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Tim Ferriss: Hello, boys and girls, this is Tim Ferriss.
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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.
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My guest today, I feel for me, has been a long time coming.
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I'm very excited to have on the podcast Dr. Gül Dölen. Dr.
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Gül Dölen is an associate professor of neuroscience at the Johns Hopkins University School of Medicine, and a pioneer and world leader of psychedelics research.
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Her laboratory has discovered a novel mechanism that could account for the broad range of therapeutic applications that psychedelics are currently being tested for.
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Her lab has discovered a novel critical period, we'll define what these things mean, for social reward learning, and shown that this critical can be reopened with psychedelic drugs such as MDMA, LSD, psilocybin, ketamine, and ibogaine.
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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.
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To test this hypothesis, she's initiated a nationwide collaborative effort to determine whether psychedelics reopen critical periods for ocular dominance plasticity, birdsong learning, anatomical plasticity in the barrel cortex, serotonergic neuronal regeneration, dendritic spinogenesis, and motor learning.
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If you don't know what those words or phrases mean, don't worry, we will define them as we go.
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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, an approach she has dubbed the PHATHOM project.
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That's P-H-A-T-H-O-M, which stands for Psychedelic Healing: Adjunct Therapy Harnessing Opened Malleability. Dr.
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Dölen earned her MD PhD at Brown University and the Massachusetts Institute of Technology, and otherwise known as MIT, where she carried out seminal work on critical periods, learning and memory, and the pathogenesis of autism.
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You can find her online at dolenlab. org. Dr.
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Dölen, welcome to the show. Nice to have you. Dr.
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Gül Dölen: Thank you for having me. It's nice to be here.
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Tim Ferriss: 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. Dr.
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Gül Dölen: I've always been somebody who learns best by comparing.
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And originally I thought, well, I'll just do a triple major of neuroscience and linguistics and philosophy.
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And the university was like, "No, no, there's no triple major.
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You can do a double major, but if you really need all three, we recommend that you do this, design your own major path."
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And so I worked with my professors in philosophy in 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, "What is the mind? What is consciousness?
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How do we know that from different perspectives?"
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And so the major was called Comparative Perspectives on the Mind, and it was a combination of neuroscience, philosophy, linguistics, art, religion.
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And really the idea was is that this is something that humans care about.
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And so we've thought about it from all of these different perspectives for millennia and what can we understand from that approach?
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Tim Ferriss: 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 — but why were these questions interesting, compelling to you at the time enough that you would attempt to have a triple major? Dr.
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Gül Dölen: I have to say I'm not really sure why exactly those, compared to everything else that I saw other people majoring in like economics or history, I just didn't care about those things the same way as I cared about.
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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.
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Whether it be the person sitting next to me on the bus or my parents or somebody's kid.
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I like thinking about things and when I'm obsessed with something, I just think about it all the time in every context.
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And so I just never had that with economics or history or any of the other topics that seem to be popular majors.
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Tim Ferriss: Didn't cause the quickening. Dr. Gül Dölen: Right.
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Tim Ferriss: There are a few terms that may come up later, we'll see.
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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 considered marine biology, but you were also interested in philosophy of mind and then a philosophical consideration called theory of mind.
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What is philosophy of mind?
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How should we think about it? What is theory of mind? Dr.
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Gül Dölen: Philosophy of mind, 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?
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So what are the things that we count when we say this is what a mind is, this is what a mind is not.
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Then there are other considerations like, "Well, how do we know mind?
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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?"
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And that would be the more epistemological approach to mind.
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And I was interested in all of those things.
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There continues to be debate about that.
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And one of the interesting ideas that I came across was this, that there 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.
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It's more like it's a point of view.
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The theory of mind is just — the shorthand way of explaining what theory of mind that I like to tell people is, it's sort of what you're doing.
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It's the neurobiological process that is going on when you're playing poker.
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It's anticipating what somebody else might be thinking and trying to see the world from their point of view.
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So in some sense it's a theory about what somebody else might be thinking.
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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.
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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.
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And that's them sort of playing with the idea that their own point of view and the person whose shoulder they're tapping might be different and that they can trick somebody by playing on that difference.
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And so this theory of mind, there was some idea out there, 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.
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And it's this thing that psychopaths, for example, are very good at.
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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.
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And so this theory of mind idea was 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."
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And I like this idea because it was a testable hypothesis.
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And one of the things that I found frustrating about being a philosopher is that the philosophers were always asking the coolest questions, the biggest questions, but just felt like they were just going around in circles and never really coming up with an answer that I found to be deeply satisfying.
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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 like tangible and like we were getting somewhere.
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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.
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Tim Ferriss: I have many, many follow-up questions.
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Theory of mind does not seem to be — based on the reading that I've done — entirely human-specific.
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And is it true that you have observed this in, for instance, and your tapping on the shoulder made me think of it, hunting behavior in octopuses? Dr.
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Gül Dölen: Those were actually not my experiments.
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Those were experiments done by really imminent octopus researcher Roy Caldwell.
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And he showed me the videos of them and as soon as I saw the videos of the octopuses hunting, it occurred to me that is exactly a theory of mind-like behavior in an octopus.
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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.
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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.
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And octopuses, by and large, are not social species.
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So if you put two octopuses of the same species into a tank together, they will kill each other.
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And there are differences in the amount of aggressiveness that we observe in octopuses.
