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Psychedelics, Metaplasticity, Critical Periods, Social Learning, Psilocybin, LSD, MDMA, Ketamine

Updated: Aug 2, 2023

Full auto-generated transcript below. Beware of typos & mistranslations!

Nick Jikomes

What kind of science do you do and what do you study in your lab?

Gül Dölen 4:53

Yeah, so I'm a neuroscientist and I study mostly social behaviors but also learn Memory, plasticity, and evolution development. These are the sort of main topics that my lab studies.

Nick Jikomes 5:11

And we're going to talk a lot today about stuff related to neuroplasticity, and how different psychoactive drugs affect things like neuroplasticity in the brain. We've talked about this on the podcast with you before, and many, many other guests. So we'll assume some knowledge from the listeners here. But can you give people just a very brief overview of what neuroplasticity is, and then maybe go into a little bit more detail on two forms of plasticity long term potentiation and depression.

Gül Dölen 5:40

Yeah, so, you know, different people use plasticity in different ways. So the term has gotten to be a little bit overused. And, you know, clinicians use it to describe basically, anything that changes over time, which, you know, I think is a little, you know, too broad, you know, neural synaptic neurophysiologist, like myself, we have a very specific understanding of what that means. And our definition is basically that when you stimulate a set of pathways between two neurons, that stimulating that pathway at a certain level, before you induce plasticity induces, you know, some baseline activity, and then after you induce plasticity, the same stimulation induces, you know, either a bigger or a smaller response. And if it's a bigger response, we call it long term depression up up potentiation. And if it's a smaller response, we call it long term depression. And it's a very specific synaptic response. But synaptic plasticity, you know, described in that way, is not just limited to the electrical activity changes, but, you know, typically is followed by changes at the level of gene expression, which then gets translated into changes in morphology. And so you know, this type of synaptic plasticity that we study and we focus on is electrophysiological. But morphological plasticity is thought to be the normal sequela of that of that type of plasticity.

Nick Jikomes 7:23

I see. So if we imagine two neurons connected to one another, talking to each other, one of them sends a signal, it induces the, the neuron listening to that one to send out its own signal, say, if you then do something, you Bay, the neurons in a drug or something like that, something changes. And if the first neuron sends out the same signal did before, and then the second neuron has a bigger response, or sends out more responses or something like that, we call that potentiation. And if you do the same thing, but the second neuron sends out a lesser response, we call that depression. That's right. That's right. Okay. And so plasticity, I mean, as you said, it's used a lot, a lot of people use it differently. You know, as a synaptic physiologist, do you have a more specific way that you use that term? The other thing I want to get your just general comments on our when we talk about neuroplasticity very often in the public, it's used, it's used in a way that almost implies that plasticity is a good thing, or it's always a beneficial thing. Can you talk about that a little bit? And whether or not that's true?

Gül Dölen 8:34

Yeah. So it's, it's not true. I mean, just like everything, you know, not all growth is good growth. So you know, a cancer biologists will tell you that, when you're developing and your body is growing, growth is normal. But even then, it's under certain constraints imposed by developmental programs. So that, you know, you're not growing hands out of your cheek, you know, there are rules and you know, growing, but there are rules. uncontrolled growth, is what you see when you see cancer. And similarly, plasticity, you know, there are rules for plasticity, associative learning rules that say, you know, you're not just learning that. Let's say, let's just give the example of you know, you go to a restaurant, you have a wonderful experience, it's the best turkey sandwich you've ever had in your life. And so you say to yourself, the next time I'm hungry, and I'm in this neighborhood, I'm gonna go back and get that turkey sandwich. And so the rule of get this turkey sandwich is conditional on your hunger level, on your proximity, and, you know, lots of other factors, accessibility, etc. And so those associations that you form are governed by rules. Whereas other types of learning for example, in addiction, they break all kinds of rules, right? So when you get addicted to a drug like let's say cocaine or fentanyl then you are essentially you like it all the time, no matter what the circumstances, whether you're hungry or not are closer, whether it's illegal, whether it's gonna cause your nose to bleed, you don't carry it, you like it, you like it, you like it. And so that it's a type of learning that breaks all of those rules. And that type of learning is actually associated with too much plasticity or hyper plasticity. That's what we see at the neuronal level when animals become addicted to drugs.

Nick Jikomes 10:30

So, so, highly addictive drugs, you know, maybe taking something like cocaine or nicotine as an example, these, the addiction itself involves hyper plasticity or new connections, sprouting, you know, to what extent is that true? And where what are some of the key circuits in the brain where we see that happening?

Gul Dolen 10:49

Yeah, so I mean, that's pretty much a Universal property of all drugs of abuse. So sometimes they induce you know, LTP life changes, so increases in dendritic spine or fallen spin dendritic spine formation, and sometimes, you know, they induce reductions, but, you know, cocaine, heroin, amphetamine, you know, all of the nicotine, alcohol, they all have the drugs of abuse, induce these types of plastic changes, and they do them in what's called the Museo cortico limbic rewards circuit, which involves the ventral tegmental area, which has all those dopamine neurons, which then projections to the nucleus accumbens, which has the receptors for those dopamine release, releasing terminals, the prefrontal cortex is also part of that circuit. And that sort of sex, drugs and rock'n'roll circuit is thought to be what's the brain regions that are involved in normally, encoding reward based learning that's constrained by certain rules. Whereas when drugs of abuse like cocaine and amphetamine and heroin takeover, they kind of use serve those functions and do them in a in a accelerated way.

Nick Jikomes 12:08

I see. So, not all plasticity is good plasticity. And in fact, all drugs of abuse share this property of causing plasticity in the so called Sex, drugs and rock'n'roll circuit, which is basically a part of the VTA to the accumbens, and it's a dopamine circuits. So dopamine is very important. There's some plasticity that happens here, hyper plasticity, and that's, that's a critical part of what the addiction processes in the brain.

Gul Dolen 12:34

That's right. And importantly, it also involves the prefrontal cortex, because there have been some people who have, you know, made a big deal about sort of what psychedelics might be doing, and they focus on the prefrontal cortex, not realizing that the prefrontal cortex is also part of the sex, drugs and rock'n'roll circuit that drugs of abuse also, impact

Nick Jikomes 12:56

I see. So maybe, you know, roughly speaking, people can imagine the nucleus accumbens, kind of sort of, kind of in the middle ish of the brain, you've got one circuit from the VTA pumping dopamine, and that's sort of coming up from behind it. And in the prefrontal cortex, you know, right behind your forehead is sort of sending information in the other direction. And those two streams are colliding, and the way that they mix together is very important for all this stuff.

Gul Dolen 13:22

Um, almost, that's all that's right. But also the dopamine neurons and projections to the to the prefrontal cortex directly, and favourable connections between all of these things that are much less studied. So we like to, you know, when we make textbooks, we draw arrows, and we make it seem like it's all going in one direction, but these brain regions are really talking to each other in a pretty substantial way. And actually, you know, one of the other things that, you know, although it's not what I'm necessarily most well known for, one of the big discoveries that I made when I was still a trainee and a postdoc is that the, the nucleus accumbens also receives a pretty important serotonergic input from another brain region called the dorsal Raphe Bay. And then that type of reward learning is a little bit sort of it, there's beginning to be more evidence that that type of reward learning is also involved in encoding the reward value of other rewards like social rewards, that, you know, are not as often implicated in drugs of abuse, but may also play a role there.

Nick Jikomes 14:36

So yeah, the brain is super complicated. There's there's lots of connections, lots of molecules involved. Not all plasticity is good plasticity. We just talked about that in the context of addictive drugs. With all of that in mind. Now there's there's something kind of interesting about psychedelics because on the one hand, they're famous for not really being drugs of abuse, you don't really they don't really have addictive properties like cocaine or amphetamine or nicotine or other things. And on the other hand, a lot of people have been talking about the ability and the relationship of psychedelics to plasticity. So they seem to be tied to plasticity in some way. And yet they're not drugs of abuse. So presumably, the plasticity that they're triggering is not the same as something like cocaine. Up until very recently, can you give us sort of a state, state of the art on what we know about, say, classic serotonergic psychedelics and the extent to which they are actually inducing plasticity per se?

