Rethinking Psychedelics, Octopuses on MDMA, and The Master Key of Metaplasticity | Dr. Gül Dölen | Transcription

Transcription for the video titled "Rethinking Psychedelics, Octopuses on MDMA, and The Master Key of Metaplasticity | Dr. Gül Dölen".


Note: This transcription is split and grouped by topics and subtopics. You can navigate through the Table of Contents on the left. It's interactive. All paragraphs are timed to the original video. Click on the time (e.g., 01:53) to jump to the specific portion of the video.


Start (00:00)

Hello, boys and girls. This is Tim Ferriss. Welcome to another episode of The Tim Ferriss Show, where it is my job to deconstruct, or at least attempt to deconstruct. Interview, shall we say, world-class performers from all different disciplines. My guest today, I feel, for me, has been a long time coming. I'm very excited to have on the podcast Dr. Ghul Dolan. Dr. Ghul Dolan is an associate professor of neuroscience at the Johns Hopkins University School of Medicine and a pioneer and world leader of psychedelics research. Her laboratory has discovered a novel mechanism that could account for the broad range of therapeutic applications that psychedelics are currently being tested for. Her lab has discovered a novel critical period we'll define what these things mean. For social reward learning and shown that this critical period can be reopened with psychedelic drugs such as MDMA, LSD, psilocybin, ketamine, and Ibogaine. Building on this discovery, she has formulated the hypothesis that psychedelics may be the long sought master key for unlocking critical periods across the brain. To test this hypothesis, she has initiated a nationwide collaborative effort to determine whether psychedelics reopen critical periods for ocular dominance plasticity, birds on learning, anatomical plasticity in the barrel cortex, serotonergic neuronal regeneration, dendritic spina genesis, and motor learning. And if you don't know what those words or phrases mean, don't worry, we will define them as we go. Importantly, understanding psychedelics through this framework dramatically expands the scope of disorders including autism, stroke, and allergies that might benefit from adjunct therapy with psychedelics. And approach, she has dubbed the Fathom Project, that's P-H-A-T-H-O-M, which stands for psychedelic healing adjunct therapy, harnessing open malleability. Dr. Dolan earned her MD-PhD at Brown University and the Massachusetts Institute of Technology, otherwise known as MIT, where she carried out seminal work on critical periods, learning in memory and the pathogenesis of autism. You can find her online at Dr. Dolan, welcome to the show. Nice to have you. Thank you for having me, it's nice to be here.

Gül'S Personal Journey And Perspectives On Autism And Neuroscience

How Gül designed her own major as an undergrad. (02:14)

So I thought we might start with your undergrad experience. And I have read that you designed your own major, and I was hoping you could describe how one designs one's own major and how you thought about going about designing your own major. I've always been somebody who learns best by comparing. And I thought, originally I thought, well, I'll just do a triple major of neuroscience and linguistics and philosophy, and the university was like, no, no, there's no triple major. You can do a double major, but if you really need all three, we recommend that you do this, design your own major path. And so I worked with my professors in philosophy and neuroscience primarily to come up with a curriculum that would span all of the different elements that I wanted to incorporate in trying to ask the question, you know, what is the mind? What is consciousness? How do we know that from different perspectives? And so the major was called comparative perspectives on the mind, and it was a combination of neuroscience, philosophy, linguistics, art, religion, and really the idea was that this is something that humans care about. And so we've thought about it from all of these different perspectives for millennia, and what can we understand from that approach? And yeah, that's basically what it was and how I came up with it. Why were those questions, and hopefully this doesn't sound like a stupid question, because at face value, perhaps they should be interesting questions to everyone since on some level, I suppose, consciousness is fundamental. Why were these questions interesting, compelling to you at the time enough that you would attempt to have a triple major? You know, I have to say, I'm not really sure why exactly those. It just compared to everything else that I saw other people majoring in, you know, like economics or history. I just didn't care about those things the same way as I cared about. You know, I just found myself wanting, I've always wanted to only study or think about things that I think are deeply interesting that I would want to talk to with anybody, whether it be the person sitting next to me on the bus or my parents or somebody's kid. I just like thinking about things, and when I'm obsessed with something, I just think about it all the time in every context. And so I just never had that with economics or, you know, history or any of the other topics that seem to be popular majors. Didn't cause the quickening. Right. So there are a few terms that may come up later.

Philosophy of mind and theory of mind. (05:11)

We'll see. And I'd love to have you just expand on them or define them because I was reading in prep for this. And you briefly consider marine biology, but you were also interested in philosophy of mind. And then a philosophical consideration called theory of mind. What is philosophy of mind? How should we think about it? What is theory of mind? Philosophy of mind, I mean, it's not really a branch of philosophy or anything. It's just a thing that has drawn the attention of philosophers from a variety of different perspectives. Like, you can imagine considering what is the mind from a metaphysical point of view. So what are the things that we count when we say, this is what a mind is, this is what a mind is not. And there are other considerations like, well, how do we know mind? Can we know mind just through introspection or is there some empirical way or some way that we can compare different people's descriptions of those things to get at what is mind? And that would be sort of the more epistemological approach to mind. And I was interested in all of those things. There continues to be debate about that. And one of the interesting ideas that I came across was this concept of theory of mind, which is not really a theory in the way that we have a theory of light or a theory of synaptogenesis or any of the more commonplace theories. It's more like it's a point of view. The shorthand way of explaining what theory of mind is that I like to tell people is it's sort of what you're doing. It's the neurobiological process that is going on when you're playing poker. It's anticipating what somebody else might be thinking and trying to see the world from their point of view. So in some sense, it's a theory about what somebody else might be thinking. And this ability to understand or to have a concept of what somebody else might be thinking is something that we develop and we get better at as we mature. So you can always tell when a kid is starting to pick up theory of mind, it first comes on around age four or five, because they start doing these funny pranking behaviors where they'll reach around your back and tap you on the wrong side and look the other way. And that's them sort of playing with the idea that their own point of view and the person who's shoulder they're tapping might be different and that they can trick somebody by playing on that difference. And so this theory of mind, there was some idea out there, you know, I'm not sure that it's really a dominant theory right now in autism, but there was an idea that this is something that people with autism are not so good at. And it makes them bad poker players, it makes them bad at lying, it makes them bad at tricking people, you know, and it's this thing that psychopaths, for example, are very good at. They have better than average theory of mind. And they use that better than average theory of mind to manipulate people by anticipating what they may or may not like and using that information to try and get whatever it is that they're trying to get. And so this theory of mind idea was sort of out there and there was some idea that, well, you need to have theory of mind in order to have consciousness, in order to have a full sense of knowing who you are compared to other people. And I like this idea because it was a testable hypothesis. And one of the things that I found sort of frustrating about being a philosopher is that the philosophers were always asking the coolest questions, the biggest questions, but just felt like, you know, they were just going around in circles and never really coming up with an answer that I found to be deeply satisfying. And on the other hand, scientists, neuroscientists, maybe they weren't getting to ask all the really big questions, but man, they were coming up with some concrete answers that felt tangible like we were getting somewhere. And so I like this idea that we could test the requirement of theory of mind for consciousness by looking at diseases where that function is impaired and learn something about the relationship between consciousness and genes that encode different proteins that are required for that theory of mind. Theory of mind does not seem to be based on the reading that I've done entirely human specific.

