's a wonderful, humble, easygoing person and obviously very, very knowledgeable, and has been at the forefront of this stuff for over a decade, obviously. His whole career is him playing the role of a pioneer and giving the credibility to psychedelics in neuroscience and science, and so he's played a huge role.
0:49:19.1 Manesh Girn: And so yes, when I was 20 years old, I was like, "Oh, I wanna work with this guy." This guy did the first study with psilocybin, and it was a little bit before he did his LSD one. Anyway. So then when it came to finishing up my Ph.D., which I'm doing now, I'll graduate in a couple months with it, and it was a no-brainer, like, "Robin, I'm gonna work with you." And originally, I was gonna go to London to work with him there, then he went to San Francisco. It's like, "Even better." 'Cause I'm from Vancouver. I'm a West Coaster, for sure. And just a few hour flight from where I grew up, and San Francisco's beautiful, lots of the stuff going on, better weather than Canada, and London for that matter. And I'm just really excited to go down there, because not only working with Robin and Adam, the whole environment there is so interdisciplinary and also inter institutional. You got Berkeley nearby, you got Stanford nearby, got a lot of people interested in psychedelics and related topics. The whole biohacking world, the tech world, obviously, Silicon Valley and all these kind of things. It just seems like the perfect environment to do rich, impactful research.
0:50:27.9 Manesh Girn: And so I knew the opportunity was there to work with Robin, and of course, I took it, and so, yeah, that's what I'm gonna be doing. And with him, what I'm personally gonna be focusing on is diving deeper into how psychedelics alter our sense of self, and our beliefs about ourselves, and how we process information related to ourselves. And this theme of the self is a major theme in the world these days and across mental health. And a lot of speakers, thinkers, visionaries often emphasize how our individualized society and our sense of separateness from each other is at the core root of a lot of problems we're facing at a civilization level, disconnection from the environment, from each other, in-group, out-group mentalities, and dehumanizing others for various traits, and this whole myself at all costs mentality.
0:51:25.7 Manesh Girn: And so with psychedelics, we all know they can induce "mystical" type experiences and feelings of connectedness and connection to others and universe and whatever you want to call it, and these are... Seem to be related to people getting better from things like depression. But the thing is the manner in which psychedelics affect our beliefs about ourself and how we process self-related information and how we conceptualize ourselves is in its infancy. There's a lot of research outside of psychedelics looking at it in cognitive psychology and cognitive neuroscience, but that research is so independent and siloed off from psychedelics. In the psychedelic realm, we have our concept of ego disillusion, we have our concept of mystical experience, but we're not intersecting nearly as much as we could be with the existing literatures in these other areas related to self and self-related processing, etcetera. And so with Robin, I wanna help create those bridges to enrich both the study of our sense of self and self-experience and self-related processing and self-beliefs. That literature itself, but also how psychedelics alter these things in a more empirically sophisticated and rigorous way, to basically understand at a deeper level how and to what extent are psychedelics making these changes for people.
0:52:40.9 Paul Austin: And so what are some of the core hypotheses that you want to explore as part of that?
0:52:45.7 Manesh Girn: Definitely. So like on the basic level, we think that... Well, I think that with psychedelic use, one, we start to hold our beliefs about ourselves less strongly in a general way. We start... We are less likely to cling to, "This is who I am, this is what I'm like," and the corollary is, "This is what the world is like, this is how things are." It kind of... I feel like psychedelics can induce a epistemic humility where we're like, "Oh, we don't really know what's going on, who I think I am and how I identify as is a construction created by my mind that is gonna change and is changing. And therefore there's no concrete basis for saying who I am fundamentally beyond saying something like you're, I don't know, the universe or the ground of all experience, or whatever. And so I hypothesize that people hold their self-identity less tightly and that the effects will be strongest for negative beliefs, where psychedelics can promote greater self-compassions, greater other compassion and reduce the strength of these negative beliefs we have about ourselves. And there's already some empirical evidence suggesting that, that negative beliefs in particular are reduced under psychedelics. But I wanna go further and see how does that relate to how the brain processes information.