Gul Dolen 15:32

All right, so in that question, I have to unpack at least three things. So let me just take them in backwards order. So first of all, I do not like the terminology, classical psychedelic, because that is, I think, misleading, it suggests that the serotonergic cycle, the so called serotonergic, psychedelics, the psychedelics like LSD, psilocybin, you know, mescaline, DMT, that target the serotonin to a receptor are somehow uniquely psychedelic, or the special category of psychedelic and everything else is, you know, kind of got thrown in there after the fact. And that's just not the case. Historically, you know, the people who first started this, you know, working in this field and defining you know, serotonin receptors, Saul Schneider, who discovered the serotonin to a receptor, included in the category of psychedelics things like MDMA and Ibogaine and ketamine, which do not bind the serotonin to a receptor. This push to kind of narrow the definition around the to a receptor has really been the focus of a lot of chemists who want to say, Okay, well, we can understand that the some of the psychedelics bind this receptor have similar properties, like hallucinations. And so that's, that's what we're going to focus on and everything else is just, you know, exception to our serotonin rule. And I think that that's putting the cart before the horse and, you know, I'm happy to talk about that as well. But we do have evidence that the serotonin to a receptor isn't especially special, you know, it's one of many mechanisms that can trigger this psychedelic experience and that and that it's, you know, over putting, putting the cart before the horse and the horse before the cart, whatever the thing is, to narrowly constrain the definition around the to a receptor. So I don't use classical psychedelic, I just call them psychedelics and I and I define them as you know, hallucinogenic, psychedelic, and pathogenic psychedelic oni oragenics, psychedelic, dissociative, psychedelic, and specifically talk about the receptors for each drug.

Nick Jikomes 17:52

So we're definitely going to dig into this more, but based on what you just said, how would you differentiate the word psychedelic in the way that you're using it from psychoactive?

Gul Dolen 18:04

Yeah, so I go active literally means that it has an action on the brain. And psychotropic means something roughly similar that you know, it has a an activity that produces a noticeable change in, you know, state, brain state that you can feel but there are plenty of drugs that are psychoactive and psycho tropic like they target the brain that, that don't produce that sort of altered state of consciousness, right? So like Benadryl is psycho active, because it, you know, causes you to feel drowsy, by targeting the brain. But it's not psychedelic, because it doesn't produce that altered state of consciousness that's shared by all psychedelics. So what is that altered state of consciousness? Well, it's a little bit tricky to describe because, you know, it's, you know, depending on how you define consciousness, right, but I think what we can kind of understand is, is that they seem to be drugs that make you share in common, this feeling that the world is a different place when you're on it. That your, your sense of smell, your sense of space, your sense, that sense of time. Your, you know, typically sensory motor systems are all they just feel shifted in a way that, you know, is unusual and a little bit, reminding you that your normal waking life is just, I mean, some people have the feeling that you know, your normal waking life is an illusion. And this new state that you're in when you're on these drugs, is the really real and that's kind of the end you have the epiphanies that you have in this altered state of consciousness are more real than you're usually have access to. And that property is called the noetic property. Some people describe a mystical sense of feeling like they are in touch with, you know, spiritual forces. And God, some people really are focused on that altered state that, that makes them feel like they're a child again, like there's their their experience in the world through fresh eyes and in a playful state that they haven't experienced since they were a child. So I know that's a sort of long winded description, but if you haven't done any psychedelics, it's saying, an altered state of consciousness doesn't really like explain it very well. So I think we need to figure out a way to more succinctly describe it. But that gives us a sense of how different the world seems on psychedelics.

Nick Jikomes 20:58

And so, you know, using terminology this way and thinking about things this way. Especially when we're talking about something so subjective here. The idea is, you know, if you've got something like LSD or psilocybin, tryptamines, which are historically referred to as serotonergic, or classic psychedelics, you've got dissociatives, like ketamine, you've gotten pathogens like MDMA. Even though the experience triggered by each of these are very different. The idea is that there's some common core here on the subjective experiential side. And even if it's very difficult to describe, to describe exactly what that is, in words, this would imply that there's also something biologically overlapping where all of these things converge. And we're going to come to that I'll ask people just to keep that in the back of their mind for now, because that was part of your recent study. But I want to give people a little bit more background on sort of plasticity and some of the neurobiology stuff here. So we talked about long term depression potentiation. And we talked about synaptic synaptic plasticity from the perspective of physiologist like you, there's also this concept of meta plasticity. And so what is that?

Gul Dolen 22:14

Yeah, so I mean, this is, this is an idea that's been around in neuroscience for roughly 2530 years. And the idea is that the rules for plasticity, as I mentioned, you know, these are these are normally functioning physiological properties when they follow their rules. And those rules change as the animal or the brain matures. Right. And so as a child, or as a young, developing brain, plasticity is easier to induce. And that's because, you know, there are these constraints on plasticity that as the brain matures get put in place. So there are molecular constraints, like the subunit composition of the receptors changes as that brain matures, there are circuit level constraints, for example, you know, inhibition, inhibitory neurons get more numerous and have more synaptic connections, and they really sort of dampen down the excitability of the entire circuit. And then there's sort of interest, neuronal space, extracellular matrix type of mechanisms that also kind of lock in the plasticity and sort of lock everything into place, I like to think of it as sort of the grout between the tiles. And as the brain matures, that really increases. And so that change in the ability to induce plasticity between a juvenile brain or a young developing brain and an adult mature brain that has stable, you know, habits and memories and learned things about the world. That change is called meta plasticity. It's sometimes also called, you know, the plasticity of plasticity that ability to change over time. And so, back to your other question about, you know, there's been this idea that, you know, psychedelics are inducing plasticity, I have to warn people that you know, a couple of those wall handful of those papers that have really made that claim that you know, psychedelics are just psycho plastic gins. Those ideas came from experiments done in tissue culture. And so you have to know that I personally have not been able to reproduce most of those findings, the way that they've been described in those papers. And I think it's because these results are a technical artifact of using a culture system to define plasticity. So what do I mean by culture system? These are basically baby neurons that are put in a dish and artificially kept alive in that ish they are they don't have the molecular signature of an adult neuron, they don't have that circuit level constraints on plasticity by inhibition. And they don't have this, you know, sort of interstitial space kind of constraints imposed by extracellular matrix. So it's a, it's a very, very artificial system that, you know, very closely approximates, you know, newborn brain, neurons in a neuron, newborn brain, but without any of the circuit constraints. And because of that, basically, it's very, very easy to induce plasticity in a culture dish. In fact, some, you know, prominent neuroscientists have said, You can spit on a culture dish and induce plasticity, right, it's just very easy to do. And so these early results that psychedelics were, you know, they were putting on bath, applying psychedelics, and getting these big, big, like morphological changes, you know, 40% of the synapses are growing, there's, you know, sprouting of not just the synapses themselves, but the dendritic arbors, you know, when I first saw those papers, I was just like, oh, no, you know, these drugs are going to be massively addictive, because they're doing these massive hyper plasticity, like changes. But then I dug into the papers and realized that they were all done in culture, I mean, some of them not even in neuron, some of them in human embryonic kidney cells, which have been immortalized. So they've been some of these constraints on plasticity that I'm talking about, have been broken down even more, right. So they're really, really artificial systems. So that being said, what my lab has done is we have seen that there is a role for plasticity, and specifically meta plasticity, in what psychedelics are doing. So what we found is that if we bath apply psychedelics, or sorry, we inject animals with psychedelics, and then we wait for two days. And so we're doing this in an adult animal where the whole brain circuits all of those mechanisms. Yeah,

Nick Jikomes 27:05

oh, I just want to make sure we got some of this background. So you were basically describing the difference between in vitro and in vivo experiments. So you can do experiments in a live animal that's fully intact, and awake and doing stuff or anesthetized and doing and not doing stuff. Or you can, you know, in some cases, grow baby neurons basically, in a petri dish. And these are different types of neurons in very different types of contexts. So if you have neurons growing in a dish, they don't have all the same constraints that neurons in a real live animal have just a completely different context. And so what you're saying is basically, when you're doing experiments in vitro, where you've got neurons growing in a dish, it's much, much easier to get the neurons to do certain things and behave certain ways and induce plasticity. So even though there were experiments, where people bathed, baby neurons growing in a dish in psychedelics, and saw really interesting, really striking plasticity results and new connections sprouting and things like this, what you're saying is, yes, they did observe those things. But in that context, in a petri dish like that, you could put on any number of things. And potentially, you can just kind of poke the dish or do anything, and you're gonna see some kind of change akin to that. Yes, that's right. And so is it, is it? Is it common that you sort of see big differences between what happens in vitro and in vivo? Or is this a special case?