What theory of mind in non-human species suggests. (09:58)

And is it true that you have observed this in, for instance, and you're tapping on the shoulder, maybe think of it, hunting behavior in octopuses? Yeah. So those were actually not my experiments. Those were experiments done by really imminent octopus researcher Roy Caldwell. And he showed me the videos of them. And as soon as I saw the videos of the octopus is hunting, it occurred to me that that is exactly a theory of mind like behavior in an octopus. And the reason that that was so interesting is because the way that people talk about theory of mind is that this is a behavior that evolved due to the selection pressures imposed by social living. Right? So when we have to live in a social group, it serves us to be able to anticipate what other members of that social group might be thinking in order to anticipate and either compete or collaborate or whatever it is that you're trying to do. And octopuses by and large are not social species. So if you put two octopuses of the same species into a tank together, they will kill each other. And there are differences in the amount of aggressiveness that we observe in octopuses Some are so aggressive that we've never even seen the males of the species because they basically when they mate, they like leave their hecticodilus arm, which is their reproductive arm in the mantle of the female and eject it and escape so that they don't get eaten. So we've only ever found their hecticodilus arm. That's how aggressive that species is. So other species of octopus aren't quite so aggressive, but they're still a social. And it was interesting because the species of octopus that does that hunting behavior is the only known social species of octopus. And so 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 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 octopuses eat shrimp and fish and they're excellent hunters. And so the idea is that maybe these ideas that social behaviors are what drive the evolution of theory of mind is not quite right in that it emerged by something earlier like hunting behavior. It strikes me as a hunter myself, which really only was adult onset hunting in my 30s when I was writing about food, I felt sort of obligated to explore these things, that you would observe behaviors that you could map to theory of mind in thousands of species that are really effective hunters.

The origin of Gül’s interest in autism. (13:23)

And I would love to bring up three words that are in your intro, which I had read earlier, that people may not associate with the conversation around psychedelics currently, autism, stroke and allergies. Where did your interest in autism begin? For 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 in under conditions of impaired theory of mind. And so how that relates to psychedelics is really sort of a longish 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 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 you know, several very large scale human clinical trials for that metabotropic 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 the mouse studies that were done, the clinical intervention, the, you know, alteration of the receptor were given either right at birth or a 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 behaviors directly with psychedelics, but rather to pair the psychedelic intervention with the intervention that we think is the 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. So I want to eventually ask you what reopening the critical period looks like chemically or neuro anatomically.

Autism facts vs. fiction. (18:24)

But before we get to that, I would love for you to help me separate fact from fiction with autism. It's not a condition that I know much about. And I am nonetheless exposed to many opinions about autism. And people say, for instance, that the prevalence is skyrocketing that it may be caused by people having children when they are older or it's caused by God knows what BPA you name it, there's probably a million different theories out there. And I would be curious to know as a scientist, what appears to be most plausible as causes of autism, our rates increasing, or are we just getting better at diagnosing or looking for that diagnosis, etc. Could you just help give us the ABCs of fact versus fiction? 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, you know, 20 years ago, it was very narrowly defined as a disease. There was only five or six different genes that had been implicated in causing autism. It was incredibly highly inherited. So, you know, if we can give a heritability score for different diseases and different 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 things like depression and anxiety are hovering more around the 0.5 range. So sometimes inherited, sometimes environmental, usually a combination of those factors, right? 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, the definition of autism got expanded. And so they're 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 know, you absolutely have to have an impairment in social behaviors and an impairment in locomotor stereotopes 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 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. And 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, you know, have been known to be a cause of autism for a long time. And more importantly, when we look at all of the other 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, right? 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 epidemiologist 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 the subset that are defined in one specific way. If we look at FMR1 as a node and a focal point, I apologize that I don't know the answer to this in advance. But does that mean that in the same way that if, say, a couple or planning on having children or someone we're looking at, say, surrogacy, you could do genetic screening, that it's possible for people to currently do genetic screening for the probability of sort of autism as an outcome in offspring? 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 was, it's still the case that people don't actually test for it beforehand. It's not like, it's not like Down syndrome also where there's any strong indication that in Down syndrome, 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 sort of 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. Got it. Let's revisit as promised the reopening of the critical period.

Critical periods. (25:41)

The idea of critical periods first came in 1935 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 Lorentz 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 Lorentz being followed around by little snow geese, right? Because they've formed this attachment. But what are snow geese? They're just a type of geese, you know, like. Okay, there we go. Just wanted to figure out. Yeah. Sounds like a little Scandinavian dwarf or something. All right. It's a type of geese. It's a type of geese. Okay. So they just followed around by these birds. They're really cute pictures. Anyway, on this imprinting behavior, though, if you wait, so if you wait until 48 hours after patching, then they don't form this behavior, right? So this attachment is only possible within the first 48 hours of hatching. And Conrad Lorentz 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 later 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, right? And so that's a critical period for language. And what my lab did is that we knew from the human literature that there was probably a critical period for social learning, right? Because we know, for example, that teenagers are much more susceptible to peer pressure than adults are. We know that they prioritize learning from their environment, from their social interactions, much more so than adults do. And that whatever social environment you grew up in, you know, is sort of your native social environment. So that, for example, when I go to Japan, I always feel like a bear in a China closet because I feel like I'm always insulting somebody without really realizing it. Because I didn't know I didn't grow up in that social environment, right? And so I don't know that it's extremely rude to hand somebody something with one hand instead of two, right? Like, these are the kinds of rules that I didn't grow up exposed to. So it's a foreign social language to me. So we have this intuition that there was a critical period for social reward learning. And that's what my lab discovered. So we discovered that in mice, just like in humans, there is this window of time where the animals are learning from their social environment much more strongly than when they are as adults, right? And we figured out a bunch of different mechanisms relating to that critical periods. Typically, the long, long arc of trying to understand critical periods has really been focused around this idea that critical periods are great. But the fact that they close means that it's really, really hard to treat brain disorders in adults because the brain is no longer flexible and able to learn from its environment in the same way as it was as a child. And so, you know, if we can understand the mechanisms, maybe we can figure out ways to reopen them for therapeutic benefit. That's been sort of the goal of neuroscience for the last 100 years or so, right? Is to try and find that and three Nobel prizes have been given for mechanisms trying to figure this out because it's understood that this would be so important. But I got to say, when I was a graduate student, this idea of finding the master key for unlocking critical periods, I never believed in it. And in fact, my lab and another lab at Harvard were kind of at, you know, in a intellectual debate with one another over this idea of can there be a master key? And I was always like, no, obviously, anything that could do that to the brain would either cause massive amnesia, would cause seizures, and possibly could cause the whole brain to melt. And I was like, there's no master key, stop it, forget about it, Harvard, you're just wrong. Okay. And so, what we've kind of come up with now is we started with the idea that, well, MDMA is sort of different from other psychedelics in that it has this very prominent pro-social component to it, right? People take MDMA and they want to cuddle, they want to be sociable. Some people, you know, 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 metoplasticity in the nucleus accumbens. And we love this idea that that was the story and other psychedelics probably wouldn't do it. That was our original idea. But then again, you know, 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 Ibogaine, neither is ketamine. And yet, all of them were reopening, are reopening this critical period for social reward learning. And so what this suggested to me immediately was 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 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. And 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 succumbens, which is part of 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 didn't know whether we don't know, still don't know, whether or not the rules are the same. But what we did know, what we did 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 downregulated 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, somatocensation, 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 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. Question back to autism. And man, must you get a lot of questions about autism? So my apologies, but I want to use that example because, and this will underscore my ignorance in so many of these topics.