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Some are so aggressive that we've never even seen the males of the species because basically when they mate, they leave their hectocotylus arm, which is their reproductive arm in the mantle of the female and eject it and escape so that they don't get eaten.
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So we've only ever found their hectocotylus arm.
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That's how aggressive that species is.
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Other species of octopus aren't quite so aggressive, but they're still asocial.
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And it was interesting because the species of octopus that does that hunting behavior is the only known social species of octopus.
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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?
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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.
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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.
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And so the idea is that, well, maybe these ideas that social behaviors are what drive the evolution of theory of mind is not quite right and that it emerged by something earlier like hunting behavior.
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Tim Ferriss: It strikes me, as a hunter myself, which really only was adult onset hunting in my thirties 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.
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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.
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Where did your interest in autism begin? Dr.
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Where did your interest in autism begin? Dr. Gül Dölen: For me, autism was something that I became interested in when I was an undergrad thinking about these problems of theory of mind
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and consciousness because I was intrigued by the possibility that autism could be thought of as an impairment in theory of mind, and that it would be sort of a case example of what happens to your ability to have a fully conscious experience in the absence of or under conditions of impaired theory of mind. And so how that relates to psychedelics is really a long-ish winding story,
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And so how that relates to psychedelics is really a long-ish winding story, which is that when I was a graduate student, my PhD work was focused on trying to find a therapy for autism.
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And we had focused in on one specific type of autism called Fragile X.
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It's the first identified cause of autism.
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It's currently the most abundant or the most common cause of autism is a mutation in the FMR1 gene, which encodes Fragile X.
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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.
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And so that was really exciting.
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Something like 26 other labs followed up on that work and several big pharmaceutical companies said, "Okay, this is it.
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This is the mechanism based therapy that we've been looking for."
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And ran several very large-scale human clinical trials for that metabotropic glutamate receptor modulator that we thought would correct the imbalance in Fragile X.
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And when they did those studies, everybody was hugely disappointed because we were expecting the drugs to work and to cure the disease.
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And we really got very little evidence to support that view.
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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.
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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."
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But a few of us took a more circumspect view and said, "Well, yeah, okay, mice aren't humans.
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But there were a lot of other differences between the human trials and the mouse trials."
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And to me, the one that really stands out is that while all of the mouse studies that were done, the clinical intervention, the alteration of the receptor were given either right at birth or at genesis or very early in development.
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Whereas all of the human trials, the drugs were given to adults.
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And it occurred to me that because of the timing of when the therapies were given, all of the mouse studies would've been trying to correct the underlying biochemical imbalance when the animal's critical periods were all still open.
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Whereas in the human trials, the relevant critical periods would've been closed by the time we gave the intervention.
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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 restoring the biochemical balance.
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And when we do that, we feel like we can restore the biochemical imbalance while reopening the relevant critical period so that the patient can learn from their social environment in the normal way under the conditions of the restored biochemical imbalance.
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Tim Ferriss: So I want to eventually ask you what reopening the critical period looks like, chemically or anatomically.
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But before we get to that, I would love for you to help me separate fact from fiction with autism.
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It's not a condition that I know much about and I am nonetheless exposed to many opinions about autism.
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And people say for instance, that the prevalence is skyrocketing, that it may be caused by people having children when they're older or it's caused by God knows what, BPA, you name it.
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There's probably a million different theories out there.
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And I would be curious to know as a scientist, what appears to be most plausible as causes of autism?
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Are rates increasing or are we just getting better at diagnosing or looking for that diagnosis, et cetera?
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Could you just help give us the ABCs of fact versus fiction? Dr.
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Gül Dölen: 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.
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So when I first started studying autism 20 years ago, it was very narrowly defined as a disease.
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There was only five or six different genes that had been implicated in causing autism.
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It was incredibly highly inherited.
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So 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.
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Whereas something like cervical cancer, which is caused by a virus, has a heritability score of closer to zero.
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And autism had a heritability score of something like 0. 96.
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So very, very highly heritable.
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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.
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So sometimes inherited, sometimes environmental, usually a combination of those factors.
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And at the time that diagnosis was so narrowly defined that you got this high heritability.
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And then for a variety of different reasons, some of them scientific, some of them socioeconomic, the definition of autism got expanded.
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In the Diagnostic and Statistical Manual of Neuropsychiatric Disease, the expanded definition started including the spectrum of autism.
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Now rather than having — you absolutely have to have an impairment in social behaviors and an impairment in locomotor, stereotypies and all of these other developmental criteria.
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It got expanded and a lot more things started being included.
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And when this happened, the heritability estimates of the disease dropped.
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And so my interpretation of those data is that basically we stopped defining a disease that was a unified single disease and started including a lot more things that were not what I would consider to be classical autism.
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Now it feels like to me that this has gotten so expansive that were 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."
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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.
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So when this happens, it's a little bit frustrating.
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And so I have tended to focus on those early identified genes like FMR1, which have been known to be a cause of autism for a long time.
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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, a thousand genes have been implicated in autism. FMR1 seems to be a node.
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So in other words, the protein that FMR1 encodes regulates roughly 25 percent of all the other autism genes.
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And so to me, that's a good place to start to try and understand autism.
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And then I will leave it up to the epidemiologists to sort out how to redefine the category so that we're capturing the right subset of patients and excluding the subset that are not going to respond to therapy if we're targeting the subset that are defined in one specific way.
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Tim Ferriss: If we look at FMR1 just as a node in a focal point, and 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 were planning on having children or someone were looking at say, surrogacy, you could do genetic screening?