Gul Dolen 28:34

No, no, that's, that's very common. In fact, there have been pull decades were lost in drug development programs at big pharmaceutical companies that were sort of built on this. I mean, this is something that neuroscientists have been failing at for the last 30 years, and just when we thought we'd learned or less than a bunch of chemists who are excited about psychedelics decided to go back and redo the same mistake that we made 30 years ago, right. And so, basically, it's very common, and has it been common to try and, you know, make a simplified prep use, you know, these dishes, these culture dishes, right, because, you know, when you do these kinds of reduced preparations, you can test hundreds of drugs. It's exactly the kind of thing that a big pharmaceutical company loves, you know, where they can literally make a pipeline of testing 1000s of drugs on a simplified prep. And, you know, it's just over and over

Nick Jikomes 29:32

again, and presumably, the reason this is done has a lot to do with the fact that much easier to do in vitro experiments much easier to screen through lots and lots and lots of drugs and look for something a good lead, rather than doing sort of the more time consuming and expensive in vivo experiments. But, but, but you need to because we've seen this happen before. It's what you're saying.

Gul Dolen 29:55

Right? And also, I think, it's not just that, you know, You couldn't say, Well, you know, if plasticity is the thing, then we can search for the lead. And then we can go back and refine it, once we've got her, you know, 10 molecules, unfortunately, because the the culture dish that they're doing it in, doesn't have the elements that you need, it turns out to understand what psychedelics are doing, what instead is going to happen is, is that you're going to engineer compounds to have a certain property that you can see in a dish, which in this case, is plasticity, which is not just orthogonal to the psychedelic property or to the therapeutic property. But as in fact, something bad, right? Like, you don't want to take a drug like I began, which is right now, you know, probably our best hope for treating heroin addiction, and engineering it in a dish, or engineer it, you know, in a chemistry lab, and then screen for those compounds in a dish looking for plasticity, because then you're just going to take a drug that's useful for addiction, and turn it into really

Nick Jikomes 31:15

make it addictive. Yeah, exactly. So, I mean, this is all I think, very important context that that people are going to love learning about and hearing, then this is going to help people think about things a little bit more of a critical way. I want to now that you're talking about critical periods, and I'll let you pick which one you want to talk about ocular dominance, plasticity or the or the behavior one, can you talk about what critical periods are in a way that enables you to explain some of these things like the maturation of inhibition, and to give some examples of that extra context that you see in vivo that you don't have in vitro?

Gul Dolen 31:49

Yeah, sure. So I mean, critical periods. You know, they're not just like special periods of time, that's a that's a formal definition of a word that was invented in 1935, to describe imprinting behavior in snow geese. So this is that behavior where, you know, if an if a bird is hatched, and within 48 hours of hatching, and it's exposed to, you know, a flying object, it'll form a lifetime attachment to that object. And usually, that's, you know, its mother. But if the mother has died or isn't around, it can be another. It can be another animal, it can be scientist, it can be, you know, airplane, right, but after that 48 hours passes, then flying objects in the vicinity don't have that special meaning or special ability to induce an attachment. And so that window of time that 48 hours, when the animal is extremely sensitive to its environment, to specific kinds of stimuli in its environment, and is able to form a long lasting connection or attachment or a learned behavior. That window of time is called a critical period. And there have been, since you know, 1935, literally dozens of these critical periods that have been described. So you mentioned ocular dominance, plasticity, that's probably the one that we've done the most amount of study on mechanistically. But there are others as well, like language learning, and motor learning and sensory touch learning. These windows of time, you know, they're different for different learned behaviors. But there they exist, you know, throughout development. And so, in the sort of almost 100 years, since we knew about critical periods, neuroscientists have had the intuition that part of the reason that we're so bad at curing diseases, especially neuro and psychiatric diseases is because by the time we intervene, by the time we get to that, that time when we can, you know, reverse the blindness or, you know, put in the cochlear implant, that the relevant critical period that supports the learning around that function has already closed. And so we've spent a huge amount of effort trying to discover mechanisms that constrain critical periods to those windows of times and trying to figure out ways to reopen those critical periods with the intuition that if we can reopen them, then we can do a much better job therapeutically. So there are basically three overarching mechanisms that we've identified for how critical periods close there, there are a lot of nuances here I'm skipping over I just kind of the view from 10,000 feet is is that basically those mechanisms are I described about what constrains plasticity are also what constrained critical periods. So, you know, meta plasticity is one of the major mechanisms that we think is responsible for, you know, the critical period closing. Another one is maturation of inhibition. And then the third one is this maturation of the extracellular matrix.

Nick Jikomes 35:25

I see. So, as development proceeds, animals can become more or less sensitive different things in the environment, they can become more or less capable of learning certain types of things. All of that involves neuroplastic changes. And the extent to which those changes can take place is governed by physical changes in the brain that happen as as the brain is maturing, so maybe inhibitory neurons are maturing, and you get more of them. And so they further constrain activity as you proceed from from step one stage of development to another, the physical, external extracellular space, and sort of like the hardness or malleability of it can change. And, you know, the, the more squishy it is, the more plasticity you might have. And the harder it is so to speak, the less plasticity you might have there are these kinds of physical changes constraining plasticity across development. And those are exactly the types of things that you're sort of missing when you're doing petri dish experiments. Okay. Yep. So you had previously in your lab, looked at the social reward learning critical period, and you had done some experiments involving MDMA, which is very, very well known to have pro social effects and to effect social behavior. So it made perfect sense that you would try this type of experiment, can you concisely just remind people what that result was? Before we go into the new experiments?

Gul Dolen 36:51

Yeah. So basically, we knew from you know, the Hume the literature, that there must be a critical period for social reward learning, which is, you know, we think is related to why teenagers are so much more susceptible to peer pressure than adults are ye you know, when you grow up in a certain culture, you are able to learn the rules of that culture. But you know, leaders later if you go somewhere else, you can be a little bit awkward, and, you know, rude potentially, well, in a different culture, because you didn't you your critical period for that type of social learning has already closed. And so we had some inkling that that existed, but what my lab did in that first paper was to formally define that critical period for social reward learning. And you can think of it as you know, learning from your social environment. And what we found is, is that just like other critical periods, by adulthood, it's closed. And animals are really not learning from their social environment, in a reward based way, the way that they do when they're juveniles. But when we gave MDMA and then waited for 48 hours, then the adult animals were able to learn from their social environment, again, just the way that the juveniles did. And we did a bunch of experiments to kind of convince ourselves that that was really what was going on control experiments. But basically, what we deduced is is that that MDMA is reopening that social reward learning critical period. And as you mentioned, you know, the reason that we did that experiment is intuitively we thought, okay, great. MDMA is pro social, this is a social critical period. So of course, it should be able to, you know, open this critical period. And we thought that the reason that MDMA was working was specifically about that, that pro social quality that's not really shared with other psychedelics, and we thought this was going to be unique to MDMA. And we were,

Nick Jikomes 38:56

and, you know, one detail, I want to point out to people there, is it significant that you give the drug, but then, you know, you wait two days, and you can still measure these changes while the drug is presumably fully out of the system?

Gul Dolen 39:09

That's right, because we were trying to measure social reward learning, we didn't want to be measuring the acute acute pro social effects of MDMA, which, you know, others have done in, you know, other animals. We've done it in octopuses, you know, they do, we can measure their acute, you know, interest in being sociable, but we didn't want to measure that we wanted to know what happens after the fact. While they're not in this acute, you know, cuddle puddle mode, right. And so, we, that's why we waited, we did actually do a time course of it. And it turns out that this ability to open this critical period, starts to come on right away, and lasts for about two weeks with MDMA and then that critical period reopening The effect goes away. And so we thought, okay lasts a little bit longer than we thought. And we thought this is probably explains why the clinicians are so focused on that integration period after the acute psychedelic effects have worn off, and how important that support that they give to the patients after the fact, really is to integrate their newly discovered, you know, remember?

Nick Jikomes 40:28

Yes, so in the context of, if you try and sort of fit your experimental results in rodents together with the MDMA assisted psychotherapy results for PTSD, the idea is the MDMA is not fixing the PTSD, it's it's making the brain more malleable, essentially, for a period of time. And that enables therapy that's happening right after the drug is administered in the days and weeks after it's administered to be more effective than it otherwise would be.