How critical periods apply to therapies for autism. (35:32)

But if we're looking at a narrow definition of autism, so we're not succumbing to the scope creep in DSM or elsewhere, we're suddenly everything. And its cousin is autism, but focusing more on the fragile X and that type of narrower, more specific definition. When I then think of a critical window, what is the interplay of the genetics and the critical window when it is untreated, right, when you don't have an intervention? Does that mean that there is a critical window, but it's narrower or for whatever reason, the child is less adaptive in that critical window. So it's not genetic determinism. It's not like if you have this particular phenotype, you're destined to get autism and that you can unwind the clock or rewind the clock in a sense with potentially something like psychedelics to give them a second shot on goal. I know I'm asking this is probably a very clumsy way because I don't understand exactly why it would work. But why would reopening the window help someone potentially with autism if they weren't able to capitalize on a similar window earlier themselves? Autism is a little bit complicated because it's a multi-factorial 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, right? 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. But if you wait and you don't remove those cataracts until their 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 for visual inputs. And once that critical period is closed, even though the primary impediment or the primary injury has been resolved, the brain can't, it missed its opportunity to wire properly for the visual environment. And so they'll be blind forever. So 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 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 critical period has closed, then they still remain socially blind, if you will, because we missed that window. So the idea is if we could pair that m-glue-r 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. Got it. Thank you. That's very helpful. And I want to just perhaps mention that, and this is actually from the microdose, which is a great newsletter.

Why might psychedelics allow us to reopen shut critical periods? (39:56)

You were featured in the microdose from UC Berkeley, not too, too long ago. And some people listening may wonder why we shouldn't always leave our critical windows open. Wouldn't that be great? We could learn everything and anything. And I just want to read something here. And then we can move on, although we could expand on it. When you talk to people who are on psychedelics, it's like hurting kittens, they're paying attention to everything. Look at this leaf. My shoe won't fit, et cetera. And they're in full explore mode, which is wonderful, but it's not very efficient habits get a bad rap, but you couldn't get out the door if you didn't have them living in a world where you're trying to learn and pay attention to everything is emotionally and energetically costly. And we could certainly expand on this. But needless to say, there is a lot to be said for a stable version of reality with certain scripts that run reliably. Is there anything you would like to add to that before I ask my next question? I would just expand on that a little bit by pointing out that 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. And, you know, if you genetically encoded everything, you probably would be very limited in what you could, how you could navigate that world. Right. And so my parents are Turkish. If I was genetically encoded with Turkish, the fact that I grew up in the United States would be, it would make my life very difficult because I wouldn't speak English. I would speak Turkish. Right. But because I have a language critical period, I am genetically, what's genetically encoded is the ability to learn a language, not the language itself. Right. That ability to learn from our environment is why we have them. But as everybody knows, right, like being a teenager sucks. It's hard. It's painful. It's 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, right, 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 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, you know, 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 can 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 have a 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 that people talk about, Zen Buddhist call it beginner's mind. If you were looking for a neurobiological description of beginner's mind, reopening critical periods would be it, right? And so what we think possibly is that, remember how I said that I was, you know, in 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, right? 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 those big questions like, well, what is consciousness? Well, what is that mystical experience? What does it mean like to feel like you're an altered state? In the course of my reading and feel free to correct anything that I misstate here, but part of what makes catalyzing pro-social behavior in octopus is so interesting with the use of, say, MDMA is that the nervous system of an octopus and the anatomical structure, sorry, as compared to humans are so different, right?

MDMA and the octopus. (46:01)

So in humans, we might attribute some of the outcomes that we see are therapeutic effects to, I believe, the nucleus of Cummins, but then you look at an octopus, no acomens, no amygdala, no default mode network, no prefrontal cortex. What have you gleaned from the octopus work as it relates to critical periods and or interesting characteristics of MDMA? 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 fMRI 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," right? 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 on by psychedelics. And from those types of analyses, we get this satisfying feeling like, "Aha, you know, MDMA is causing the nucleus-acumbins 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 we have an answer. And what it says instead is that, "Yeah, okay, those anatomical results matter, and they're telling us something, but they're not 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. What are some other ideas in your mind that need challenging or that could be challenged, just writ large in psychedelics or psychedelic related science?

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 a little bit, let me just challenge the idea that we can only understand what psychedelics are doing in humans, right? That, I think, for the last decade in the early part of this one, there has been this idea that really the cool and interesting part of psychedelics, you can only understand by studying it in humans because humans are the only ones who do the behaviorally complex enough things that you would want to know about what psychedelics are doing. And I consider Alexander Shulgan to be an elder in this field for me. I met him when he came to visit MIT. I have this goofy picture of myself as this young little neuroscientist, all enamored of Alexander Shulgan. And I think he was very much a proponent of this view that he needed to take the psychedelics himself because really the interesting part of what psychedelics are doing, you can only know on a personal level. And I want to push back against that idea because I think that as we start to get a better handle of what they're actually doing in mice, we may be able to come up with things that generalize because after all humans didn't just emerge out of nowhere, we weren't plopped here on Earth by aliens. We evolved just like all other animals on Earth. And so we were subject to a lot of the same rules. And we came up with some mostly overlapping solutions and some unique ones. And so I think we will eventually get to a point where we can study the really cool and interesting parts of what psychedelics are doing in animals as well as in humans. And I think that our critical period idea is one step in that direction. Many people in your audience may have also heard of the idea that psychedelics are inducing plasticity.

Plasticity. (51:41)

And I'm very careful not to use that word if I can avoid it because plasticity is a word that 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 the 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 some people have tried to make the argument that what psychedelics are are so-called psychoplastigens or drugs that induce plasticity. 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 bi-directional 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 the breaks on learning and memory that are normally part of naturally rewarding stimuli that allow memories to be 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 a, 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 constraints on when we want the thing. And, you know, we like 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 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, you know, they're starting to be other evidence to support this view are enabling what's called metoplasticity, which I know that it's confusing terminology, hyperplasticity versus metoplasticity. But metoplasticity is an idea that's been around 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. So you're mentioning that plasticity can be a lot of different things to different people. So in this case, the ability to induce plasticity, what does plasticity mean to you in this use? So the metoplastic 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 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 very narrowly defined again. So metoplasticity 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 implicated in learning and memory and specifically also learning and memory with regards to visual processing. Does that mean that ketamine would have any particular applications to studies involving visual processing?

