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Dr. Gül Dölen

lines on the record: 110
first: 2023-04-19
most recent: 2023-04-19
sittings or episodes: 1
sources: podcast

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“Might be beneficial in allergy sort of independent of this learned association framework that I'm proposing around the critical period. So we just don't know yet. I like the idea though because there are a few anecdotal stories of, you know, I think Andrew Weil has a story where he cures himself of.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Immune system, which is ordinarily used to fight off parasitic infections, is left jobless. So the idea is that in that state of joblessness, it sort of goes out looking for another threat to fight against, to protect the body against. And in this formulation, I am thinking, well, what if how that threat gets assigned is really through the brain. The brain is saying, okay, well, that dog is barking at you and your immune system is left jobless. That's threatening. Go fight against the dog proteins, right? If that's true, at least in a subset of patients,”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Well, first, I should premise this by telling you that my mom is an immunologist and she hates this idea. So she and I spar. So we spar over this. And, you know, we have a very different view of the relationship between the immune system and the nervous system. She basically lives in an immune-centric world where the nervous system is just like an effector, you know, downstream effector of the immune system, which is the primary controller of everything. And obviously, I think it's the other way around. So the idea with allergy is this. There is some epidemiological evidence to suggest that allergy has a higher prevalence in countries where the food and the water is largely parasite-free. And so that part of”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Might be caused by a failure to properly close the critical period. So even though theoretically, I like the idea of combining negative allosteric modulator of the M gluR with a psychedelic that can reopen, say, the social critical periods through metaplasticity in this case of a different receptor. I think in this case it would be the oxytocin receptor that would be the relevant one. I am a little bit hesitant to jump into human trials for that without first testing the safety of this in mouse models because again, there's this tension between there's some idea that the pathogenesis of the disease is related to a failure to close the critical periods properly. So I'm not sure that reopening them later is going to be necessarily the right way to go. So, you know, it's still a hypothesis that we're testing.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“You're very close, and you're actually sort of picking up on something that is a hesitation I have about using psychedelics and autism. So there's another, a third type of glutamate receptor that I love. It's called the metabotropic glutamate receptor, the M gluR. And the metabotropic glutamate receptor, we think is the one that whose signaling is so altered in fragile X. The metabotrobic glutamate receptors are also implicated as the brain matures, their expression goes down. And so we think that that coincides with the closure of the critical period. And what we think is that in fragile X, that MGLUR signaling is exaggerated. It's kind of not being curtailed in the right way. And so we have some evidence to suggest that autism”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Synaptic plasticity when the glutamate binds to that receptor. And that is the sort of original first classical understanding of what a metaplastic change would look like. It would be the change in the subunit composition of the NMDA receptor that enabled the baby receptors to induce plasticity more readily than the adult receptors do.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Interfere with memory. They do cause impairments in memory because they mess with the receptor that we think is super important for encoding memories. Now, in terms of this critical period idea, NMDA receptors, they're made up of different subunits and the composition of those subunits changes over development, right? So very early in development, the NMDA receptors have the subunit, the B subunit, is more predominant. The way I remember that is that that's the NR2B subunit is for baby. And then the A subunit is for adults. So as the brain matures, then the subunit switches out and it goes from being too B heavy to being 2a heavy. And what that does to the receptor is it makes it more or less likely to be able to induce that”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“The way the receptor is designed is that it's blocked usually by magnesium. And only when the neuron is active or the membrane potential changes and the magnesium no longer wants to sit in there, that magnesium comes out. Because of that property, the NMDA receptor is thought to be a natural coincidence detector. So it can detect when two neurons are firing at the same time. And that has gotten neuroscientists super excited about the idea that this is exactly the type of coincidence detection that would be necessary at a cellular level in order to encode memories. It's why people are excited about the NMDA receptor. Incidentally, it's also thought to be why ketamine and PCP”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Are a variety of things that have been attributed to the NMDA receptor. For a long time, it was my favorite receptor. And here's why. I know it's super nerdy to have a favorite receptor, but I'm into it. So NMDA receptors are fast neurotransmitter receptors, but they're not, they're