Gul Dolen 40:55

Well, to be clear, that's what we think now. But at the time that that first paper came out, that's not really the the emphasis we put at that time, because we thought, oh, it's prosocial, that this is really about the therapeutic alliance with the with the clinician, or being able to love yourself again, and we really thought it was all about the social, this idea that maybe what MDMA and all psychedelics are doing is that they are reopening critical periods is really the insight of the new paper. And so when we think that

Nick Jikomes 41:33

yeah, what was the rat, why did you go down this route? What made you think that, you know, as we said, MDMA was, is a great candidate drug for something like being able to influence the social reward, learning critical period, just because of how, how famous the pro social effects of MDMA are, what made you think it could be possible that something like Ibogaine or LSD would would potentially have a similar effect?

Gul Dolen 41:58

Right, so I mean, basically, when we did that experiment, I thought, well, they're not none of the other psychedelics are going to do it right. Because nobody's doing a 60 person cuddle puddle on LSD or Ibogaine, right, like it, they're just not particularly prosocial. So when we did that first experiment with LSD as a control really, and LSD also reopened it, I thought there was some sort of mistake, we redid it. As we tried to the other psychedelics, and all of the psychedelics were reopening. This

Nick Jikomes 42:29

was you were using like LSD as a control. There's, as a brief aside, there's this very famous book in molecular biology called the eighth day of creation. And there's this beautiful anecdote that's sort of very beautifully described in that book, and sort of the punchline is something like, and then the control became the experiment, then you just remember,

Gul Dolen 42:50

Exactly, that's exactly what happened. You know, because we, we had already done the cocaine experiment, and cocaine doesn't reopen this critical period, which, you know, you know, is an important control, because there is some

Nick Jikomes 43:04

psychoactive, it's, it's inducing plasticity, but it doesn't reopen this critical period.

Gul Dolen 43:09

That's right. And it's also you know, a stimulant drug works on some of the same, there's overlap in terms of mechanism with MDMA. So it was a really important control. And so we had the cocaine experiment, and I thought the LSD was going to be the same thing. And it wasn't. And so when it wasn't, that immediately put into our mind that, you know, while MDMA is different from the psychedelics, because of this pro social property, it's in the same category as other psychedelics, because it also induces this altered state of consciousness shared by all of the psychedelics. And so maybe we thought, this altered state of consciousness is really just what it feels like to reopen critical periods. And, you know, that's sort of a wild idea, but we have a couple of pieces of information that support that view. One is, you know, they all do it. The other is and cocaine doesn't. The other is that we found that there is a proportionality between the duration of the acute subjective effects of the psychedelics and the duration of the open state of the critical period that we can induce. So for example, we know that psychedelics vary a huge amount in how long they last right? So ketamine lasts about 30 minutes to two hours, MDMA and psilocybin more like three to five hours LSD, like eight hours, I begin, you know, 36 to 72 hours, you know, is just extremely long trip. And what we found is that just like that variability in the duration of acute subjective effects, the open state induced by them is similar. It's proposed tional So, ketamine opens for 48 hours by a week it's closed, psilocybin and MDMA open for two weeks. And by three weeks are closed LSD open for three weeks, close by four weeks, I begin open, you know, as long as we've ever looked, so four weeks was the longest we ever looked. So that proportionality says, Oh, these things must be related. Right. And so that's another piece of evidence. And

Nick Jikomes 45:28

so, basically, just to summarize, you have a way to assay social reward learning in mice. So you have, we don't need to go into details there. But you guys can measure this in the lab. It's been done before many times. You give each of these drugs, MDMA, psilocybin, LSD, Ibogaine, ketamine, they all have different mechanisms of action, to some extent, compared one to the other. They all last for variable lengths of time, some of them relatively short, some of them much longer, like Ibogaine, if you give each drug to mice, and then you wait, and the drug goes out of the system, and then you measure, you know, day after day after day, are they capable of this social reward learning? Is that critical period open? The answer with all of them as Yes. And the amount of time after the drug is out of their system that remains open? Seems to be proportional to the amount of time the acute effects of the drug last? That's right. Exactly. Interesting. So, so you do those experiments, you find that result? What about his one? One sort of personal question I have around those particular experiments. And that result is, you know, they all have different lengths of subjective effects, because they're tied to how long they sit at the receptor. So you probably would expect them expect some kind of relationship like that the longer the drug lasts longer, sort of the inertia of its molecular consequences is going to last. Is there a particular reason why you didn't test something like DMT, or five Meo DMT? Just given the intensity and the short duration of those drugs?

Gul Dolen 47:02

Yeah, so we, I get that question, basically, every time I present, and it's a really good experiment, and I'll tell you, the real reason we didn't do it is just like boring technical reasons. Like, you know, it's not easy to deliver DMT, you know, by we just aren't set up to give inhaled DMT. And then, you know, we couldn't give it orally, but then we have to give,

Nick Jikomes 47:28

oh, the amount of wine. That's why, and

Gul Dolen 47:31

there's a lot of reports from humans that, you know, there's a lot of nausea associated with that. And mice can't vomit. And so we thought,

Nick Jikomes 47:42

you know, I didn't even think about that. Yes, yeah. That'd be

Gul Dolen 47:45

you know, nauseated for, you know, however long

Nick Jikomes 47:49

and other factor. Yeah. So

Gul Dolen 47:51

but we did, we did do an experiment to try and get at the same thing, which is we, we gave LSD in massive amounts, right. So we, we did 50 times the dose that would be normally sufficient to reopen that critical period, in mice. And when we did that, that 50 times dose, presumably, would be a much more intense experience, kind of like the throwing somebody out of a helicopter description of the DMT experience. And yet, the critical period didn't stay open longer, because we gave a more intense LSD experiment. So it stayed the same amount of we expect that as you, as you hinted at, it's not the intensity of the experience. It's the duration of the, I think probably something like receptor occupancy, you know, we know from LSD that when it sits in it receptor, it sits there for an unusually long amount of time. And that long receptor occupancy, or that very slow half off rate is what it's called, triggers a type of signaling called beta arrestin, which is known to kind of be involved in internalizing receptors and essentially hitting the reset button, which is exactly the kind of molecular mechanism we would expect when we, you know, talk about reopening critical parents, sort of a molecular reset of the synapse. We also are aware that, you know, ketamine has a, you know, pretty slow off rate off of the NMDA receptor that it binds to. So maybe what's going on and we don't we haven't tested this yet. We're still, you know, this is just a hypothesis at this point. But basically, the idea is, is that maybe the the thing that is common across the drugs that are able to do this, is that they're sitting in their receptor too long, and that is telling the synapse. Oh, no. Something bad is happening. In excitotoxicity is going to happen if we don't hit the reset button, and it causes a reset. So this reset could be because of too much activity, or sometimes, you know, you hit the reset on your computer if the screen freezes, right,

Nick Jikomes 50:16

so changed in some significant way,

Gul Dolen 50:19

some significant way that the brain says, This is not good reset, and then it pulls in the receptors sets off the molecular machinery that, you know, degrades extracellular matrix, you know, turns on a bunch of genes and says, Let's reset

Nick Jikomes 50:37

is happening. Okay, so just to summarize and lead into like sort of the next part of this. We know that these drugs work in different ways, right? So like the psychedelic effects of LSD, and psilocybin depend on their ability to activate 5g to a receptors. Not true for ketamine, right? It's acting through NMDA receptors and other things not true for Ibogaine, it's doing yet other things. Not true for MDMA, it's sort of just running serotonin transporters and stuff in reverse. So there's overlap between them to some extent, but they have very different ways that they work molecularly. And yet, they're all capable of inducing this reopening of the social reward, critical period. So there must be some kind of common denominator that they all converge on is what you would think. And so you guys dug into that. And so what did you find there?