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That it's possible for people to currently do genetic screening for the probability of autism as an outcome in offspring? Dr.
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Gül Dölen: 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.
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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 have to balance doing a screening test against the possibility that the test itself is going to cause problems with the pregnancy.
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So there is a sort of a judgment call there and unless you had a family history of Fragile X, I think that it's still the case that people don't actually test for it beforehand.
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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.
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For schizophrenia, there seems to be a correlation between the age of the father and getting schizophrenia.
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But for autism, as far as I know, there is no age-dependent correlation with your likelihood of getting it.
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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.
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Tim Ferriss: Let's just revisit, as promised, the reopening of the critical period. Dr.
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Gül Dölen: The idea of critical periods first came in 1935 by Konrad Lorenz, who was a ethologist, who was studying imprinting behavior in snow geese.
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So this is the behavior that shortly after hatching, the animals will form a long lasting attachment typically to their mother.
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But if the mother isn't around and instead it's sort of a motorized airplane, or the scientist in that case, Konrad Lorenz himself, then they'll form that attachment to that other moving object in their vicinity.
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And there are all these funny pictures online of Konrad Lorenz being followed around by little snow geese because they formed this attachment.
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Tim Ferriss: Wait, what are snow geese? Dr.
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Gül Dölen: They're just a type of geese.
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Tim Ferriss: Okay, there we go.
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Yeah, just wanted to figure out.
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Sounds like a little Scandinavian dwarf or something. All right, got it. Just a type of geese. Dr.
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Gül Dölen: Type of geese, bird.
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So they followed around by these birds.
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They're really cute pictures.
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Anyway on this imprinting behavior though, if you wait, so if you wait until 48 hours after hatching, then they don't form this behavior.
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So this attachment that is only possible within the first 48 hours of hatching and Konrad Lorenz called that period of time when the animals are extremely sensitive to their environment and conformed these long-lasting memories, he called that window of time the critical period.
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And critical periods since then have been described for so many different things.
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So probably the one that most people will be familiar with is the critical period for language learning.
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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.
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You always have an accent.
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It's not easy to incorporate that into your first language.
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And so that's a critical period for language.
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And what my lab did is that we knew from the human literature that there was probably a critical period for social learning because we know, for example, that teenagers are much more susceptible to peer pressure than adults are.
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We know that they prioritize learning from their environment, from their social interactions much more so than adults do.
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And that whatever social environment you grew up in is sort of your native social environment.
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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.
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Because I didn't grow up in that social environment.
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And so I don't know that it's extremely rude to hand somebody something with one hand instead of two.
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These are the kinds of rules that I didn't grow up exposed to.
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So it's a foreign social language to me.
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So we had this intuition that there was a critical period for social reward learning, and that's what my lab discovered.
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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.
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And we figured out a bunch of different mechanisms relating to that critical periods.
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Typically, the long, long arc 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.
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And so if we can understand the mechanisms, maybe we can figure out ways to reopen them for therapeutic benefit.
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That's been the goal of neuroscience for the last hundred years or so, is to try and find that.
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And three Nobel prizes have been given for mechanisms trying to figure this out because it's understood that this would be so important.
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But I've 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.
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And in fact, my lab and another lab at Harvard were kind of in an intellectual debate with one another over this idea of, "Can there be a master key?"
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And I was always like, "No.
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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."
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And I was like, "There's no master key. Stop it.
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Forget about it, Harvard, you're just wrong." Okay?
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And so what we've come up with now is we started with the idea that, well, MDMA is different from other psychedelics in that it has this very prominent pro-social component to it.
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People take MDMA and they want to cuddle, they want to be sociable.
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Some people talk about this incredible feeling of empathy and being able to see other people's pain.
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It's just a very pro-social type of psychedelic.
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In fact, some people even want to call it an empathogen rather than a straight up psychedelic.
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And so we started with that idea that, "Okay, we're trying to reopen a social critical period.
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We know it follows a lot of the same rules as other critical periods, but maybe MDMA is the way to do it."
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And in fact, we did find evidence that MDMA reopens the social critical period, and it does so by restoring oxytocin metaplasticity in the nucleus succumbs.
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And we loved this idea that that was the story and whatever.
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Psychedelics, other psychedelics probably wouldn't do it.
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That was our original idea.
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But then again, mother nature, tricky.
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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 puddle.
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Not that I've seen anyway, right?
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But LSD is not prominently a pro-social type of psychedelic.
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Neither is ibogaine, neither is ketamine.
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And yet all of them are reopening this critical period for social reward learning.
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And so what this suggested to me immediately was is that the whole social part of the MDMA story is a little bit of a red herring.
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Really what psychedelics are are this master key for unlocking critical periods.
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There's not just one critical period, there are lots of different critical periods.
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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, will or have been implicated in the closure of, say, the visual critical period or the touch critical period or the motor critical period.
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What's different is that the social critical period is different from those in that it's not a sensory motor.
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It's an emotional critical period that we think is encoded in a different part of the brain, the nucleus accumbens, which is part of the limbic system.
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It's a different type of brain region than the classical critical periods which have all been defined in the cortex.
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So we don't know, still don't know, whether or not the rules are the same.
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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
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that get up and down regulated in response to psychedelics, but not cocaine, share a lot of overlap in terms of their molecular identity with the molecules that have been implicated in the closure of other types of critical periods like vision, somatic sensation, motor. So beginning to see lots of circumstantial evidence that the psychedelics are all doing
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So beginning to see lots 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.