different from AMPA receptors, which are the other major subtype of glutamate receptor because they have something that”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“So the metaplastic definition, I mean, it's a very specific definition, plasticity of plasticity. And in that case, it was defined by Mark Baer and Cliff Abraham. And it was a synaptic physiology. So it's, you know, synaptic plasticity, the change in response of stimulating one synapse and the magnitude of the response changing when you're recording the post-synapse. So a very narrowly defined again. So metaplasticity originally was used to define what happens in the reopening or the closure of the critical period for ocular dominance plasticity. And it was defined primarily in terms of the change in the subunit composition of the NMDA receptor, which is one of the receptors that's been so heavily. heavily implicated in learning and memory and specifically also learning and memory with regards to visual processing.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“For over 20 years now that says that the ability to induce plasticity also can change over time typically. So when you're young, your ability to induce plasticity is greater than when you're older. The ability to induce plasticity declines. And there are molecular things that control that.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Constraints on when we want the thing. And a drug of abuse like cocaine or nicotine, it sort of doesn't matter if you're hungry or you're in the right neighborhood or, you know, it's not out of your way. You just like it always. And that very ability to override that constraint is what we think the hyperplasticity is encoding and enabling and making those drugs so much more addictive. And so I wouldn't want people to confuse that property, that hyperplastic property with what we think is actually happening with psychedelics, which is that psychedelics, we believe, and there's starting to be other evidence to support this view are enabling what's called metaplasticity, which I know that it's confusing terminology, hyperplasticity versus metaplasticity, but metaplasticity is an idea that's been around.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“The breaks on learning and memory that are normally part of naturally rewarding stimuli that allow memories to be sort of encoded in a way that are driven by limitations on associations. So let me give an example because I'm sort of fumbling a little. So the example I like to give is that a natural reward like food, for example, we like food and if I like, let's say a turkey sandwich, I might remember the memory that I formed to a turkey sandwich that I just ate and loved would be something like, oh, I love that turkey sandwich. Next time I'm hungry and I'm in this neighborhood, then I'm going to go to that store and buy that sandwich again. I loved it. But for drugs of abuse, we override those kinds of associative”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“And this is an inaccurate and confusing terminology that I would really hope we could abandon because there are drugs that cause plasticity in the way that that word implies. And they're all drugs of abuse. So heroin, nicotine, cocaine, amphetamine, these are all psychoactive drugs that cause robust bidirectional plasticity. They cause the neurons to sprout. They cause the neurons to shrink. They cause robust changes. And it's that very plastic or hyperplastic property that we think underlies their addictive potential because that exaggerated sprouting or that exaggerated plasticity, we think is what enables drugs of abuse to kind of override.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“I think the two big ones that I have, let me start with since I'm already beating up on the people who do human research. Is thrown around a lot and it means a lot of different things to a lot of different people. So for a synaptic neurophysiologist, it has a very specific meaning. It's about something that you can record from doing wholesale recordings or patch clamp recordings or even unit recordings in the brain, but it's an electrophysiological property that is defined between two synapses. Whereas the clinicians basically use plasticity to mean anything that changes over time, which is so general it sort of loses meaning. And so I try not to use that word as much as possible, and especially in the context of psychedelics, because, you know, some people have tried to make the argument that what psychedelics are are so-called psychoplastogens or drugs that induce plastic.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Telling us the general rules of how you build complex behavioral functions from synapses, circuits, brain regions. And instead what they're telling us is something like the historical accident or the evolutionary byproduct of one animal's history of how they came up with this solution, but we haven't really learned anything about what are the generalizable principles, what are the motifs, what are the rules governing those circuit-level rearrangements that enable complex behavior.