Gul Dolen 51:25

Right, so we we started, you know, as you said, looking at the things that we predicted based on the LSD, so we looked at the two way receptor, we looked at beta arrestin signaling. And, you know, we found that those things were important for, you know, some sub types of psychedelics, but not the universal mechanism that could account for all of the psychedelics, but we did have the intuition that it might not be at that receptor or biochemical level anyway, because of how long these effects were lasting, right? So, you know, with MDMA, working, you know, showing open state of the critical period for two weeks, you know, Ibogaine for four weeks, even ketamine at 48 hours, we were thinking, Well, gosh, that's not going to be just sitting at the receptor for 48 hours, or even changing the biochemical signaling cascades for 48 hours or two weeks or a month, it's got to be at the level of translation, transcription, you know, editing of, of the molecular machinery and the DNA. And so we did some RNA sequencing experiments in and we took advantage of the fact that we had not only different psychedelic time courses, so we knew that, you know, ketamine was going to keep it open for 48 hours, but be closed at two weeks, whereas LSD was going to be open at two weeks, and 48 hours, we also knew that cocaine was not going to do it, but all the psychedelics were. And so we we ran, we took, we injected animals with these different drugs and waited different amounts of time. And then we microdissected out that nucleus accumbens that we talked about earlier, as being an important part of that mesocorticolimbic reward circuit. And we just looked at the transcriptional profile across all of those different conditions. And when we did that, what was amazing is, is that we were able to narrow it down, you know, let genes change all over the all the time, right. And so, if you aren't careful about how you design your experiment, you can just end up with, you know, 20,000 genes changed, and you have no idea what's going on. But we're using this very, sort of narrowly defined, you know, set of circumstances that are an open state versus the not open versus the closed state, we were able to narrow it down to 65 genes that were differentially expressed in the open state compared to the closed date. And when we did that, what we noticed is that roughly 20% of those genes are regulators of the extracellular matrix or components of the extracellular matrix. And that was just super exciting to us, because, as I mentioned, extracellular matrix regulation had already been implicated, you know, in other critical period, the closure of other critical periods. And this was just mind blowing, because even though nobody had ever looked at extracellular matrix regulation, with regard to critical periods and the nucleus accumbens, and even though the molecular identities of the of the genes wasn't identical, they were in the same category, right? So in the visual cortex, people had really focused on matrix metalloprotease Nine and we came up with You know, mmm, which is MMP MMP 16 and the nucleus. So not identical, but the same family to us.

Nick Jikomes 55:08

So roughly the idea here is, again, you get the same basic result with respect to reopening this critical period with Ibogaine, LSD, psilocybin, MDMA, ketamine, they're all touching different receptors to different extents. But after they do that they are affecting which genes are being turned on and off inside of neurons. And there's sort of a common core that seems to be common to all of them that they all eventually arrive at through their own different ways. And many of those genes involve regulating how, what's a good way to say this, how squishy the extracellular matrix is? Yeah,

Gul Dolen 55:47

I mean, I think I mean, we didn't, we're still digging into this, in the follow up experiments, but my are working model is, is that what they're doing is, as you said, acting at their own receptors hitting hitting the reset button in some way. And that what is going on is that that is telling the neuron degrade extracellular matrix, make a bunch of, you know, enzymes that are going gonna go out into the extracellular matrix and chew it up and take it apart. Right, so and that degradation of the extracellular matrix, you know, is is a is a event that is encoded by the set of genes that we found. And what we're, what we're finding with those genes is just the sort of homeostatic response to kind of okay, we did write it, and now we used up all of those things, we need to make new to replace the things that we did write it, so. But that's the idea is, is that it's dissolving or degrading the extracellular matrix, taking it down, so that new memories can be formed via, you know, new meta plasticity that's enabled by this sort of cleaning house of the extracellular matrix. And once those new memories get laid in the new extracellular matrix, we'll get down to sort of lock those memories in place.

Nick Jikomes 57:12

And so, you know, with all of this, all of these results in mind, and everything you've been telling us, you know, I want to get into a discussion of the therapeutic relevance of the psychedelic or psychoactive effects that these drugs have. And so earlier, you know, we were talking about, we were talking about nomenclature, and what words to use to describe these drugs, how we classify them. And there's also you know, their effects and what they have in common or don't have in common, and on the one hand, it's super hard to talk about because very subjective, and many of these experiences are so alien to our normal experience that, you know, your your linguistic faculties literally break down if you take enough acid. So it's really hard to talk about this stuff. And but I think people with a lot of personal experience with these drugs would probably tell you is that, you know, a deep ketamine experience and a deep LSD experience are as different from each other as they are from everyday waking consciousness. And so you know, that common denominator is almost nothing other than the unnormal pneus of the experience. I'm reminded of William James, he, you know, famously had his description of what he imagined a newborn baby's conscious experience was like, and he called it a blooming, buzzing confusion. And so if you're sort of hit it hitting this reset button, and the details of the experience and everything are different for, you know, something like say psilocybin versus something like ketamine or Ibogaine, what they have in common is that the the spatial, temporal, temporal dynamics or the statistics of what's going on are being sort of scrambled, they're not as regular as they are, when we are, you know, sitting sitting here and having this conversation and having our normal, normal experiences. So what they have in common is sort of just this general reset, and this general being different from from everyday normal experience. How do we start to tie that to the question that everyone's interested in right now, and different people are pursuing different ways of whether or not you can engineer out the sort of subjective psychedelic experience from these drugs and still have the therapeutic potential that we're seeing?

Gul Dolen 59:24

Yeah, so my intuition on that last part is that no, we won't be able to engineer out the psychedelic effect. And that's partially based on that proportionality experiment that I described. In other words, you know, as you shorten the duration of the effect, you shorten the ability to reopen the critical period and if reopening critical periods is the thing right that is responsible for these not just like, you know, I think people are excited about psychedelics because because they are not just next generation SSRIs or next generation anxiolytics are not exciting because, you know, we're gonna have to take them for life and, you know, medicalized people and treat their symptoms, rather, people are excited, because this could be a cure, you know, you take it, maybe one or two times, maybe five times, if it's a really entrenched, you know, memory that needs a lot of work to be resolved. But then your cure, you don't have to take them again, and you don't have to be on them forever, you know, and that excitement is that, you know, we could have a neuro psychiatric cure, that's similar to say, you know, putting in a new valve, if you have a heart problem, right, like, a sort of surgical, you're cured after this intervention. And I think that all of the effort to engineer out the psychedelic, quote unquote, side effect is really, you know, following the old fashioned, you know, big pharma model of, you know, we're looking for symptom treatment. And I think, for me, you know, as an MD, I can't say that that is particularly exciting. I, I'm really excited about these, as you know, this surgical type of model of we're going to cure people of their diseases. Getting back to your your more philosophical question about, you know, maybe what's common to these things is just that they're inducing such a radical shift in your perception of the world that that is that that's really the only thing that's common to them, and that that's somehow triggering critical period reopening. And I think that that's maybe right. I actually think that if we think about what it is why it is that we have critical periods, right, and why does they close, and then why it is that a brain might want to have a ready made mechanism for reopening them, we can sort of think about the fact that you know, critical periods exist, because there aren't enough genes to encode all of the things we might need to learn in the world, right, that there aren't enough genes to encode 250 different languages. So instead, we have genes that encode the ability to learn 250 different languages, and you learn the one that's relevant to the environment that you were born in, right. So that ability to learn from your environment is why we have critical periods, but then, you know, all that sort of flexible learning and being sensitive to the world and being hyper aware of what's in in your environment. It's exhausting, emotionally exhausting. I mean, who wants to be a teenager again, where you have to care about the exact right shade of acid washed jeans, you're gonna wear, right? It's sucks. It's hard, it's, it's raining, it helps it distracts you from being able to focus on other things. And so, in general, what we think is the critical periods close because, you know, it's not an efficient way to navigate the world to be constantly hyper aware and learning, you literally

Nick Jikomes 1:03:11

couldn't survive, you really couldn't in the limit, like, right, you can't be on DMT for days and weeks.

Gul Dolen 1:03:19

You can see it also in kid like, I friends, kids, I go on nature walks with them sometime in the park, and like, you know, what I would normally do in an hour takes us three hours, because they are just noticing everything, you know, like, Oh, look at that leaf. And, you know, oh, what is this thing? And you know, it's just not an efficient way to, you know, do the walk and come back because they're learning because they're hyper aware. And you just couldn't navigate the world that way normally, and you know, people on psychedelics are the same, you know?

Nick Jikomes 1:03:53

I mean, if it's sort of this general picture is true that these kinds of drugs are sort of a master key for rebooting the brain temporarily and reopening critical periods. Generally, a natural question that I'm sure you and others are pursuing, to some extent is, well, you guys looked at the social reward during a critical period, you guys looked at this particular form of oxytocin dependent plasticity in one particular part of the brain. The Drugs aren't limited to that part of the brain, they're getting everywhere. Are you guys doing experiments looking at ocular dominance, plasticity, critical periods, and all these other things and confirming that they are this sort of general reboot mechanism?