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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.
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That's 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.
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Tim Ferriss: Question back to autism.
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And, man, must you get a lot of questions about autism, so my apologies.
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But I want to use that example because — this will underscore my ignorance in so many of these topics.
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But if we're looking at a narrow definition of autism, so we're not succumbing to the scope creep in DSM or elsewhere where 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, when you don't have an intervention?
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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?
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So it's not genetic determinism.
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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.
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I know I'm asking this in 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? Dr.
37:05
Gül Dölen: Autism is a little bit complicated because it's a multifactorial disease.
37:05
Let me just give a different example to help clarify and maybe make it clearer what we think is the way that psychedelic could be used for autism. And that's with vision.
37:20
One of the early observations of critical periods is that if a child is born with bilateral cataracts and then you remove those cataracts and they can see, but if you wait and you don't remove those cataracts until they're age six or seven, then even though the physical impediment to vision is gone, the brain cannot adjust to the visual inputs anymore, and so the child remains blind forever.
37:57
That's because there is a critical period for setting the strength of the synapses for visual inputs.
38:05
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.
38:24
The idea there is, if you missed 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
38:45
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. With autism, it's the same idea. We're saying, "Okay, there's a genetic impairment that causes
39:03
With autism, it's the same idea.
39:03
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.
39:16
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."
39:24
So the idea is if we could pair that mGluR therapy with a psychedelic, then we could restore the imbalance and also restore the ability to learn from the social environment so that they can, under those corrected conditions, have a shot at learning the ways of social interaction the way they would've during natural development. Tim Ferriss: Got it. Thank you. That's very helpful.
39:55
I want to just perhaps mention that — and this is actually from The Microdose, which is a great newsletter.
40:02
You were featured in The Microdose from UC Berkeley not too long ago.
40:06
Some people listening may wonder why we shouldn't always leave our critical windows open. Wouldn't that be great?
40:16
We could learn everything and anything.
40:16
I just want to read something here and then we can move on, although we could expand on it.
40:26
When you talk to people who are on psychedelics, it's like herding kittens.
40:29
They're paying attention to everything.
40:29
"Look at this leaf," "My shoe won't fit," et cetera.
40:33
You're in full explorer mode, which is wonderful, but it's not very efficient.
40:33
Habits get a bad rap, but you couldn't get out the door if you didn't have them.
40:37
Living in a world where you're trying to learn and pay attention to everything is emotionally and energetically costly.
40:46
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.
40:49
Is there anything you would like to add to that? Dr.
40:57
Gül Dölen: 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 genetically encoded with everything that we need to survive in the world, is because the world is big and varied.
41:16
If you genetically encoded everything, you probably would be very limited in how you could navigate that world. My parents are Turkish.
41:32
If I was genetically encoded with Turkish, the fact that I grew up in the United States, it would make my life very difficult because I wouldn't speak English, I would speak Turkish.
41:43
But because I have a language critical period, what's genetically encoded is the ability to learn a language, not the language itself.
41:52
That ability to learn from our environment is why we have them.
41:58
But as everybody knows, being a teenager sucks. It's hard. It's painful.
41:58
It's really very emotionally draining to constantly be checking yourself, trying to figure out how you fit in.
42:19
Sometimes, you want to just get on with it, and if the environment that you're in is stable, then you don't need to necessarily be adapting or adjusting your model of the world every single move that you make.
42:32
That's why we think that critical periods close.
42:36
But then another question is, well, why does the brain have a sort of readymade mechanism that psychedelics can tap into for reopening critical periods?
42:41
Why can we reopen them so easily if the brain wasn't already built to do this?
42:48
This is really me speculating, but I suspect it's because when we have these habits, they're adaptive so long as the environment is stable.
43:02
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.
43:13
Going back to the language example, as long as everybody around you speaks English, it's probably not all that adaptive to be learning Spanish.
43:19
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.
43:34
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.
43:58
Here's another rule that applies across critical periods, is that deprivation is a technique.
44:06
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. So it's very hard.
44:17
You're not deprived of English, you're just exposed to Spanish.
44:21
Whereas in Guatemala, almost nobody speaks English and so you're deprived and you get the language.
44:26
That's one idea that we have. We haven't proven it.
44:31
But the other part of that is that it's 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.
44:48
Zen Buddhist call it beginner's mind.
44:55
If you were looking for a neurobiological description of beginner's mind, reopening critical periods would be it.
45:01
So what we think, possibly, is that — remember how I said that I was as an undergrad, I was really interested in getting around to using neuroscience to answer the really big questions that philosophers seem to have exclusive domain for?
45:22
Well, this might be it, right?
45:22
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.
45:39
Then this explanation, this critical period explanation, gives us a mechanistic handle to start answering those big questions like, well, what is consciousness?
45:52
Well, what is that mystical experience?
45:52
What does it mean to feel you're an altered state?
45:58
Tim Ferriss: 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 octopuses 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.
46:25
So in humans we might attribute some of the outcomes that we see or therapeutic effects to, I believe the nucleus accumbens.
46:31
But then you look at an octopus, no accumbens, no amygdala, no default mode network, no prefrontal cortex. Dr. Gül Dölen: Yeah.
46:41
Tim Ferriss: What have you gleaned from the octopus work as it relates to critical periods and or interesting characteristics of MDMA? Dr.
46:53
Gül Dölen: 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."
47:12
And they get this sort of warm and fuzzy feeling like, "I understand now what's happening."