Favorite neurotransmitter receptors. (57:25)

I'm just thinking, given the seems like there's a decent effect at the NMDA receptor level with ketamine when you look at chronic pain and other things. Is that the case or is not so much? Yes, there are a variety of things that have been attributed to the NMDA receptor. For a long time, it was my favorite receptor and I hear why. I know it's super nerdy to have a favorite receptor, but I'll admit it. So NMDA receptors are fast neurotransmitter receptors, but they're different from AMPA receptors, which are the other major subtype of glutamate receptor, because they have something that basically 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. So 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. And this idea has been around for a while now. It's why people are excited about the NMDA receptor. Incidentally, it's also thought to be why ketamine and PCP interfere with memory. So 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. And I, the way I remember that is that that's the NR2 B 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 too A heavy. And what that does to the receptor is it makes it more or less likely to be able to induce that synaptic plasticity when the glutamate binds to that receptor. And that is the sort of original first classical understanding of what a metoplastic 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. Got it. And just to try to recap my understanding, which will hopefully help the audience track as well, jumping back to the autism example. And the fragile X or if FMR one, the joint therapy would look like using compounds such as possibly a psychedelic to increase the metoplasticity followed by or maybe simultaneous with the administration of the drug that was so disappointing in human trials, because it was administered to adults who had already switched to a different dominant subtype. I'm getting close. I'm not quite there. No, 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-glue R. And the metabotropic glutamate receptor, we think, is the one that who's signaling is so altered in fragile X. And the metabotropic glutamate receptors are also implicated as their 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 is that in fragile X, that M-glue R signaling is exaggerated. It's kind of not being curtailed in the right way. And so we have some evidence to suggest that autism might be caused by a failure to properly close the critical periods. So even though theoretically I like the idea of combining negative allosteric modulator of the M-glue R with a psychedelic that can reopen, say, the social critical periods through metoplasticity, 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. How do allergies fit into this? I've become very, very interested in allergies and all sorts of not to paint with two broader brushes, sort of autoimmune questions specifically as related to psychedelic compounds.

Therapeutic Effects And Potential Applications Of Psychedelics

Can psychedelics cure allergies? (01:03:20)

How do allergies fit in? Well, first, I should premise this by telling you that my mom is an immunologist and she hates this idea. 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 a 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. Like, 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 the 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 and fight against the dog proteins, right? If that's true, at least in a subset of patients with allergy, then you can imagine that reopening that learned sort of threat, that critical period for the learned threat of, you know, that's misassigned would enable people to unlearn the association between dog and allergy. Now, that that's a very different way, for example, of looking at it than the way that some people focus on psychedelics to think of it as they have these anti-inflammatory properties, which I think are true, independent of this critical period explanation. And that property might be beneficial in allergy, sort of independent of this, 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 Wile has a story where he cares himself of, yeah, I was going to bring him up. Cats. Yeah. And I love the idea because I actually kind of wanted to be a veterinarian, but I'm allergic to horses, dogs, and cats. So, you know, I would love to take psychedelics and cure myself of those allergies. And while I love this idea, I don't believe it enough yet to, you know, take a bunch of psychedelics and go snuggle up to a horse. Like, because I think, you know, we could be looking at anaphylactic shock in that situation. So I don't believe it yet, but I like the idea as something that we could test. Okay. So I'm glad you brought up, Andy, and not the sole example. I mean, I have an understanding plural of anecdote is not data, but nonetheless, sometimes helpful for generating hypotheses. This is something that's been in the, in the conversation with, with numerous anecdotes for a while. And I guess what I want to ask next is whether it's autism, stroke, or allergies, and I do want to come back to stroke. When we were talking about reopening critical windows, and in the introduction in your bio that I read, we had MDMA, LSD, psilocybin, ketamine, and Ibogaine, which act on quite a number of different receptors, LSD seems particularly promiscuous, maybe Ibogaine as well. But broadly speaking, are we talking about increasing postsynaptic sensitivity, in which case they could be hitting different receptors, but as long as it's eliciting that type of sensitivity that is associated with earlier critical windows, it fits the description of reopening the critical window. Is that... So let me back up for a second and just explain that there's sort of a debate going on in the field right now. If you look back in the textbooks written in the 70s and 80s about psychedelics, you know, textbooks written by people like Solomon Snyder, who started my department at Johns Hopkins and discovered almost every neurotransmitter receptor you've ever heard of, including, by the way, the serotonin 2A receptor, their definition of what a psychedelic is was very broad, right? So they basically said, "It's anything that causes this altered state of consciousness, altered perception of time, space, body, self. These were all sort of things that psychedelics do." And they included psychedelics ranging from ketamine, PCP, all of the class... What people are now trying to call the classical serotonin psychedelics like LSD, Mescaline, psilocybin, DMT. And then also the weird ones like MDMA and Ibogaine, and you know, both Snyder and Alexander Shulgan consider all of those drugs to be psychedelics. More recently, there has been this push mostly led by the chemists to say, "Oh no, no, no, no, no. If we look at the receptor binding properties of these drugs, the classical psychedelics, the hallucinogenic psychedelics, they're all serotonin 2A receptor binding, and even though they're promiscuous, even though they're binding to a bunch of different receptors, the psychedelic effects seem to be mediated by this receptor using, you know, pharmacology studies in humans. And they are really pushing hard to kind of exclude MDMA and Ibogaine and ketamine from the definition of classical psychedelics. But I personally feel that this is putting the cart before the horse because we don't know that that is necessarily a good boundary for defining psychedelics. First of all, because we know that most of the psychedelics are very promiscuous in their binding. Second of all, we don't really understand whether or not the 2A receptor is required for the therapeutic properties, right? So there is some evidence that there are antidepressive properties that may or may not be blocked by serotonin receptor antagonist. There's two papers that have exactly opposite results about this right now. I am not entirely convinced that those antidepressive properties that they're measuring have anything to do with the durable context dependent long-term therapeutic effects of psychedelics that we see in humans. And so I think it's up for debate whether or not this serotonin 2A receptor is required. But what we do know is that psychedelics that have primary binding at NMDA receptors, serotonin transporters, serotonin 2A receptors, capo-opioid receptors, ones that span the diversity of receptors, all show some therapeutic effect, right? And so our lab has really been focused in trying to understand, well, what's the commonality across all of those receptors?

Seeking a common pathway for the therapeutic effects of psychedelics. (01:11:33)

And so to kind of in a long-winded way, get back to your original question, what we wanted to know is what's downstream of those receptors that's common to all of those psychedelics? And we don't have the complete answer yet. But the answer that we're coming up upon is that it's not the receptor, it's not even one step downstream of that. People have been excited about the possibility that changes in biochemical signaling at the level of beta arrestin might be the next step after the receptor that might be common. We don't see that to be the case in our studies. And what it seems to be is downstream of that even more, which is regulation of the extracellular matrix, which we think is sort of the final common pathway that happens. And the working model that we have is that psychedelics get bind to their receptor. And when they sit in that receptor for too long, it signals to the cell, "Oh no, oh no, excited toxicity is coming," hit the reset button. And what that does through a variety of different mechanisms is we think, and we don't have strong evidence to support this, but this is our working model, is that that hit the reset button involves calling in all of the receptors, internalizing them, cleaning up the synapse, degrading the extracellular matrix that is sort of holding the synapse together and the last step of making a synapse mature and stable. And that sort of hard reset is enabling the reintegration of those baby receptors that are more sensitive and able to induce plasticity. That's sort of our working model. So I'm curious just to revisit Kappa Opioid for a second, because the only Kappa Opioid agonist that I'm familiar with is Salvador and A.

Potential applications for kappa-opioid agonists. (01:13:32)

Some people may know Salvia Divinorum, which from a phenomenological perspective to get real fancy, subjectively people find it typically pretty dysphoric. And I'm just wondering how perhaps it's not Salvador and but any Kappa opioid agonist might be used therapeutically, what applications might exist. I mean, people have been excited about Kappa Opioids because it's sort of thought to be like that's going to be the one that's going to make you not be addicted to it, and it's not very pleasurable, but because it's- That's for sure. Because it's not very pleasurable, you know, nobody wants to take it. I don't want to overstep the Kappa Opioid stuff. The reason that we got interested in it is because the Ibogaine also has high affinity for Kappa Opioid receptors, but it also acts as serotonin transporters. So I really don't know what the answer is there. I thought the beta-arrestin story was going to nicely sew everything up and it just didn't. What is beta-arrestin? I'm going to plead ignorance. I don't know what that is.