Gul Dolen 1:04:32

Yeah, so we're definitely pursuing that. We have some, you know, very preliminary data suggesting that they do reopen other critical periods, like critical periods for motor learning critical periods for ocular dominance, plasticity. So we're definitely that's that's the next area. But let me just go back one second and finish talking about why it is that we might have a general mechanism a master key for unlocking critical period it. And the idea there is that normally, habits are great, and they help you navigate the world as long as the environment is stable. But imagine that there's a radical shift in your environment, you move to a new country where nobody speaks your language, entire social group gets eaten by a wolf, or there's a, you know, giant pandemic, right? Under those circumstances, or the elders in your social community die in there, under those circumstances, you can imagine that it would be very adaptive for the brain to kind of reopen certain critical periods in a context dependent way, and be able to reconfigure those habits that are specific. So I think your intuition that, you know, maybe what's common about psychedelics is that they are a very assertive or efficient way of triggering that massive alteration in your status, stable environment could be right, and we have some evidence that that's true. Because historically, one of the other ways that people have, you know, master key style reopened other critical periods is by massive deprivation experiments, right? So you can do visual deprivation and visual critical periods, you can do sensory somatosensory deprivation, and reopen touch critical periods, auditory deprivation, to reopen auditory critical periods, we have some, you know, preliminary evidence that says that social deprivation can reopen the social critical period. And what's amazing is that all of the deprivation techniques are what, you know, a lot of religious and mystical traditions have used in order to get to that mystical state that is common between, you know, religious practices and psychedelics. And so we think it's not a coincidence, for example, that, you know, Zen Buddhists go and live in a hermitage or a monastery, you know, do massive social deprivation experiments, essentially, or, you know, these meditation practices and silent retreats and stuff. These are deprivation experiments, essentially, to get to what the Zen Buddhists are calling beginner's mind. I mean, if you were looking for a neurobiological term, to explain beginner's mind, critical period, reopening would be it. And so to me, this is more circumstantial evidence that that altered state of consciousness, that mystical experience that's common to psychedelics, and religious practices, is just what it feels like to reopen critical periods.

Nick Jikomes 1:07:49

Yeah, I mean, that would, that makes a lot of sense to me intuitively, I mean, you could also, you know, the deprivation side, I didn't even think about this piece. But but it makes a lot of sense. People have historically used deprivation to do neuroscience stuff. But you know, people also report going into the sensory deprivation tanks, completely sober and having something like a psychedelic experience. And it would just be to sort of restate what you're saying. These are non pharmacological ways to radically changed the statistics of what's coming into the brain, such that the brain sort of goes through this reboot process, so to speak.

Gul Dolen 1:08:26

Yeah, that's what we think.

Nick Jikomes 1:08:28

Interesting. So what are the potential risks and downsides here? So you know, obviously, well, before we actually get to that, so one of one of the exciting things about this, assuming all this stuff really sort of turns out to be true is we can we can do things to help people where it was, it was just too late before so for example, if someone's born with autism, being agnostic about what exactly caused that, but you know, they go through their social reward learning critical period of some kind, they become an adult, the extracellular matrix is now hardened. And it's really hard for them to relearn or unlearn things, the idea would be, we could make their brain squishy again, so to speak, for a limited period of time, give them the right kind of social stimuli, and, you know, treat or potentially even cure or something like that. But we couldn't do that before, because we had no way. You know, even if we had therapy and other tools, there was their brain just wasn't going to be receptive to the requisite stimuli, that that it needed to re sculpt itself or remake itself. So is this the hope here that now we can go in and treat or potentially even cure certain types of neuropsychiatric conditions by temporarily making the brain receptive to the right kind of stimuli again?

Gul Dolen 1:09:46

That's right. That's exactly the way that we're thinking about it. And we are looking at autism because, you know, that's one of the major focuses of my lab, I will say, and we're but we're also focused on things like Stroke, where you know, after you have a stroke, there is a sort of, there's a motor critical period in general, and it gets reopened when you have a stroke. And that stays open for about three months, but then it closes again. And today, the only way to reopen it is to give yourself another stroke, and who wants to cure stroke by giving themselves a stroke, right. So being able to give them you know, in theory, a psychedelic to reopen that motor critical period after a stroke would be, you know, exactly as you describe, you know, pairing the psychedelic with the physical therapy could really, you know, enable us to, to treat these brain diseases that we just don't have any other hope for at this point. So it would be a massive, massive paradigm shift for all of neuropsychiatric disease, and neurology and psychiatry and neurosurgery. Everybody would be impacted. But also, you know, like, I can imagine, you know, language schools opening up, right, it would be potentially, you know, a game changer and ability to rapidly induce this, restore restoration of that state of malleability. I would just say, you know, you mentioned, well, what are the what might be some of the downsides. And I just want to kind of go back to this idea of, you know, the critical period. I mean, when I was a graduate student, at MIT, we were in a little bit of a heated debate with another lab at Harvard. And, you know, the debate was kind of like, is there a master key? Could there be a master key for reopening critical periods, and I was very much on the side of no way. Anything that can do that is going to, you know, essentially, either be, you know, amnestic, or going to cause seizure, or is going to disrupt the structural integrity of the brain, right, based on our understanding of the mechanisms of critical period, and I call that the melty brain problem. So how is it that psychedelics might be circumventing the melty brain problem? Like, how, what are they doing? And my intuition is that the way that psychedelics circumvent the melty brain problem is that they are their effects are context dependent. So it's not like you take a psychedelic, and all critical periods are just open all the time, and you're just you're able to learn anything. The subset of synapses circuits, you know, memories that become available for modification, seem to be context dependent or activity dependent, right? So it's not like you can take MDMA and go to a rave and expect to cure your PTSD, you really need to pair that MDMA. With the psychotherapeutic context, we also have some evidence that, you know, you need the social contexts to reopen the social critical period. But if you're trying to reopen a modal critical period, the social context doesn't matter. Not a social critical period.

Nick Jikomes 1:13:10

Do you think you think this sort of this context dependency has something potentially to do with the potential relevance of the subjective effects themselves? So So for example, you know, if someone, you know, I talked to someone on the podcast a couple years ago, who was an early participant in psilocybin assisted therapy, for for addiction, he was a severe alcoholic, and he described it and it worked beautifully for him. That's great. And then he also described that the specific content of the experience was very, very much related to his addiction, he saw an alcohol bottle breaking and turning into sand and turning into dust. And he interpreted that to mean that his alcohol lism was leaving him. And, you know, one reaction to that could be like, you know, that's just a side effect. It's great. That's a wonderful experience. But another way to think about that is, you know, if you're having that kind of experience as an alcoholic versus a trip where none of the none of the content has anything to do with your alcoholism, that represents a different set of circuits being engaged in a different kind of way, when you have the one experience versus the other. And so, do you think there's, there's something there?

Gul Dolen 1:14:26

Yeah, for sure. I mean, I think that, basically, you know, we did this, we did do an experiment in the paper that just came out that where we looked at whether or not the psychedelics seem to be having, you know, a direct effect on addiction like behaviors using all of the sort of typical neuroscience, you know, I come from an addiction lab. And, you know, we looked at you know, does it change the reward value that would be the prediction like it changes the reward value drug of abuse, no longer addict addictive you know, in the in the sort of classically defined dopamine reward value type of way. And it didn't it did the psychedelics had no effect on those things. Instead, what we think is happening and this is very much in line with the patient narratives is, is that it's not changing the reward value of the drug itself. Going back to that prefrontal cortex, part of the medial cortical limbic reward circuit, what we think is, is that it's changing the narrative a person has like, enabled them to write a different narrative around the why they're using the drug and what need they're trying to solve a problem they're trying to solve by using the drugs. So the epiphanies that people describe are not like, suddenly, I lost my taste for nicotine, the way that people describe when they take zibin, or, you know, one of these other drugs, like sort of drug addiction type of typical drugs. Instead, what they're describing is, I had an epiphany. And after that epiphany, I realized that, you know, the problem that I was trying to solve doesn't exist anymore. And so, you know, smoking a cigarette to solve that problem, seems as foolish as leaving out cookies and hoping that a fat man will come down the chimney and leave me presents, right? It's just a myth, I don't believe anymore. And so that cognitive reappraisal, that cognitive flexibility, is very much going to be driven by the context that you go into the psychedelic experience with, right, like, if you go into the psychedelic experience, you know, already kind of priming yourself preparing yourself for, these are the set of memories that I want to examine when I'm on this trip, then they become available for modification and become sort of malleable for those kinds of changes.