47:19
And as a neuroscientist, I am susceptible to that interpretation as well. I don't do it with fMRI.
47:25
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 whole-cell 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.
47:49
And from those types of analyses, we get this satisfying feeling like, "Aha, MDMA is causing the nucleus accumbens neurons to light up.
48:02
It's causing the oxytocin neurons and the hypothalamus to fire and release oxytocin. We got it.
48:09
We understand how these work."
48:09
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, we're 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.
48:31
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.
48:53
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.
49:08
But we haven't really learned anything about what are the generalizable principles? What are the motifs?
49:13
What are the rules governing those circuit level rearrangements that enable complex behavior?
49:21
Tim Ferriss: 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? Dr.
49:36
Gül Dölen: I think the two big ones that I have, let me start with — since we're 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.
49:54
That I think for the last decade and 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.
50:14
And I consider Alexander Shulgin to be an elder in this field for me.
50:21
I met him when he came to visit MIT.
50:21
I have this goofy picture of myself as this young little neuroscientist, all enamored of Alexander Shulgin.
50:36
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.
50:47
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.
51:01
Because after all, humans didn't just emerge out of nowhere.
51:01
We weren't plopped here on earth by aliens.
51:08
We evolved just all other animals on Earth.
51:08
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.
51:24
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.
51:30
And I think that our critical period idea is one step in that direction.
51:37
I think that many people in your audience may have also heard of the idea that psychedelics are inducing plasticity.
51:47
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.
52:00
So for a synaptic neurophysiologist, it has a very specific meaning.
52:00
It's about the something that you can record from doing whole-cell recordings or patch-clamp recordings or even unit recordings in the brain.
52:18
But it's an electrophysiological property that is defined between two synapses.
52:26
Whereas the clinicians basically use plasticity to mean anything that changes over time, which is so general, it sort of loses meaning.
52:32
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 so-called psychoplastogens or drugs that induce plasticity.
52:53
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 word implies.
53:09
And they're all drugs of abuse.
53:09
So heroin, nicotine, cocaine, amphetamine, these are all psychoactive drugs that cause robust bidirectional plasticity.
53:17
They cause the neurons to sprout, they cause the neurons to shrink, they cause robust changes.
53:24
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 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 association.
54:06
So let me give you an example because I'm fumbling a little.
54:08
So the example I like to give is that a natural reward, like food, for example. We like food.
54:15
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.
54:29
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."
54:36
But for drugs of abuse, we override those associative constraints on when we want the thing.
54:41
And a drug of abuse, cocaine or nicotine, it 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.
54:57
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.
55:12
And so I wouldn't want people to confuse that property, that hyperplastic property with what we think is actually happening with psychedelics, which is that psychedelics, we believe, and there's starting to be other evidence to support this view, are enabling what's called metaplasticity.
55:29
Which I know that it's confusing terminology, hyperplasticity versus metaplasticity.
55:36
But metaplasticity 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.
55:53
So when you're young, your ability to induce plasticity is greater than when you're older.
56:01
The ability to induce plasticity declines and there are molecular things that control that.
56:08
Tim Ferriss: You were mentioning that plasticity can mean a lot of different things to different people.
56:11
So in this case, the ability to induce plasticity, what does plasticity mean to you in this use? Dr.
56:16
Gül Dölen: So the metaplastic definition, I mean it's a very specific definition, plasticity of plasticity, and in that case it was defined by Mark Bear and Cliff Abraham, and it was a synaptic physiology.
56:30
So it's synaptic plasticity.
56:30
The change in response of stimulating one synapse and the magnitude of the response changing when you're recording the post synapse. Tim Ferriss: Got it. Dr.
56:48
Gül Dölen: So very narrowly defined again.
56:48
Metaplasticity originally was used to define what happens in the reopening or the closure of the critical period for ocular dominance plasticity.
57:03
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 in memory and specifically also learning in memory with regards to visual processing.
57:25
Tim Ferriss: Does that mean that ketamine would have any particular applications to studies involving visual processing?
57:33
I'm just thinking given the — seems like there's the decent effect at the NMDA receptor level with ketamine, when you look at chronic pain and other things.
57:47
Is that the case or is not so much? Dr.
57:47
Gül Dölen: I mean, yes, almost certainly.
57:51
Almost certainly the NMDA receptors, there are a variety of things that have been attributed to the NMDA receptor.
57:53
For a long time it was my favorite receptor, and here's why.
57:58
I know it's super nerdy to have a favorite receptor, but — Tim Ferriss: No. I'm into it. I'm into it. Dr.
58:01
Gül Dölen: 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.
58:21
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.
58:36
So because of that property, the NMDA receptor is thought to be a natural coincidence detector.
58:43
So it can detect when two neurons are firing at the same time.
58:43
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.
58:57
And this idea has been around for a while now.
59:06
It's why people are excited about the NMDA receptor.
59:12
Incidentally, it's also thought to be why ketamine and PCP interfere with memory.
59:12
So they do cause impairments in memory because they mess with a receptor that we think is super important for encoding memories.
59:27
Now, in terms of this critical period idea, NMDA receptors, they come in, they're made up of different subunits, and the composition of those subunits changes over development.
59:34
So very early in development, the NMDA receptors have the subunit, the B subunit is more predominant.
59:50
And the way I remember that is that that's the NR2B subunit is for baby, and then the A subunit is for adults.