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“On by psychedelics, and from those types of analyses, we get the satisfying feeling like, aha, MDMA is causing the nucleus incumbents neurons to light up. It's causing the oxytocin neurons and the hypothalamus to fire and release oxytocin. We got it. We understand how these work. And I think the really, really compelling thing about the octopus study and why so many people who are not lay people just regular scientists were a little bit shaken by this octopus paper is because it challenges that very comfortable place that we've all been sitting with circuit mapping that you know we have an answer and what it says instead is is that yeah okay those anatomical results matter and they're telling us something but they're not”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Tim, I'm really glad that you asked that question because I think that possibly a lot of people in your audience know a little something about psychedelics and they've seen the studies where people have been given psychedelics and they take an ephMRI image and they point to this brain region or that brain region and say aha, this is where psychedelics are working and they get this sort of warm and fuzzy feeling like I understand now what's happening. And as a neuroscientist, I am susceptible to that interpretation as well. I don't do it with fMRI. I do it with circuit mapping and viral mediated gene transfer and look at it at a much higher resolution than fMRI imaging allows. So my lab, we do wholesale patch clamp electrophysiology so we can do single neuron resolution of these kinds of anatomical maps of what neurons are getting turned.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Answering those big questions like, well, what is consciousness? Well, you know, what is that mystical experience? What does it mean to feel like you're in an altered state?”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“That people talk about Zen Buddhists call it beginner's mind. If you were looking for a neurobiological description of beginner's mind, reopening critical periods would be it. And so what we think possibly is that, remember how I said that I was as an undergrad, I was really interested in getting around to using neuroscience to answer the really big questions that philosophers seem to have exclusive domain for Well, this might be it. It might be that if what it feels like to be in that altered state of consciousness or that mystical experience that we think of with psychedelics is just what it feels like to reopen critical periods, then this explanation, this critical period explanation gives us a mechanistic handle to start answering.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Also, reopen our social critical period. So here's another rule that kind of applies across critical periods is that deprivation is a technique. And so this might be the explanation, for example, for why it's easier to learn Spanish if you go to Guatemala than if you go to Costa Rica, because in Costa Rica everybody speaks Spanish, but everybody also speaks English, right? So it's very hard. You're not deprived of English. You're just exposed to Spanish. Whereas in Guatemala, almost nobody speaks English. And so you're deprived and you get the language. So that's one idea that we have. We haven't proven it. But the other part of that is that it's an interesting to note that historically, religious practices across many, many different cultures have used deprivation techniques to get to that mystical state.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Environment is stable. But then there's a radical shift in the environment. Then you can imagine that it would be adaptive to be able to reopen critical periods and relearn from your environment. So going back to the language example, as long as everybody around you speaks English, it's probably not all that adaptive to be learning Spanish. But if you move to Spain or you move to Central America, then suddenly nobody's speaking English and you want to be able to learn the language that everybody's speaking around you. And so we have a little bit of other evidence that this deprivation technique of reopening critical periods, which has been described for things like the visual system, the sensory system, a little bit in the motor system, there's evidence for this, that this deprivation-induced, you know, can”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Sucks. It's hard. It's painful. It's really very emotionally draining to constantly be checking yourself, trying to figure out how you fit in. And sometimes you want to just get on with it. And if the environment that you're in is stable, then you don't need to necessarily be adapting or adjusting your model of the world every single move that you make. And so that's why we think that critical periods close. But then another question is, why does the brain have a sort of ready-made mechanism that psychedelics can tap into for reopening critical periods, right? Like, why can we reopen them so easily if the brain wasn't already built to do this? And this is, you know, really me speculating, but I suspect it's because when we have these habits, they're adaptive so long as the”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“I would just expand on that a little bit by pointing out that, you know, the reason that we have critical periods at all rather than being sort of genetically encoded with everything that we need to survive in the world is because the world is big and varied. If you genetically encoded everything, you probably would be very limited in how you could navigate that world. My parents are Turkish. If I was genetically encoded with Turkish, you know, the fact that I grew up in the United States would be make my life very difficult because I wouldn't speak English, I would speak Turkish. But because I have a language critical period, I am genetically what's genetically encoded is that the ability to learn a language, not the language itself. That ability to learn from our environment is why we have them.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Compare that MGLUR therapy with a psychedelic, then we could restore the imbalance and also restore the ability to learn from the social environment so that they can, under those corrected conditions, have a shot at learning the ways of social interaction the way they would have during natural development.