Nick Jikomes 1:16:58

I mean, one of the things that's interesting here, when we sort of step back from the science side of this a little bit, and you know, you talked about things like parallels between second drug induced psychedelic experiences, and different forms of sensory deprivation, and different religious, religious rituals and things like this, you know, when you think about human beings, just compared to other animals, generally, human beings are sort of the most context adaptable, you know, we populated the globe, we've had to more than almost any other creature go into and out of different contexts all the time. You know, taking off your just your hat purely as a scientist for a moment. What do you think about that? What do you think about do you think that things like a lot of the ritual practices that often have often take the form of religions and things like this? Do you think that has something to do with sort of humans adaptability, and our ability throughout history to have spread into so many radically different contexts that we've come up with behavior, self imposed behavioral paradigms, with or without the assistance of substances that enable us to, you know, flip the switch and adapt to radically new environments?

Gul Dolen 1:18:11

Yeah, I mean, I think that, um, I mean, these are big questions, and I just, you know, recently applied for a big sort of high grant. And this is basically the question that I was trying to get at. And the way that I think about it is, I want to take the evolutionary view, I am generally of the belief that humans aren't as special as we think we are, we just, we just noticed what we do more because it's us, right? But I like taking the evolutionary view. And, you know, I think that we can learn a lot by taking a massive step backward and look and sort of up and out. And look at species like octopuses were, you know, they are radically different from us in many, many ways. And yet, they are also very adaptable, they can live it massively different temperatures compared to what we can survive, and they, you know, taken over the entire ocean there, you know, lots of different species they have, you know, they're very, and they learn, and they learn from their environment, and they seem to have these abilities, but we don't know if they have critical periods if they have, you know, they might not right, so like they can lose an arm and regrow it. So they might not have a motor critical period, because why would you need one if your arm can always grow back, right. On the other hand, you know, we have some evidence that they can mostly they're a social, but in some species, if you rear them under social conditions, they can adapt and be socially tolerant and not, you know, kill all of the other animals in the tank, right? And so, they do have this adaptability, but it might be that this human sort of adaptive ability, the reason that we're so interested in being able to reopen critical periods, either by drugs or by religious practices is because we live for a really long time, right? So, you know, the rules of the worlds that you learned when you were 12 might not be the same as when you're 65. And so it's, I think it's not that surprising that, you know, people have a midlife crisis and oftentimes go on some religious experience, pilgrimage, and they reset, because they need to adapt to a world that's very different than the one that they, you know, adapted to when they were children. So we'll see we octopuses don't live that long. There are some species that do, but the ones that we're interested in, you know, live shorter, more like mice. And so, you know, let's see, but it's definitely an exciting question.

Nick Jikomes 1:20:55

Yeah, I mean, it is interesting that deprivation is a stimulus that reliably induces certain changes in the brain and an experience, it's doubly interesting that it's sort of a major thing that most of us are lacking these days, most of us, you know, we're constantly plugged into all of our technology, and we're hyper connected. And it's interesting that the deprivation is it seems to be capable, at least in certain contexts of mimicking some of the, the pharmacological effects that we're talking about here.

Gul Dolen 1:21:26

Yeah, well, I do actually believe that the pandemic was a massive deprivation experiment, although it went on too long. And so, you know, if you socially deprived animals for too long, then instead of reopening critical periods, it looks like what it's doing is, you know, causing depression and anxiety. So, like, the duration matters, right. But it's just become the new thing. But I think for some people, you know, early on in the pandemic, when we were socially depriving before we had kind of tipped over into too long, and now it's, you know, pathological, you know, that people did have that kind of experience of, whoa, the world is so weird. And, you know, it's true that we are much more plugged in, in many ways. And, you know, it'd be interesting to do some sort of epidemiological study to look across cultures and, you know, difference, illness conditions. I mean, I suspect that this is this happens to one degree or another, more commonly than we are really aware of, depending on what your circumstances are. But I also think, for example, the reason that it's easier to learn a new language or new to learn Spanish, in Guatemala, compared to Costa Rica, is, is that in Costa Rica, everybody speaks English. So even though you're surrounded by Spanish, you're not deprived, but of English first, whereas Guatemala, you have the deprivation, the English deprivation, combined with the Spanish immersion, and then I think you're in that open state, which makes it easier to learn Spanish.

Nick Jikomes 1:23:11

I see. Yeah, that makes a lot of sense. You know, one of the things that you point out earlier is, you know, one of the reasons why this is so exciting, these kinds of results with with psychedelics is, it really does seem like we could be on the cusp of seriously being able to talk about curing certain psychiatric diseases, rather than just treating some of the symptoms that some of them have. And you made some comments around, you know, our tendency to medicalize, you know, everything that we see and just sort of paper over symptoms, how so? So sort of in the traditional way that we've approached, treating psychiatric problems for people, where we're diagnosing people based on symptoms, we are giving them drugs, often for very, very long periods of time, potentially permanently to treat the symptoms, rather than cure the cause of the symptoms. How much of that? Or can you just talk a little bit about the extent to which we've been doing that simply because we're ignorant, and we haven't learned enough about the brain to be able to cure things and all we can do is treat some of the symptoms? And how, to what extent is that due to the sort of, you know, the fact that it's very convenient from a business standpoint, to just give people drugs to treat symptoms chronically. And there's kind of inertia involved in sort of the general structure of how those businesses work is to what extent is this ignorance versus, you know, business motives and things and and how do you see that maybe changing in the next five to 10 years?

Gul Dolen 1:24:46

Well, honestly, I think it's the business thing. I think it's just, you know, the market is driving the interventions. And, you know, unfortunately, I'm a little bit concerned that psychedelics are about to be co opted by that business model, because there's just such a inertia around, you know, funding for these types of questions funding for these types of companies, you know, it's hard to convince venture capitalists that they need to, you know, invest in something that there might not be a back end on, because, you know, the people will just be cured, and that the best molecules are the ones that humans have been using for 1000s of years, right. It's just, there's a lot of momentum financially. And these clinical trials are expensive, you know, it costs $200 million to run a, you know, well, double blind, placebo controlled, you know, large scale clinical trial, right. So, it's, it's expensive. And so, I think that's where the momentum is coming. And I fear that, you know, psychedelics are going to be the same thing, you know, it's going to people that are going to try and patent new molecules, based on, you know, suppose it improved properties that are not necessarily going to be improvements. And if we're not careful to understand the true mechanism to understand that, what the therapeutic benefits we've seen so far, are really about learning and memory, not about, you know, some property like hyper plasticity that you can measure in a dish, then we're gonna end up with another fentanyl face plant. And it's not going to be good for the patients, and it's not going to be good for the credibility of, you know, translational neuroscience.

Nick Jikomes 1:26:45

So it sounds like from your position as a neuroscientist, if you were advising people in the private sector, the second out private sector on this, you know, whether it's VCs or entrepreneurs or anyone else, it sounds like your basic position is that you would be you would not be bullish on companies solely focused on trying to produce non psychedelic psychedelic derivatives.

Gul Dolen 1:27:07

Right, I would say that those are likely to fail. And I would say that there's plenty of evidence now that even the sort of traditional SSRIs, you know, this, this whole model that there's, you know, a happiness pill that you can take is not right. And that, you know, really, if we think about what is causing depression, it's a learned set of behaviors. And that you have to learn something different from those experiences, or you have to not treat every single sort of bump in the road as if it's depression, but rather a potential learning experience that enables resilience, like even resilience is a learned behavior. It's not a pill that you take, right. And so I think that if we start to treat psychedelics like SSRIs, we're going to end up with, you know, some effects in the beginning that get people excited, but in 30 years, they're going to be no different from SSRIs, which is basically that they don't work. You know, they don't work if you try and narrowly push them into that model of depression. In fact, we don't even, you know, Our results suggest that these anti depressive properties may exist, but they might not. But they're probably orthogonal to the ability to reopen critical periods. They're just, you know, these drugs can have lots of different properties, because they bind to lots of different receptors. And so even if you believe that depression is a property that you could target, pharmacologically, it doesn't it's not clear to me that psychedelics are antidepressants in that way, or that that's the at all the same thing. Is this context dependent, right. So that's the key, right, like, all of these other properties that people are describing exhilarated property, anti inflammatory property, anti nociceptive property, these are properties that seem to exist, independent of the context. But the critical period reopening property is context dependent, just like these durable therapeutic effects are context dependent, right? If you compare the clinical trials that you know, maps did, where they really focused on the psychotherapeutic context, then you got these massive results and, you know, sort of cured for life type of results from these patients for PTSD, with MDMA assisted psychotherapy, whereas in the trials were you know, it was really the psychotherapy was there just in case somebody had a bad trip, then you know, it was kind of lackluster like barely better than not bad not at all better than SSRI just kind of Like, start onset faster, ketamine works faster, but then you have to take it again in a week. Psilocybin not better than SSRIs in terms of efficacy, you just didn't get the same Wow effects that you got with MDMA assisted psychotherapy. And to me, the difference between those trials is not the drug. It's that it's the emphasis of context. And so antidepressant properties are not context dependent. But critical period reopening is context dependent.