0:54:01.7 Manesh Girn: And to make this all concrete, here's an example of how to test it. We could... For example, let's say I gave you five different little short stories and then asked you to imagine yourself as somebody in that story and then reflect on or choose from a list of like 20 beliefs what thoughts and beliefs about yourself would emerge in this context, and how would you feel about it? And then also you can look at how their brain's responding to this kind of thing. So let's say one story... Let's say I have been in a marriage for 30 years. You go on a vacation by yourself, you come home and you notice your room smells like somebody else's cologne or perfume, or something's off. There's some kind of ambiguous thing that happened that could be triggering if you're feeling insecure or uncertain. So we'll have that story laid out. It's like, imagine you're this person, how would you feel? And then some... You could choose and say, "I feel like the belief that, "Oh, I'm not really worthy of this person. They chose somebody else," or, "I'm not really worthy of love," or, "I'm not enough," or...
0:55:15.3 Paul Austin: I'd be fucking pissed off. That's what... I'd be angry probably, I think.
0:55:19.8 Manesh Girn: Right, right. Yeah, yeah. Right, yeah. What emotions are you feeling? Are you feeling hurt and sad or angry and resentful? So all these things combined. And that one's a bit clear, like you'd probably be pissed off and suspicious, but the poll point is making them very ambiguous. So you could interpret it in a more charitable way, but you can also interpret it in a more, taking it personally and maybe almost insecure kind of way. Do you know what I mean?
0:55:43.9 Paul Austin: Sure.
0:55:44.7 Manesh Girn: And as a way to tease out what are their beliefs, 'cause you can ask people what your beliefs are, but it's more accurate to tease 'em out, 'cause then they can't really hide them and try to appear a particular way. And so getting 'em to do something like that before and after a psychedelic experience, maybe even during, under a certain dosage to see how are these things shifting for people. And then correlating that with... You can do biometrics, you can do brain changes, you can do other psychological measures, you can do depression scores. And you're seeing how does all this stuff hang together, and how could that help inform how psychedelics are working at a deeper level.
0:56:20.6 Paul Austin: One thing that I've always thought to be true about psychedelics, which is reflected in Terence McKenna and the first book that he wrote, which was, not "Food of the Gods", nor was it "True Hallucinations." But the first book that he wrote was "The Archaic Revival." And so what I've always been interested in is how do psychedelics help us... In terms of this sense of self, how do they help us to identify with this sort of ancient sense of self, a self that is potentially tens of thousands of years old, a self that is beyond modernity and beyond sort of the distraction and noise of 21st century life, to really slow down and get back into what has made us human.
0:57:07.7 Paul Austin: You know, one of my other favorite authors and a good friend is Douglas Rushkoff. He wrote this book, "Team Human." Because right now, we're also experiencing a emergence of AI and robots and the sort of technocratic transhumanism approach. And so what I find to be most interesting about psychedelics and how they help us to perceive our sense of self is, one, this shift from atheism to spirituality. There's a lot of people, I think Michael Pollan talks about this, who are formerly identify with being an atheist that have a mystical experience through psychedelics and now actually believe that there might be something greater out there. And another one, which is more metaphysical, is the shift from maybe a physicalist or materialist worldview to a pan-psychic or idealist worldview. Does that map on at all to what you're talking about in terms of a sense of self, or is what you're talking about different or slightly different than these metaphysical or conceptual things?
0:58:17.9 Manesh Girn: Yeah, yeah. It definitely intersects with them because who we are... They construct our conception of who we are. "I am an atheist." People identify with that strongly, and that actually then has an influence on how they emotionally react to things, how they interpret things, how they navigate the world. So I think those things are relevant to the extent that we take them apart of our fundamental identity. And so our metaphysical standings and so on are related to that. But I think, partially, I think people who do psychedelics with an intentional mindset and are very open to it and couple it with some kind of spiritual practice, whether it's meditation or yoga or whatever their preferred modality is, are less likely to strongly identify with any label like that. 'Cause those are just concepts. They're constructions of our mind. And I think psychedelics tell you that and throw that in your face, how they are that.
0:59:09.0 Manesh Girn: And so I think it's interesting even to think about that as a studiable hypothesis. Like, to what extent do... Again, I just kind of I said this earlier. It's like, do our... All of our things that we say comprise our identity. Do they all start to fall away? Do we start to just be like, "Oh, actually, I'm just gonna... I'm more comfortable, perpetual uncertainty about myself and the world. Maybe God does exist. Maybe it doesn't. Maybe this is all this consciousness. Maybe it all is this inner to physical matter in complex configurations that seem to give rise to life and give rise to things that are beyond the physical." And maybe we don't know any of these things. And maybe you're okay in that state of unknowing. And I think psychedelics can help with that. But it's like... One question is, what percentage of the population go that route? What predicts that? How can we... How are their brains different? And so there's so many questions on these different ways that people can go, which I think are so interesting. 'Cause I think it's fundamental. It's very relevant to each of us on our own journey and trying to understand who we are and how we make this dance between certainty and uncertainty, known and unknown and all these things. I think it all, in some way, intersects with what do we identify with? Who are we? That's always the fundamental question, I think.