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Psychedelics, then the idea would be that if psychedelics can reopen visual critical periods, then the idea would be that you would be able to restore vision because you would be pairing the primary intervention, which is the cataract removal surgery, with the reopening of the critical period to give the opportunity to learn from the visual environment in the natural way. And so with autism, it's the same idea. We're saying, okay. There's a genetic impairment that causes autism, which we think is related to an imbalance at this one specific receptor, which we can correct by targeting that receptor. But if we just do that alone after the social period has closed, then they still remain socially blind, if you will, because we miss that window. So the idea.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“But if you wait and you don't remove those cataracts until they're age six or seven, then even though the physical impediment to vision is gone, the brain cannot adjust to the visual inputs anymore. And so the child remains blind forever. And that's because there is a critical period for setting the strength of the synapses or visual inputs. And once that critical period is closed, even though the primary impediment or the primary injury has been resolved, it missed its opportunity to wire properly for the visual environment. And so they'll be blind forever. The idea there is, if you miss the window and the child didn't have their cataracts removed until they were seven or eight years old and you paired cataract removal surgery with”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Autism is a little bit complicated because it's a multifactorial disease. So let me just give a different example to help clarify and maybe make it clearer why what we think is the way that psychedelics could be used for autism. And that's with vision. So one of the early observations of critical periods is that if a child is born with bilateral cataracts, okay. And then you remove those cataracts and they can see.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“That the social critical period, the social part of it is irrelevant and that this is really tapping into molecular mechanisms that are conserved across all the different types of critical periods. And if that's true, then it suggests that these drugs might be useful for reopening all kinds of critical periods, including the visual critical periods, including the touch critical periods, including the motor critical periods. And so that's kind of the next direction that the lab is heading is testing the idea that psychedelics are in fact this master key for unlocking lots of different critical periods.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Figure out is that when we did RNA sequencing or genetic profiling, transcriptional profiling of what happens to this brain region when we give psychedelics and we reopen this social critical period, the molecules that get up and down regulated in response to psychedelics but not cocaine share a lot of overlap in terms of their molecular identity with the molecules that have been implicated in the closure of other types of critical periods like vision, somatic sensation, motor. And so beginning to see lots of sort of circumstantial evidence that the psychedelics are all doing the same thing. They're reopening this critical period. And they're doing it in a way that suggests”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“We are beginning to get a sense that many of the critical periods close using the same sort of governing principle, the same kind of molecules, if not the exact same molecules, have been implicated in the closure of, say, the visual critical period or the touch critical period or the motor critical period. What's different is that the social critical period is kind of different from those in that it's not a sensory motor, it's an emotional critical period that we think is encoded in a different part of the brain, the nucleus circumbents, which is part of, you know, the limbic system. It's a different type of brain region than the classical critical periods, which have all been defined in the cortex. And so we don't know, still don't know whether or not the rules are the same. But what we did”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“But then again, Mother Nature, tricky. So when we did the control experiments to look at what other psychedelics are doing, we found that all of the psychedelics reopened this critical period, even though nobody is taking LSD and doing a 60-person cuddle pedal. Not that I've seen anyway, right? The LSD is not prominently a pro-social type of psychedelic, neither is IBAN, neither is ketamine. And yet All of them are reopening this critical period for social reward learning. And so what this suggested to me immediately is that the whole social part of the MDMA story was a little bit of a red herring and that really what psychedelics are are this master key for unlocking critical periods. There's not just one critical period. There are lots of different critical periods, but”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Prominent pro social component to it. People take MDMA and they want to cuddle, they want to be sociable. Some people talk about like this incredible feeling of empathy and being able to see other people's pain. It's just a very pro-social type of psychedelic. In fact, some people even want to call it an empathogen rather than a straight up psychedelic. And so we started with that idea that, you know, okay, we're trying to reopen a social critical period. We know it follows a lot of the same rules as other critical periods, but maybe MDMA is the way to do it. And in fact, we did find evidence that MDMA reopens the social critical period and it does so by restoring oxytocin metaplasticity in the nucleus circumbents. And we love this idea that that was the story and whatever, psychedelics, other psychedelics probably wouldn't do it. That was our original idea.