Beta-arrestin developments. (01:14:45)

Basically, most of the psychedelic drugs except for ketamine and PCP are acting at what are called G-protein coupled receptors. When I was talking about NMDA receptors versus M-glue-R receptors, the difference is M-glue-R are G-protein coupled receptors and NMDA receptors are ion channels. So they're inotropic receptors. So metabotropic, inotropic, it has to do with how they're coupled to internal signaling. So all of the G-protein coupled receptors, including almost all of the serotonin receptors, they work by when the drugs binds to their binding pocket, they induce a series of biochemical events, either excitatory or inhibitory biochemical changes downstream that are sort of the second messengers, if you will, of the receptor binding. Now, that's just how they normally signal. But when a drug like LSD binds to the serotonin 2A receptor, Brian Roth's group has shown that when it sits in its receptor, it has an unusually long off rate. So normally, when transmitters get in their receptor, they jump in and they jump right back out. So they pop in, pop out really, really fast, less than a second time scale. LSD, when it sits in the serotonin 2A receptor, binding pocket, a little lid kind of comes down and locks it into place. And when that lid locks the LSD into place, its off rate goes to four and a half hours, which is insane. It's going to be a long night. It's going to be a long night, exactly. So, and that's the half off. So only half of it comes off in four and a half hours, right? And so, this was like a really important insight into why it is the LSD's effects last so long. But when it sits in that receptor for too long, instead of signaling through the normal G-protein coupled signaling pathway, what happens is it starts sending signal to the cell, no, instead of G-protein, you need to hit a different biochemical pathway, we need to trigger beta arrestin. And beta arrestin is just another biochemical pathway that gets triggered by that receptor being activated too long. And what is thought that beta arrestin does is rather than do the second messenger signaling, it says to the cell, pull that receptor out, we're about to get toxic damage from too much receptor activation. So beta arrestin signaling historically has been thought to be a signal to the cell that says pull in the receptors, right? And so, I really loved the idea that even though not all psychedelics bind to the serotonin 2A, most of them, you could imagine a scenario where they were triggering beta arrestin signaling over G-protein coupled signaling, and that if you knocked out the beta arrestin protein, that you could block the ability of psychedelics to reopen critical periods. And while that was true for some of the psychedelics, it turned out not to be the universal mechanism that spans across all of the psychedelics. So, that was a little bit of a bummer, I have to say, because I thought, all right, we'll solve it, it'll be done, and you know, I can rest easy, but it didn't work out that simple. And mother nature always likes to trip us up like that, so. The mother nature curveballs seem to come more often than not. I do want to get to strokes and how they fit in, but before we get there, I have to scratch an itch because I've been wanting to ask you for a while now, first, a bit of background.

On Sasha Shulgin. (01:18:24)

You mentioned Alexander Shulgen, also known as Sasha Shulgen for people who don't recognize the name. Incredibly adept, incredibly prolific biochemists. Very much recommend people check out PCOL and TECOL, which he wrote with his wife. But the contrast you drew earlier was one of, say, maybe human centricity. So he not only created or resurrected hundreds, maybe thousands of different psychedelic compounds, but also was a very dedicated self-experimenter. And the tasting parties were very famous, of course. Where do you most strongly perhaps agree or align with Sasha? What are things that you perhaps have in common, if anything comes to mind? I got to tell you a funny story of when he came to visit MIT when I was a graduate student. It was sort of the opening party for the new building. And I won't name any names, but there were, you know, everybody had invited a bunch of Nobel Prize winners who had discovered, you know, every cool thing in biology. And they all got up there and not necessarily knew anything about neuroscience. They were all sort of older, and they kind of gave a little biography and then sat back down. And then Sasha got up on stage, and he was just basically the same age as everybody else, the only person without a Nobel Prize on that stage. And yet he was so alert and so adept. And he was like, oh, and then we added this methyl group over here. And this happened in, you know, the behavioral response. And then we did this and we got ego this and we put that on there. And all of the neuroscientists were just like, wrapped attention, right? Because this is it. Like this is what we all dream of as neuroscientists is to have some manipulation that we can give, in this case, a drug that is dramatically altering the way that the brain is functioning and interpreting the world around it. And here is this chemist, you know, sort of explaining to us how this could be done just by adding a methyl group in this position versus that position. And we were all just like blown away. I don't think there was anybody who walked away from that lecture thinking, gosh, you know, psychedelics should just stay in the backwaters. We shouldn't care about this as neuroscience, obviously not, right? And in fact, it's how I got excited about neuroscience to begin with. I took this class when I was an underrad called drug-sprain and behavior. And in that class, the first day I saw the photograph of the molecule of LSD sitting right next to the molecule of serotonin and the similarities between them, I was like, this is it. This is how we're going to crack it. This is how we're going to get at those hard questions of neuroscience, because here are chemicals that can alter our entire sense of reality, consciousness, perception, time, self, space, everything, right? And I am not alone. I think most neuroscientists who have tried psychedelics would have exactly the same response. And the difference between me and Sasha, really, in terms of our approach is that Sasha comes from an older tradition in science, which was very much prioritized the sort of do the experiment on yourself idea. And that has a long and glorious tradition in science. For example, we have a cure for ulcers because there was a biologist who was convinced that those were caused by a bacteria, but nobody believed him. So he drank a vial of bacteria, gave himself ulcers, and then took a bunch of antibiotics and cured himself of the ulcers. And he won the Nobel Prize for that, right? The difference is with psychedelics is that that's a little bit trickier to do, right? Because psychedelics have this property, which William James pointed out over a hundred years ago, of creating this sense of what he called the noetic property, this feeling that now that I've had this experience, I know the really real. The true truth has been revealed to me, and everything before this moment was just a facade or some lesser truth or some limited access to the truth. But now I really know. And so for a scientist, that's pretty dangerous, right? For a scientist, you always want to be able to have a little bit of skepticism about what it is that you have discovered. You always want to keep your ideas as sort of provisional until the next test comes along, until it should always be a working model, never a this is the 10 commandments of neuroscience, right? That's not the way that we do science. And so the noetic property, I think, does mean that that experiment where you take a bunch of bacteria and give yourself ulcers is a little bit harder to justify in this in this second Alex. So that's how I hard to be an objective or strive to be an objective scientist if you turn yourself into David Koresh accidentally.