59:57
So as the brain matures, then the subunit switches out and it goes from being 2B heavy to being 2A heavy.
1:00:04
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.
1:00:18
And that is the original first classical understanding of what a metaplastic change would look like.
1:00:24
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. Tim Ferriss: Got it.
1:00:35
And just to try to recap my understanding, which will hopefully help the audience track as well.
1:00:44
Jumping back to the autism example and the Fragile X or FMR1, the joint therapy would look like using the compounds such as, possibly a psychedelic, to increase the metaplasticity 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.
1:01:21
I'm getting close, I'm not quite there, but — Dr.
1:01:27
Gül Dölen: You're very close and you're actually picking up on something that is a hesitation I have about using psychedelics in autism.
1:01:32
So there's another, a third type of glutamate receptor that I love.
1:01:40
It's called the metabotropic glutamate receptor, the mGluR and the metabotropic glutamate receptor, we think is the one whose signaling is so altered in Fragile X.
1:01:55
And the metabotropic glutamate receptors are also implicated in — as their brain matures, their expression goes down.
1:02:03
And so we think that that coincides with the closure of the critical period.
1:02:10
And what we think is that in Fragile X, that mGluR signaling is exaggerated.
1:02:10
It's not being curtailed in the right way.
1:02:20
And so we have some evidence to suggest that autism might be caused by a failure to properly close the critical periods.
1:02:27
So even though theoretically I like the idea of combining negative allosteric modulator of the mGluR with a psychedelic that can reopen, say the social critical periods through metaplasticity in this case of a different receptor, I think in this case it would be the oxytocin receptor that would be the relevant one.
1:02:51
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.
1:03:11
So I'm not sure that reopening them later is going to be necessarily the right way to go.
1:03:16
So it's still a hypothesis that we're testing.
1:03:16
Tim Ferriss: How do allergies fit into this?
1:03:24
I've become very, very interested in allergies and all sorts of — not to paint with too broad a brush, but sort of autoimmune questions specifically as related to psychedelic compounds. How do allergies fit in? Dr.
1:03:37
Gül Dölen: Well, first I should premise this by telling you that my mom is an immunologist and she hates this idea.
1:03:43
So she and I we spar over this and we have a very different view of the relationship between the immune system and the nervous system.
1:03:58
She basically lives in an immune centric world where the nervous system is just like an downstream effector of the immune system, which is the primary controller of everything.
1:04:10
And obviously I think it's the other way around.
1:04:10
So the idea with allergy is this, there is some epidemiological evidence to suggest that allergy has a higher prevalence in countries where the food and the water is largely parasite free.
1:04:28
And so that part of the immune system, which is ordinarily used to fight off parasitic infections, is left jobless.
1:04:35
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.
1:04:52
And in this formulation, I am thinking how that threat gets assigned is really through the brain.
1:05:00
The brain is saying, "Okay, well that dog is barking at you and your immune system is left jobless, that's threatening.
1:05:04
Go fight against the dog proteins."
1:05:11
And 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 that's mis-assigned, would enable people to unlearn the association between dog and allergy.
1:05:33
Now 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, independent of this learned association framework that I'm proposing around the critical period.
1:06:08
So we just don't know yet.
1:06:14
I like the idea though, because there are a few anecdotal stories of, I think Andrew Weil has a story where he tears himself up.
1:06:21
Tim Ferriss: I was going to bring him up. Cats. Yeah. Dr.
1:06:26
Gül Dölen: And I mean, I love the idea because I actually kind of wanted to be a veterinarian, but I'm allergic to horses, dogs, and cats.
1:06:28
So I would love to take psychedelics and cure myself of those allergies.
1:06:35
And while I love this idea, I don't believe it enough yet to take a bunch of psychedelics and go snuggle up to a horse because I think we could be looking at anaphylactic shock in that situation.
1:06:49
So I don't believe it yet, but I like the idea as something that we could test.
1:06:54
Tim Ferriss: Okay, I'm glad you brought up Andy and not the sole example.
1:07:01
I mean I have an understanding the plural of anecdote is not data, but nonetheless sometimes helpful for generating hypotheses.
1:07:08
This is something that's been in the conversation with numerous anecdotes for a while.
1:07:16
And I guess what I want to ask next is whether it's autism, stroke, or allergies?
1:07:21
And I do want to come back to stroke.
1:07:21
When we are 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.
1:07:42
LSD seems particularly promiscuous, maybe ibogaine as well.
1:07:42
But broadly speaking, are we talking about increasing post-synaptic sensitivity?
1:07:50
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 window, it fits the description of reopening the critical window. Dr.
1:08:13
Gül Dölen: So let me back up for a second and just explain that I think there's a debate going on in the field right now because if you look back in the textbooks written in the '70s and '80s about psychedelics, 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.
1:08:37
Their definition of what a psychedelic is was very broad.
1:08:45
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.
1:09:02
And they included psychedelics ranging from ketamine, PCP, all of 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.
1:09:18
And both Snyder and Alexander Shulgin consider all of those drugs to be psychedelics.
1:09:26
More recently, there has been this push mostly led by the chemists to say, "Oh, no, no, no.
1:09:34
If we look at the receptor binding properties of these drugs, the classical psychedelics, the hallucinogenic psychedelics, they're all serotonin 2A receptor binding.
1:09:46
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 pharmacology studies in humans."
1:09:59
And they are really pushing hard to exclude MDMA and ibogaine and ketamine from the definition of classical psychedelics.
1:10:07
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.