Nick Jikomes 1:30:32

What are some other critical periods that we know about in rodents? And I'm only asking about rodents, just because in principle, we can start to understand mechanism there. And in some cases, maybe we already do understand something besides the social reward learning critical period that you guys have focused on and that we talked about today. Are there other critical periods that involve learn behaviors? And if so, that that have been worked out to some extent in terms of like, maybe how they work? And if so what are those in rodents?

Gul Dolen 1:31:01

Well, theoretically, you know, critical periods were defined as behaviors that are changed, right? So the imprinting behavior in snow geese is a behavior. Other critical periods that are behavioral only, I mean, I think we, I we enrolled in so I'm not sure that we can say that there's a language critical period. But we know from birds that there's no such thing as a behavior that is changed. But in rodents, the reason that we use rodents is that it enables us to be able to do electrophysiology and more of these types of circuit mechanisms. And so the most famous critical periods in rodents are not behavioral so much as circuit rearrangements, in response to, you know, visual stimulation changes or somatosensory stimulation changes or auditory inputs that can get changed as a main critical periods. And that's not because there's any reason to believe that mechanistically, they're different, it's just that we have studied them in rodents, so that we would be able to look at these kinds of circuit level changes rearrangements following perturbation.

Nick Jikomes 1:32:21

You know, one of the things that's interesting about humans that you pointed out earlier, as we live for so long, and this, just the longer you live, the likelihood is that you're going to have to deal with new contexts that may or may not sprout up in your environment over time. Do you think like, so when we sort of just take the bird's eye view of say, the trajectory of people's mental health generally, and the types of illnesses that we see, you know, being diagnosed more and more, or in different ways, or in different times, things like that? How much of that do you think it has to do with the fact that you know, over time, as technology in society have developed, we are now doing different things at different times. And so what I mean by that is, you know, we used to, for example, start families and have babies, not long after we became physiologically competent to reproduce. But you know, over time that's gotten pushed further and further back. And you know, the reaction or the ability of one to adapt to say that new social context, you know, you're gonna have a different level of squishiness in your brain when that first happens. Do you think that you know, any of the, you know, when we look at rates of depression and things like this, do you think any of that might have to do with the fact that as we've changed our own environment, technologically and things, we have tended to put ourselves in different circumstances at different phases of development, that our ancestors tended to have those experiences? And does that? Does that make sense?

Gul Dolen 1:33:51

It does, but I don't think that that's, I don't think that I think that the increase in the rates of depression is because we have I mean, I my lab made mainly is a social neuroscience lab. And I, my intuition is, is that the way that our social lives are structured, are really bad for the social brain, right? I think that, you know, the way that we evolved, we were meant to live in communities. We were meant to live in one place for our whole lives and have a stable social group of, you know, maybe 100 or so people. And now we live kind of socially isolated from each other. I talked to a real estate broker told me that average american moves every six years, you know, it's just we don't have the same quality of stable social interactions and generational stability in our social environment. And I think that these impairments in or the degradation of our social lives, is made worse by some Some of the modern technologies, I think that social media should really be called anti social media because what you're basically exposing yourself to is a bunch of anxiety around social interactions, but you're doing it sitting by yourself in a dark room or staring into your cell phone. Without the sort of social buffering of fear that happens when you're hanging out with your buddies when you're, you know, socially well connected. And there's more and more evidence that this has major impact on life expectancy, morbidity, mortality, you know, it has immune consequences, it has, you know, consequences on you know, all of your, your, sort of outside of the brain systems that are, you know, controlling your heart rate, your blood pressure, your, you know, ability to process foods well, and I just think that we sort of live in a, in a social world that's more like Velveeta and less like, Cam and bear. Right? And so we need to go back to Ken membayar, social living in my view.

Nick Jikomes 1:36:14

I'm like, how do we do that? Like, are you your, Are you a parent?

Gul Dolen 1:36:20

And my What?

Nick Jikomes 1:36:21

Are you a parent?

Gul Dolen 1:36:22

I am not a parent. Okay. Parent, I like to think I am deeply embedded in my, say, this beautiful, I have these these beautiful paintings that were made for me by my

Nick Jikomes 1:36:35

and those are those octopuses.

Gul Dolen 1:36:37

There's, you know, they know I love octopuses and mushrooms. So I have, you know, several octopuses. And this one right here is an octopus living inside of a mushroom. So my friend's kids do them for my birthday. And I, you know, I saved them, I love them. So yeah, I I definitely enjoy being sort of cool anti Google, although that and that keep it real, you know, like, they're one of them, was telling me, the 10 year old was telling the seven year old, you know, Google knows a lot about animals, but not that much about dinosaurs.

Nick Jikomes 1:37:19

Yeah. Okay, um, you know, I don't want to take too much more of your time. I want to be respectful. I know you've got you've got things to do. Is there anything you want to reiterate, or any final thoughts you want to leave people with about sort of the just the general subject matter that we covered today?

Gul Dolen 1:37:35

Um, I guess the only other thing that we really didn't get spend a lot of time is that, you know, I really am very excited about the the clinical trial that we are raising money for, to look at whether or not we compare psychedelics with motor learning and specific types of motor training to get much better stroke recovery outcomes. And so, you know, if anybody's really interested in the stroke stuff, I encourage them to look up the Fathom project, which is P Fathom with a pH, which stands for psychedelic healing, adjunct therapy, harnessing open malleability. We have a, you know, a project page for that. And you can watch a little video of how we're going to do it. And, you know, we're raising money for it. So if you know somebody who wants to make a big donation, you know, those trials are expensive, but we are really excited. That that's the the next direction to take. And,

Nick Jikomes 1:38:37

you know, very briefly, what are some of the obvious next experiments and next questions that you guys are doing to follow up the recent paper?

Gul Dolen 1:38:46

Yeah, so we're definitely trying to test this idea that psychedelics are the master key. So we're looking at lots of other critical periods, we really want to get a handle on this molecular mechanism, like how does the cell know when it's in the right context. So we're trying to test the idea that there's some sort of molecular coincidence detection, that saying, this neuron is recently active, therefore, you know, if it's hit that the reset button, these are the ones around whom you want the extracellular matrix degraded? And so we're working on trying to understand that, and then, you know, my, my lab is, we're really close to being able to publish the genome of this octopus. And we think that understanding using psychedelics as a tool for understanding evolutionary mechanisms is something really powerful. And, you know, what, what another big direction that we're going.

Nick Jikomes 1:39:46

So it sounds like it might be possible that this, you know, enhanced malleability, this increase of meta plasticity, it's possible that there is some spatial specificity to that it's not like you have to sort of just make the end higher brain a little bit more malleable. Potentially you could do this in a more spatially refined way.

Gul Dolen 1:40:07

I'm not sure I'm not sure that, um, it's a matters. I think that the way that the brain makes it refined is by context, right? So I think if there are 100 synapses, and every memory requires activation of five of them, right, the specificity isn't brain region selectivity. The specificity is recently active. And so I think the brain already kind of does that specification or psychedelics are taking advantage of a rule that's in the brain that enables that specificity. And again, this gets back to how I think they circumvent the melty brain problem.

Nick Jikomes 1:40:54

I see. Yeah, that makes a lot of sense. All right. Well, I've taken enough of your time, Dr. Gould Dolan, thanks for joining me again on the podcast. Fascinating work. And I look forward to seeing what you guys do in the coming year too.

Gul Dolen 1:41:07

Right. Thank you. It's my pleasure to speak with you again. And yeah, hopefully, you'll have me back and I'll tell you about some cool octopus stuff next time.

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