Strokes. (01:24:05)

So how do strokes fit into this? For a long time now, clinically, we have known that right after you have a stroke, you have this very short window of time, you know, kind of really, really close by three months, but really you want to get in there within six weeks to two months or so where physical therapy is going to have its maximal effect or benefit for helping you to recover the motor function that you lost because of the stroke. Okay. And that window of time, we don't exactly know why it closes, but it seems to be that it's not that the damaged part of the brain suddenly re sprouts neurons. It's that the brain regions immediately adjacent to the damaged part of the brain become flexible again and able to perform or control the motor functions that were lost by the brain region immediately next to it. Okay. And that window closes just like all other critical periods close. And so far, the best way that we have for reopening that critical period is to give another stroke, but nobody wants to cure stroke by giving another stroke, right? So it's just not a clinically useful way. Hard to sell hard to sell that. Yeah, definitely even harder. And so we're sort of we like the idea that maybe we could branch out into other critical periods like this one to see whether or not psychedelics can reopen that critical period for stroke. And we have a collaboration with Steve Zylar, who's a neurologist at Johns Hopkins, who has developed a rodent model for that that critical period of motor recovery following stroke. And he also has a stroke clinic at Hopkins. And so we're working closely with them to see whether or not this idea really, really can help these patients, which basically it's a 400,000 patients a year in the United States who have debilitating lasting impairments because of stroke. So it's a huge number of people. And if this ends up being true, it's super exciting because here's something that we started out with, oh, I'm just curious what MDMA will do in an octopus. It was totally curiosity based science. And to see it evolve into something that can potentially help so many people is as a scientist, just super gratifying. It's pretty rare. Nobody really gets to have those kinds of success stories. And so that's very gratifying to me on a personal level. But also, I think that for all of the psychedelics enthusiasts out there, it's a lesson in how important it is to never stop learning, never stop questioning. I think there was an intuition a few years ago that, well, indigenous people have been using psychedelics forever. We don't really need to understand their mechanisms. We don't really need to dig into how it is these things work because we know they're going to work because they've got this long history behind them. But I think that if this ends up being true, that this mechanistic explanation can really open up whole new avenues that people hadn't been thinking of before, then I think that that's a testament to the importance of always keeping open mind, always look for more answers, more questions, and keep searching. Absolutely. And I would also say even if, let's just say, hypothetically, these various indigenous cultures have figured it out.

Future Of Therapies And Challenges In Scientific Research Funding

Cross-cultural considerations. (01:28:11)

Let's just take that as an assumption for a second. They figured out how to use these things, but the scale at which they're used and the context within which they're used are on the order of, say, max 100 or several 100 people within the safety net of certain rituals and familial and social support structures that it cannot be replicated at scale in, say, a Western treatment paradigm. You need new tools, right? And that requires exploration and testing. Let me just riff on that for a second because I think that that's a really important point about the context, right? So the context of disease is also different in this culture versus other cultures and how a disease is defined is different across cultures and how you might approach a disease is defined differently across cultures. And so a good example is the way that Ibogaine is used traditionally. And these cultures that using Ibogaine for traditional healing practices, it's not just that the person taking it as has a disease and they're being treated. It's sort of a mix between they have a disease, but they also have something to share with the rest of their community. And the whole Ibogaine experience is encapsulated in a bunch of things that we as Western doctors might dismiss as just ritual, but include things like face painting and social touch and the whole community is involved for this three day long trip that a person goes from one house to another, right? And it turns out that a lot of those elements that we might not necessarily recognize as important that we might dismiss as ritual in a mouse, we can recapitulate, right? We know that MDMA's ability to reopen the social critical period is social context dependent, right? If we give it in isolation, then it doesn't reopen. So it turns out that there are all of these elements that go beyond just the molecule and we can't just import, take the thing that we decide is the most important element, the molecule, and import it into our medicinal practices and our cultural history without understanding it because many of those elements of the ritual might be actually really important to how these drugs are working therapeutically. And unless we understand it from our context, we won't be able to readily adapt them, I think. 100%. And to maybe clarify the point I was trying to make somewhat inelegantly, I think all of these practices are worth studying, especially the things that have had some degree of longevity and persisted over time that seem to be adaptive or could potentially plausibly be helpful in the therapeutic effects. And I push back, maybe it's because I'm in Austin and you can't throw a rock without meeting someone who did a weekend online course and is now a self-proclaimed shaman. So I have a certain sensitivity to it. But this romanticized, I think very naive notion that you can just copy and paste things whole cloth from one area to another is not just naive, but also quite dangerous. And I appreciate you saying what you just said. If you flash forward in your mind, I recognize there's some imagination and speculation required here.

What do these therapies look like 10 years from now? (01:31:49)

But if this critical period work and maybe the offshoots of that work continue to gain support through rigorous science and evidence, what might therapeutic interventions or treatments look like 10 years from now, I'm pulling that number kind of out of nowhere. But I'm curious to know sort of in your mind's eye what you think things could look like if this continues to develop in the direction that at least now you're pursuing research. I think for me, if this ends up being true, then it's going to be a pretty big paradigm shift from neuropsychiatric treatments because, let me just back up and say, I have to give a little bit of credit to maps here because maps did a lot of really hard work to convince the FDA that the way to design clinical trials around psychedelics was to abandon the sort of one variable at a time test model and say, look, we really need to pair these drugs with psychotherapy because the drugs are not doing the magic by themselves. It's really this combination that's working. And so that I think was a big shift in the way that the FDA wants us to test drugs in clinical trials. And I think that we're beginning to see more and more evidence that that context is really what matters. So for example, the clinical trials where context is sort of secondary, where the psychotherapy is essentially there in case somebody has a bad trip, but it's not really front and center to the intervention, then I think those trials for psilocybin, for example, aren't working as well as the trials where it's really seen as an adjunct to the primary therapy, which is the psychotherapy. Now, if we're right and the critical period reopening explanation is this shift in the framework for how we understand these therapeutic effects, then in 10 years from now, the way that psychedelics are going to be used is going to be trying to identify that right context for the right disease. So while an interdirected trip with a lot of psychotherapy makes a lot of sense for PTSD and addiction and depression, it's probably the wrong context for stroke, whereas doing a lot of physical therapy and movement and playing virtual reality motion games might be the right context for giving the psychedelic for stroke. For allergy, maybe the right context is snuggling up to that horse or that dog or that cat that you're allergic to. And so I think the future, the therapeutic potential for this is going to be the opportunity is huge, but the devil is going to be in the details in terms of identifying the right context and figuring out how to get activation of the right neural circuit that's relevant for the brain transformation that you want to see happen. If we take the case of stroke patients, for instance, if we just assume for the moment that we're using human subjects, how might you think about currently what type of experimental design you would use with respect to dosing?

Gauging minimum effective dose. (01:35:30)