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“On, try and pick up another language, it's harder. You always have an accent, it's not easy to incorporate that into your first language.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“No, no, no. Type of geese, birds. Okay, so they just followed around by these birds. They're really cute pictures. And this imprinting behavior, though, if you wait. So if you wait until 48 hours after hatching, then they don't form this behavior, right? So this attachment is only possible within the first 48 hours of hatching. Conrad Lorenz called that period of time when the animals are extremely sensitive to their environment and can form these long-lasting memories. He called that window of time the critical period. And critical periods since then have been described for so many different things. So probably the one that most people will be familiar with is the critical period for language learning. So it's so much easier to learn your first language that you learn as a child than if you live.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“The idea of critical periods first came in nineteen thirty five by Conrad Lorentz, who is a ethologist who was studying imprinting behavior in Snow Geese. So this is the behavior that shortly after hatching, the animals will form a long-lasting attachment, typically to their mother. But if the mother isn't around and instead it's sort of a motorized airplane or the scientist in that case Conrad Lorenz himself, then they'll form that attachment to that other moving object in their vicinity. And, you know, there are all these funny pictures online of Conrad Lorenz being followed around by little snow geese, right? Because they form this attachment.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Also, where there's any strong indication that in Down syndrome, you know, there seems to be, there is a correlation between the age of the mother and the likelihood of getting down syndrome. For schizophrenia, there seems to be a correlation between the age of the father and getting schizophrenia. But for autism, as far as I know, there is no age-dependent correlation with your likelihood of getting it and all of the causes of autism are each individually so rare that there's no screening test that is generally applicable that would be worth doing.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“I believe, I mean, it's been a long time since I was in medical school, but last time I was, I looked into that, I believe it was still the case that FMR1 was rare enough that it wasn't worth it to do the screening test to try and find it because, you know, you have to balance doing a screening test against the possibility that the test itself is going to cause problems with the pregnancy. And so there is a sort of a judgment call there. And unless you had a family history of fragile X, I think that it's still the case that people don't actually test for it beforehand. It's not like Down syndrome.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Genes that have been implicated in autism. So now we're somewhere in the approximately 1,000 genes have been implicated in autism. FMR1 seems to be a node. So in other words, the protein that FMR1 encodes regulates roughly 25% of all the other autism genes. And so to me, that's a good place to start to try and understand autism. And then I will leave it up to the epidemiologists to sort out how to redefine the category so that we're capturing the right subset of patients and excluding the subset that are not going to respond to therapy if we're targeting, you know, the subset that are defined in one specific way.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“What I would consider to be classical autism. And so now it feels like to me that this has gotten so expansive that we're essentially including things like ADHD with social anxiety or all kinds of other things that while they might be in the realm of autism, it makes it much harder to identify it and say this is what's being caused. As a scientist, I find this to be something that makes my life much more difficult if we are no longer defining the disease in a very narrow way. And so when this happens, it's a little bit frustrating. And so I have tended to focus on those early identified genes like FMR1, which have been known to be a cause of autism for a long time. And more importantly, when we look at all of the other”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Economic, the definition of autism got expanded. In the Diagnostic and Statistical Manual of Neuropsychiatric Disease, the expanded definition started including the spectrum of autism. And so now rather than having you absolutely have to have an impairment in social behaviors and an impairment in locomotive stereotypes and all of these other developmental criteria, it sort of got expanded and a lot more things started being included. And when this happened, the heritability estimates of the disease dropped. And so my interpretation of those data is that basically we stopped defining a disease that was a sort of unified single disease and started including a lot more things that were not.