1:00:25.7 Paul Austin: And that's, I think, what's so interesting about this postdoc work that you wanna do with Robin, is, although you're a neuroscientist, and Robin is definitely a neuroscientist. I don't consider him really to be a philosopher whatsoever. What you are exploring is starting to be philosophical, right? What is our sense of self? How does our sense of self change, evolve, grow, adapt as a result of working with psychedelics? And I think, to go back into the point that you were making earlier in the podcast, when we look at the ecology of the brain, everything is connected. And I think the same approach, the same interdisciplinary approach when we're looking at neuroscience is then what is the philosophy? What are the metaphysics that undergird the research that we are carrying out? Because as you know, as I know, as many of our listeners know, science can be corporatized, or science can be bought. And so being very lucid and clear and objective in terms of why are we asking the questions that we are asking, I think is just as important as the actual questions that we ask because that metaphysical undergird will actually influence then the impact that those questions have and the impact that that research has beyond just the laboratory.
1:01:39.8 Manesh Girn: Definitely. And I think for me, these things are so interconnected. Like, I think the whole... The world we live in academically is fundamentally more and more interdisciplinary. You can't just be a neuroscientist or be just a philosopher or just a whatever. You're intersecting with many different fields. Then you get things like neuro-archeology, or neuro-anthropology, or neuro-archeo-anthropology, and it's like you're just mixing all these different disciplines. And then we realize how artificial these distinctions are in the first place. Like, they were created perhaps as a stage of our knowledge to differentiate in order to understand. But now we're coming back to reintegration to understand the linkages.
1:02:20.9 Manesh Girn: And so when I... Sure, my training's in neuroscience, but I read just as much into philosophy and like to ask those questions, to discuss those and see how it intersects with other disciplines. I mean, that's what we have to do moving forward, because again, these divisions are artificial constructions of just institutions and language. They don't necessarily point to real demarcations in the world. And I think... This is why I love psychedelics, 'cause they really cut across inter disciplinary divides. You need to bring in the anthropology, the religious studies, the philosophy, with the neuroscience psychology, the psycho-pharmacology. And they all intersect in the most fascinating ways. And I think you have to... You can't just silo yourself off these days.
1:03:04.3 Paul Austin: I love that. Alright, there's no siloing. And maybe that's a... That's probably a great way to even wrap the podcast conversation up. There's no siloing. Everything is interconnected. The brain is interconnected. We can't just silo it to beat the default mode network. There are way more complex systems that are at play that we're learning more and more about. We touched on some of those today. I remember before we went live, I asked you what are three things that we want to cover to help people realize that psychedelics go beyond just the default mode network. That we all have varied responses to psychedelics and that psychedelics change our brain temporarily in terms of how we process things. And that depends on set and setting. That depends on the amount that we take. And that depends on all three of those things. And I feel like we adequately covered all of those. So to me this has been a successful conversation and podcast. Manesh, thank you for joining us. If folks wanna learn more about your work, if they want to, for example, read the research paper that we briefly talked about, just point them in a general direction. And we will have links on Third Wave's website to all of this in case people are driving or can't pull up the thing immediately.
1:04:09.5 Manesh Girn: Yeah, totally. Psychedelic Scientist on YouTube, on Instagram. On Twitter, I'm MGirnNeuro. You could just probably just search Manesh on Twitter, you'll find me. Also on LinkedIn, Manesh Girn. And if you want access to the paper, I do have a link to free access, to enable free access to it.
1:04:27.0 Paul Austin: Share that with us, Manesh, and we can put it in the show notes...
1:04:30.6 Manesh Girn: Yeah, definitely.
1:04:30.7 Paul Austin: For the people to be able to check out as well. That would be dope.
1:04:34.3 Manesh Girn: Yes.
1:04:34.4 Paul Austin: So The Psychedelic Scientist on Instagram and YouTube, or MGirnNeuro on Twitter. And then we'll have a link to that paper as well. What's the title of that paper, Manesh?
1:04:43.7 Manesh Girn: So the title of the paper is A Complex Systems Perspective on Psychedelic Brain Action.
1:04:49.2 Paul Austin: Oh, cool. I love it. All right. Well, thank you so much for joining us, Manesh.
1:04:53.1 Manesh Girn: Yeah, thank you.
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