1:10:20
First of all, because we know that most of the psychedelics are very promiscuous in their binding.
1:10:25
Second of all, we don't really understand whether or not the 2A receptor is required for the therapeutic properties.
1:10:31
So there is some evidence that there are anti-depressant properties that may or may not be blocked by serotonin receptor antagonists.
1:10:46
There's two papers that have exactly opposite results about this right now.
1:10:46
I am not entirely convinced that those antidepressant 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.
1:11:05
And so I think it's up for debate whether or not the serotonin 2A receptor is required.
1:11:05
But what we do know is that psychedelics that have primary binding at NMDA receptors, serotonin transporters, serotonin 2A receptors, kappa-opioid receptors, ones that span the diversity of receptors all show some therapeutic effect.
1:11:30
And so our lab has really been focused in trying to understand, "Well, what's the commonality across all of those receptors?"
1:11:41
And so to, 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.
1:11:52
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.
1:11:57
It's not even one step downstream of that.
1:11:57
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.
1:12:08
We don't see that to be the case in our studies.
1:12:14
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.
1:12:25
And the working model that we have is that psychedelics bind to their receptor, and when they sit in that receptor for too long, it signals to the cell, "Oh, no. Oh, no.
1:12:41
Excitotoxicity is coming. Hit the reset button."
1:12:47
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 holding the synapse together.
1:13:12
And the last step of making a synapse mature and stable.
1:13:12
And that hard reset is enabling the reintegration of those baby receptors that are more sensitive and able to induce plasticity.
1:13:29
That's sort of our working model.
1:13:29
Tim Ferriss: So I'm curious, just to revisit kappa-opioid for a second, because the only kappa-opioid agonist that I'm familiar with is Salvinorin A.
1:13:41
Some people may know Salvia divinorum, which from a phenomenological perspective, to get real fancy, subjectively people find it typically pretty dysphoric.
1:13:48
And I'm just wondering how, perhaps it's not Salvinorin A, but any kappa-opioid agonist might be used therapeutically, what applications might exist? Dr.
1:14:02
Gül Dölen: Yeah, I mean, people have been excited about kappa-opioids because it's thought to be like, that's going to be the one that's going to make you not be addicted to it.
1:14:11
And it's not very pleasurable.
1:14:15
Tim Ferriss: That's for sure. Dr.
1:14:15
Gül Dölen: It's not very pleasurable. Nobody wants to take it.
1:14:20
I don't want to overstep the kappa-opioid stuff.
1:14:24
The reason that we got interested in it is because the ibogaine also has high affinity for kappa-opioid receptors, but it also accesses serotonin transporters.
1:14:32
So I really don't know what the answer is there.
1:14:38
I thought the beta-arrestin story was going to nicely sew everything up and it just didn't.
1:14:43
Tim Ferriss: So what is beta-arrestin?
1:14:43
I'm going to plead ignorance.
1:14:47
I don't know what that is. Dr.
1:14:47
Gül Dölen: Basically most of the psychedelic drugs, except for ketamine and PCP, are acting at what are called G-protein coupled receptors.
1:14:51
So when I was talking about NMDA receptors versus mGluR receptors, the difference is mGluRs are G-protein coupled receptors.
1:15:06
And NMDA receptors are ion channels, so they're inotropic receptors.
1:15:12
So metabotropic inotropic, it has to do with how they're coupled to internal signaling.
1:15:12
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.
1:15:43
Now that's just how they normally signal.
1:15:43
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.
1:16:00
So normally when transmitters get in their receptor, they jump in and they jump right back out.
1:16:07
So they pop in, pop out really, really fast, less than a second time scale.
1:16:10
LSD, when it sits in the serotonin 2A receptor binding pocket, a little lid comes down and locks it into place.
1:16:17
And when that lid locks the LSD into place, it's off rate goes to four and a half hours, which is flicking insane.
1:16:31
Tim Ferriss: It's going to be a long night. Dr.
1:16:31
Gül Dölen: It's going to be a long night. Exactly. And that's the half off.
1:16:34
So only half of it comes off in four and a half hours. Right?
1:16:34
And so this is a really important insight into why it is that LSDs effects last so long.
1:16:48
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.
1:16:55
"No, instead of G-protein, you need to hit a different biochemical pathway.
1:17:01
We need to trigger beta-arrestin."
1:17:07
And beta-arrestin is just another biochemical pathway that gets triggered by that receptor being activated too long.
1:17:13
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."
1:17:26
So beta-arrestin and signaling historically has been thought to be a signal to the cell that says, "Pull in the receptors."
1:17:37
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.
1:17:58
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.
1:18:10
So that was a little bit of a bummer, I have to say, because I thought, "All right, we'll solve it.
1:18:14
It'll be done, and I can rest easy."
1:18:19
But it didn't work out that simple.
1:18:19
Mother nature always likes to trip us up like that.
1:18:24
Tim Ferriss: Yeah, the mother nature curve ball seems to come more often than not.
1:18:29
I do want to get to strokes and how they fit in.
1:18:29
But before we get there, I have to scratch an itch because I've been wanting to ask you for a while now. Excuse me.
1:18:36
First, a bit of background.
1:18:36
You mentioned Alexander Shulgin, also known as Sasha Shulgin.
1:18:41
For people who don't recognize the name, incredibly adept, incredibly prolific biochemist, very much recommend people check out PiHKAL and TiHKAL, which he wrote with his wife.