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Inheritance patterns, hair color, and eye color might give you a heritability score of one, whereas something like cervical cancer, which is caused by a virus, you know, has a heritability score of closer to zero. Okay. And autism had a heritability score of something like 0.96, so very, very highly heritable. And it made it different from almost all of the other neuropsychiatric diseases out there because, you know, things like depression and anxiety are hovering more around the 0.5 range. So sometimes inherited, sometimes environmental, usually a combination of those factors. And at the time, that diagnosis was so narrowly defined that you got this high heritability. And then for a variety of different reasons, some of them scientific, some of them socioeconomic.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“This is a great question and one that I'm only going to be able to give you a partial answer for because things are changing rapidly around this. So when I first started studying autism 20 years ago, it was very narrowly defined as a disease. There was only five or six different genes that had been implicated.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Directly with psychedelics, but rather to pair the psychedelic intervention with the intervention that we think is restoring the biochemical balance. And when we do that, we feel like we can restore the biochemical imbalance while reopening the relevant critical periods so that the patient can learn from their social environment in the normal way under the conditions of the restored biochemical imbalance.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Mouse studies that were done, the clinical intervention, the alteration of the receptor were given either right at birth or at Genesis or very early in development, whereas all of the human trials, the drugs were given to adults. And it occurred to me that because of the timing of when the therapies were given, all of the mouse studies would have been trying to correct the underlying biochemical imbalance when the animal's critical periods were all still open, whereas in the human trials, the relevant critical periods would have been closed by the time we gave the intervention. And so the way that I'm imagining that a psychedelic might be useful in the case of autism is not to cure the primary underlying problems with social behavior.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Glutamate receptor modulator that we thought would correct the imbalance in fragile X. And when they did those studies, everybody was hugely disappointed because we were expecting the drugs to work and to cure the disease and we really got very little evidence to support that view. And I think at the time, all the people who were doing human research and clinical trials were just willing to throw their hands up and say, well, see, we told you a mouse is not a human. And that's why the trials didn't work, because all of the human trials were based on mouse studies. And this was just where we went wrong. But a few of us kind of took a more circumspect view and said, well, yeah, okay, mice aren't humans, but there were a lot of other differences between the human trials and the mouse trials. And to me, the one that really stands out is that while all of”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Type of autism called fragile X. It's the first identified cause of autism. It's currently the most abundant, the most common cause of autism is a mutation in the fMR1 gene, which encodes fragile X. And what we had found is that we could do a biochemical manipulation to correct a cellular imbalance that in mice corrected many of the symptoms of autism that we could measure at the time. And so that was really exciting. Something like 26 other labs followed up on that work and several big pharmaceutical companies said, okay, this is it, this is the mechanism-based therapy that we've been looking for and ran several very large scale human clinical trials for that metabatrop.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Me, autism was something that I became interested in when I was an undergrad thinking about these problems of theory of mind and consciousness because I was intrigued by the possibility that autism could be thought of as an impairment in theory of mind and that it would be sort of a case example of what happens to your ability to have a fully conscious experience in the absence of or under conditions of impaired theory of mind. And so how that relates to psychedelics is really sort of a long-ish winding story, which is that when I was a graduate student, my PhD work was focused on trying to find a therapy for autism, and we had focused in on one specific”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“The idea is that maybe these ideas that social behaviors are what drive the evolution of theory of mind is not quite right and that it emerged by something earlier like hunting behavior.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT
“Social species of octopus, it seems like an interesting opportunity to test these ideas about what are the selection pressures that make theory of mind develop across evolution and what are the species' specific advantages to having a theory of mind. But it's interesting also because even though the larger Pacific Stripe octopus, which is the octopus that does that hunting behavior, is social, it's not using this behavior in a social context. It's using it in a hunting context, which suggests that, you know, maybe theory of mind originated from a hunting behavior where you can imagine it would be useful for the animal to be able to anticipate where its food might hide if it was being chased because, you know, octopuses eat shrimp and fish and they're excellent hunters.”
2023-04-19 · The Tim Ferriss Show · #667: Dr. Gül Dölen on Rethinking Psychedelics, New Applications (Autism, Stroke, and Allergies), The Neurobiology of Beginner’s Mind, Octopuses on MDMA, and The Master Key of Metaplasticity · IDENTIFIED FROM THE TRANSCRIPT