Because if you have this less interdirected, say, higher dose experience with the potential for these noetic qualities that you describe, but rather you're following instructions, you are practicing skills using potentially VR. Give any thoughts on how you design the study or what the minimum effective dose might look like. So there are two questions in there. Let me just pull them apart for a second. So the dose issue that we've done so far suggests that there's a pretty narrow dose response for reopening critical periods. It matches what we see in humans for the acute subjective effects, but we don't see any evidence that increasing the dose necessarily increases the opening of the critical period or how long the duration of the critical period opens state. So basically what we find is that if the acute subjective effects are short, like with ketamine, then the window only stays open for a very short amount of time, like less than a week. Whereas if the acute subjective effects last a really long time, like with Ibogaine, which lasts 36 to 72 hours, then the window, the critical period window stays open for much longer. In my stats, four weeks in humans that make translate to four weeks or four months, we're not sure. But it's not the case, for example, and then, you know, psilocybin, MDMA, and LST are in the middle there between those two extremes. But it's not the case that if you double the dose of LSD, then you can get LSD to open the critical period longer, for example. And so that dosing business, I think, you know, is going to be a little bit of a heartbreak for all of the pharmaceutical companies out there that are essentially trying to engineer out the psychedelic effects by shortening the duration of the psychedelic effects to, you know, get less side effects and a shorter journey that will be easier to manage in a clinical setting. And again, what can you do? Nature is nature. But I do think that it changes the model of how we approach these rather than thinking of these as next generation anxiolytics or next generation, anti-depressives or SSRIs. What we really need to be thinking of these as is more like surgery, right? Like who wouldn't, if you have a heart attack, you go and you have open heart surgery, it lasts for eight hours. You have maybe two or three weeks afterwards where you are required to be on bed rest and take things easy. But then you're cured, right? And so who wouldn't rather be cured of, you know, a heart attack than have to be on a medicine for the rest of their lives? I think most people see that as the major promise of psychedelics. So in terms of the therapeutic approach, I think the way I'm framing this stroke trial is really like, I'm not worried about the fact that they're going to have to do a psychedelic and potentially the maximum benefit is going to be from these long-acting psychedelics because I think that, you know, these motor critical periods are pretty strong closes. And so you want to reopen them for as long as you possibly can to get the maximal effect. And we'll have to work out the how to do them back to back to back. But that's sort of how I'm thinking about it there. The second sort of thing I want to unpack about your question is that you mentioned for the stroke that you were imagining that we would be giving the psychedelic and the person would be practicing a bunch of things in a very specific directed way. And actually, that's not how I'm imagining that this will work. I got it would be more sequential, not concurrent. No, no, no, it would be concurrent, but I would say it's not going to be practice-based. So one of the things that I would want to emphasize is part of the reason that I paired up with Steve Zylar and John Krakow at Hopkins is that their approach for treating stroke during the normal, while the critical period is already open, is that they've said, well, most of the physical therapy that patients receive is very goal-directed. I need to learn how to zip my pants with the other hand. I need to learn how to comb my hair with the other hand. And so it's very much practical solving the problem another way. Whereas the way that we learn those motor patterns when we're children is much more sort of goal undirected, kind of play, wandering, don't care if I fall down a million times. I mean, there's this great idea that children walk when they're learning how to walk will walk the equivalent of seven football fields in an hour. Now, the only time I've ever seen an adult do that is on MDMA, right? They will just dance and they don't care if they look like fools, they don't care if they're not good dancers. It's not goal-directed. They're just enjoying the play of doing the motion, right? And so what I like about Steve and John's approach to motor rehabilitation sort of without psychedelics is that their virtual reality system that they've built is very much capitalizing on this non-goal-directed play-like behavior. And I think that's going to be the key. And so I think if we can get people on psychedelics plus put them in this play, motor play context, then we can maximally recapitulate the conditions that we learn how to do motor function when we're developing as children. So speaking of fun, I want to go back in time to Bears Lab at MIT.

The funding frustrations that almost made Gül give up science. (01:41:55)

And this is from Spectrum News reading a section of this. He had stressed the importance of science being fun. And the quote is, "If you lose sight of the fun in science, it's hardly worth continuing," end quote he used to say. Dolan decided that if she was indeed going to give up a life of science, she would go out on her own terms. So could you unpack that last sense? Were you considering giving up a life of science? And then how did that lead to octopuses? Because it seems like that focus then opened up Pandora's Box in the most positive way, right? So I want to go back and sort of do a little bit of postmortem on what exactly happens. So please, if you wouldn't mind, just tell the story of that period. When you start your own lab, you get a bunch of money and that startup package is great to kind of get you started, hire some people, buy some equipment, you know, get your lab established without having to worry too much about the funding. When I started my lab, I got a nice startup package. I immediately got a couple of private foundation grants, which were very helpful to help me establish the lab. But you really can't in academia survive unless you can also get funding from the NIH, right? And these big NIH grants have in my career in my lifetime have gotten harder and harder to get. And it used to be that people who were young and had a lot of creative ideas were had much higher success rates than people who were older and kind of just redoing the same experiments with a very conservative kind of rinse and repeat type of experiments. And over my scientific career, I have seen that situation essentially reverse, right? So people over the age of 65 are getting most of the NIH grants. Junior people are really struggling. And there have been some attempts to correct that, but they just haven't worked. And it's just incredibly difficult to get funding. And then if you add on top of that, the funding has gotten so conservative that basically the way that I write NIH grants right now is like once I have all of the results that are going to make a cool nature paper, I write a grant on all of the sort of boring experiments that I didn't do it for that paper, but that I think that somebody, the reviewers might ask me for, and I package that together and I send that to the NIH. That's how conservative my grants really are when I apply to NIH funding. And that's been successful, but there was a moment sort of a few months before the octopus paper, before we even did that experiment, where I was just beginning to feel like, you know, I'm not going to make it. Like I applied to the NIH 17 times before I got my first NIH grant. Wow. And I think part of it was because I was proposing these crazy ideas that people were like, there's no critical period for social behavior. What? Nobody's ever going to use psychedelics clinically. What? No, that'll never work. Oh, you made those mice too bad. You didn't use them for the experiment that I would have used them for. You're just a junior person. You have no established track record. No, no, no, no, no, no, no, no. And I was feeling really demoralized. And I was like, I can't do this. Like, I thought I was becoming a scientist because I was going to get to pursue these big questions and be creative and steer my own ship. That's what I had worked so hard for as a graduate student, as a postdoc and as a medical student. That was the dream that I was sold. And I was pretty devastated by how many rejections I got. And so in that moment, when I was like, all right, I'm going to try a couple more times. But if I don't get it, that's it. I'm out. My department was very supportive. They're like, you'll get there. You'll get there. You'll get there. We'll cover you. Don't worry. Don't fire anybody. You're good. But still, like it's at blow to your ego if you can't convince your peers at the NIH to give you that money, right? And so going out on my own terms, I was just like, look, I've always wanted to study evolution. I've always wanted to do something to do with marine neuroscience. I have this opportunity to look at what happens to this behavior in an octopus. I'm just going to go for it and it'll be fun. And even if it doesn't work, even if it is not useful for my career in any way at all. I mean, I would go to these meetings with the faculty meetings and meetings with my department chair. And I tell them we were planning to do this octopus stuff and he'd be like, "Cool, what are you doing? We hired you to cure autism. What is this octopus stuff?" Like, what? And I'd just be like, "Look, you got to back off. This is what I want to do. This is what's going to make me feel like science is fun. Like I'm doing it not in a goal-directed way in a kind of playful, just out of curiosity. I just want to know what happens." And then it worked and it revived my sense of play and joy and feeling like you can do those crazy experiments that everybody thinks are crazy and just to have fun with it. So you, I wouldn't say bet the farm, but you were willing to go out and sort of ablaze of glory and meaning just focusing on fun and trying to break new ground.

Taking risks. (01:48:00)

It worked. How do you think about, if you do, sort of preserving that type of willingness? Maybe the octopus work kind of bought you a golden ticket to now continue to do work that is not rinse and repeat. But perhaps I'm just spinning a story here, but I can imagine as you get more established, maybe you feel like you have more to protect. So maybe there's an inclination to take fewer risks. How do you think about risk-taking moving forward? I think that risk-taking is, first of all, I don't want to oversell how big of a risk it was for me to do that experiment. We were already working on MDMA. We already had reasonable response from nature about the MDMA critical period experiment. The octopus thing was really kind of like, well, we had the MDMA around and I've always been curious and I just wanted to see what would happen. And then a collaborator was like, well, we have seven octopuses that we can lend you for a week. And I was like, come on down. He flew down. He slept on my couch. We stayed up until like two o'clock in the morning every night. Like just doing it mad scientist because we had to send the octopuses back by the end of the week. And yeah, it was just like this mad scientist fun time. And so how do I preserve that? Well, I guess part of, I think, the reason that we as scientists are seeing less and less of that kind of crazy stuff is really the funding. I mean, the funding, like I'll just just to give a sense of this, I think this is a really missed point, especially with tech, right? So in the 50s and 60s, the NSF, the National Science Foundation and the NIH were sort of funding all kinds of crazy stuff that they just never thought would ever be useful or have a goal. They were just funding it. And so when Thomas Brock was like, there are these weird bacteria that live in these thermal vents in Yellowstone National Park. Give me some money to go figure out how they can survive those temperatures. NSF was like, yeah, sure, here you go. And if they hadn't given him that money, the PCR test that we all learned about during the pandemic would not be possible because that enzyme that is required for that test is made by those bacteria that live in those weird thermal vents, right? And so I think this non-gold-directed curiosity-based science, it doesn't show any usefulness for 40, 50 years, right? So it takes that long for something meaningful to come out of that kind of discovery-based, curiosity-based science, right? And I think that the way that funding constraints and the way that the sort of tech and even private foundations are very goal-oriented, right? It's like, well, how can we sell this? How can we market this? How can we... And you know, the private foundations have names like "Cure Autism Now." They're very goal-directed. And I think that that sort of kills the motivation or the impetus to just do the weird stuff that's just for fun and curiosity. And I would say every person who becomes a scientist at one point or another had that as their motivation. And the strain of the funding crisis is essentially what has forced people to get more and more and more conservative. And so I don't think I'm unique for wanting to just see what happens when you give octopuses MDMA. In fact, I think the reason that everybody responded to that paper so well worldwide is because every single one of us has that curiosity, has that, "I wonder what would happen," you know? And it resonated with people. And I just think it mostly gets beaten out of us because of funding constraints. Is there any solution there? I mean, if you could wave a magic wand, are there any structural changes that would help to alleviate that?

What would Gül change about the way research is funded today? (01:52:34)

I'm just wondering if anything comes to mind, aside from just like, "Come on, guys, we need the exploratory stuff, the weird stuff. Otherwise, we're not actually investing in the sort of long-term serendipity that has produced all of these world-changing technologies," aside from just having drinks with people at NIH or NSF or elsewhere and having this conversation, are there other levers that could be pulled or other changes that could be made? I would say that this is sort of venturing off into politics, which is a hobby, not my area of expertise. But I would certainly say that if we look at the percentage of taxpayer money that, well, first of all, in the '50s and '60s, you know, we collected a lot more taxes. Today, we give away more in tax breaks than the entire discretionary budget. Back to big corporations' incentives and tax breaks, but really, most of those corporations, the thing that they are making and selling right now, especially in the tech industry, really are possible because the taxpayers in the '50s and '60s made those investments in the science and technology areas to develop all of the computing and software building science and research that that stuff was built upon, right? Like Facebook and all of these tech ventures that we, and Google, and cell phones and computers, they didn't just happen to arise out of America for no reason. They came because the United States for years understood that this was an investment for the way, way future. And so I think changing our tax structure to sort of reinvest in the future of science, it's either going to happen or it's not. It's going to move to other countries and places like China that are investing in science and technology and the sort of non-goal-directed, just throw money at it and eventually something cool will pop out attitude. I mean, that's just much too sense. So how about an insult like half your audience, but that's what I think. I don't think you've insulted half the audience. But I think I do think it's important to say that the priorities of the government and nation state affect so many different components of life and the future of innovation in this country.

Most Gifted Books

Books most gifted. (01:55:11)

And if you do look back, as you mentioned, to many of the innovations that came out of, say, DARPA and other organizations that were fundamentally funded by taxpayer dollars, I mean, it is remarkable to look back at how fundamental many of these technologies have become. Switching gears, just to ask a few more questions. Do you have any books that you have shared, recommended, or gifted the most to other people or recommended often to other people? Any favorite books that come to mind? Oh, God. How did we wander into this political sphere? Probably the ones that I have gifted the most is a book called Invisible Women by Carolyn Criado-Pérez. I really love it because I think it's a book of feminism that is accessible and I think resonates with people whether or not you're a man or a woman, right? It's just data it's like, all right, well, here's how much it costs to keep ignoring women and if you fix it, your city can save a million dollars a year, right? It's all about the structural stuff. It's not about your feelings about whether women deserve to be in the kitchen or not. It's not about that. It's just here's how ignoring data about women's body sizes, women's travel patterns, ends up costing society at large and I think it's an excellent way of kind of getting that. And then the other book that I love the most is called The Dawn of Everything, A New History of Humanity by David Graeber. I actually love everything that that guy wrote. I started with this book called Bullshit Jobs, which I was dealing with, like, the bureaucracy of academia and feeling very frustrated and I read that book and it was very cathartic and then I just kind of went down the rabbit hole and have enjoyed all the other books. But The Dawn of Everything, like, it's a big book and it's pretty thick but the last chapter has some really cool stuff about psychedelic uses in other cultures and then the third one that I really love is The Immortality Key by Brian Marescu. I love that book so much. Like, I designed my entire Halloween decoration this year all around that book and, you know, I sent pictures of it to Brian and he was like, "Oh my God, you nailed it. I got up my Halloween game." So yeah, those are the three books that I would recommend. Yeah, The Immortality Key is the only of the three that I've read but fantastic book, really, really exceptional and it has made me want to try to meet archaeochemists and have more conversations about recreating the elixirs of Midas and many others. So we'll see if I ever get around to that. I have to maybe cut back on my podcasting to make time for that. Well, I loved that book also because my family's from Turkey and one of the places that he mentions is Ephesus, which is an hour and a half drive away from my mom's house and, you know, I'm definitely next time I go to Turkey, I'm visiting Ephesus to try and figure out all those those hecate, you know, carvings and maybe take a little soil sample. Just a little soil sample. Customs loves soil samples.

Concluding Remarks

Parting thoughts. (01:59:10)

So cool. This has been a wonderful conversation. We've covered a lot of ground. Is there anything else that you would like to add any closing comments, anything we didn't discuss that you'd like to make mention of or draw attention to before we wind to a close for at least this initial conversation? Oh, God, I can't think of it. I think this has been one of the most fun meandering conversations. I feel like we covered everything. I look forward to doing it again sometime because I really do think that in the next few years, we're going to have some pretty pretty ground shifting stories coming out and I would love to come back and share them with you. Absolutely. Things are moving quickly. Things are developing quickly and I think we're going to have a lot of very exciting, interesting and provocative questions on the forefront of science in the next few years, which I'm looking forward to and I'm glad that you are very willing and capable of challenging the maybe dominant beliefs or the beliefs to get traction and are willing to take risks with the science that you pursue. So thank you for doing the work that you do and it's the best place for people to find your work, Is that where you would point people? Yes, yes. Perfect. Well, Teshikura, thank you for taking the time today. Oh wow, excellent pronunciation. Thank you. Yeah, I love Turkey. I love Turkey. The language I'm fascinated with, that's a conversation for another time, very similar grammatically to Japanese, oddly enough, which is where I've spent more time. But I really appreciate you taking the time today and being willing and so game to explore so many different subjects and to everybody listening, we'll have links to the various terms, stories, people, names, books, etc, that we discussed, including studies. In the show notes, as always, at and until next time, experiment widely, be just a bit kinder to yourself and others than is necessary and thanks for tuning in. you you you you you you you you you

Great! You’ve successfully signed up.

Welcome back! You've successfully signed in.

You've successfully subscribed to Wisdom In a Nutshell.

Success! Check your email for magic link to sign-in.

Success! Your billing info has been updated.

Your billing was not updated.