1:18:56
But the contrast you drew earlier was one of, say, maybe human centricity.
1:19:05
So he not only created or resurrected hundreds, maybe thousands of different psychedelic compounds, but also was a very dedicated self-experimenter.
1:19:11
The tasting parties were very famous, of course.
1:19:18
Where do you most strongly perhaps agree or align with Sasha?
1:19:25
What are things that you perhaps have in common, if anything comes to mind? Dr.
1:19:31
Gül Dölen: Yeah, I've got to tell you a funny story of when he came to visit MIT when I was a graduate student.
1:19:37
It was the opening party for the new building.
1:19:37
I won't name any names, but everybody had invited a bunch of Nobel Prize winners who had discovered every cool thing in biology.
1:19:52
They all got up there and not necessarily knew anything about neuroscience, they were all older, and they gave a little biography and then sat back down.
1:20:05
Then Sasha got up on stage.
1:20:05
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.
1:20:12
He was like, "Then we added this methyl group over here and this happened and the behavioral response.
1:20:19
Then we did this and we got ego this, and we put that on there."
1:20:24
All of the neuroscientists were just rapt attention because this is it.
1:20:30
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.
1:20:50
And here is this chemist explaining to us how this could be done just by adding a methyl group in this position versus that position.
1:20:57
We were all just blown away.
1:20:57
I don't think there was anybody who walked away from that lecture thinking, gosh, psychedelics should just stay in the backwaters, we shouldn't care about this as neuroscience. Obviously not.
1:21:08
In fact, it's how I got excited about neuroscience to begin with.
1:21:12
I took this class when I was an undergrad called Drugs, Brain, and Behavior.
1:21:18
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.
1:21:31
This is how we're going to crack it.
1:21:31
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." And I am not alone.
1:21:50
I think most neuroscientists who have tried psychedelics would have exactly the same response.
1:21:57
The difference between me and Sasha really in terms of our approach is that Sasha comes from an older tradition in science, which very much prioritized the do the experiment on yourself idea.
1:22:14
That has a long and glorious tradition in science.
1:22:14
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.
1:22:28
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.
1:22:39
The difference is, with psychedelics, is that that's a little bit trickier to do because psychedelics have this property, which William James pointed out over 100 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.
1:23:03
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."
1:23:15
For a scientist, that's pretty dangerous.
1:23:23
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 provisional until the next test comes along.
1:23:37
It should always be a working model, never "This is the 10 commandments of neuroscience."
1:23:43
That's not the way that we do science.
1:23:43
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 neuroscience now. Let's not lie.
1:24:05
Tim Ferriss: In psychedelics. Yeah.
1:24:05
Hard to be an objective or strive to be an objective scientist if you turn yourself into David Koresh accidentally.
1:24:17
So how do strokes fit into this? Dr.
1:24:17
Gül Dölen: For a long time now, clinically, we have known that right after you have a stroke, you have this very short window of time, really, really closed 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.
1:24:46
That window of time, we don't exactly know why it closes.
1:24:53
But it seems to be that it's not that the damaged part of the brain suddenly resprouts 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.
1:25:17
That window closes just like all other critical periods close.
1:25:25
So far, the best way that we have for reopening that critical period is to give another stroke.
1:25:33
But nobody wants to cure stroke by giving another stroke, so that's just not a clinically useful way.
1:25:39
Tim Ferriss: Hard to sell. Hard to sell that. Dr.
1:25:43
Gül Dölen: Yeah, definitely hard to sell.
1:25:43
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.
1:26:01
We have a collaboration with Steven Zeiler, who's a neurologist at Johns Hopkins who has developed a rodent model for that critical period of motor recovery following stroke.
1:26:12
He also has a stroke clinic at Hopkins.
1:26:22
We're working closely with them to see whether or not this idea 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.
1:26:38
It's a huge number of people.
1:26:38
I think if this ends up being true, I think it's — it's super exciting because here's something that we started out with, "I'm just curious what MDMA will do in an octopus."
1:26:51
It was totally curiosity-based science.
1:26:57
To see it evolve into something that can potentially help so many people is, as a scientist, just super gratifying. It's pretty rare.
1:27:06
Nobody really gets to have those kinds of woo-hoo success stories.
1:27:13
So that's very gratifying to me on a personal level.
1:27:18
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.
1:27:25
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.
1:27:49
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 keep an open mind, always look for more answers, more questions, and keep searching. Tim Ferriss: Absolutely.
1:28:10
Tim Ferriss: Absolutely. I would also say, even if, let's just say hypothetically, these various indigenous cultures have figured it out, let's just take that as an assumption for a second, they've figured out how to use these things, but the scale at which they're used and the context
1:28:28
within which they're used are on the order of, say, max 100 or several hundred 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,
1:28:43
You need new tools, and that requires exploration and testing. Dr.
1:28:50
Gül Dölen: Let me just riff on that for a second because I think that that's a really important point about the context.
1:28:57
The context of disease is also different in this culture versus other cultures.
1:29:04
How a disease is defined is different across cultures and how you might approach a disease is defined differently across cultures.
1:29:17
A good example is the way that ibogaine is used traditionally.
1:29:17
These cultures using ibogaine for traditional healing practices, it's not just that the person taking it has a disease and they're being treated.
1:29:32
It's a mix between they have a disease but they also have something to share with the rest of their community.
1:29:38
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 the person goes from one house to another.
1:30:00
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.
1:30:16
We know that MDMA's ability to reopen the social critical period is social-context dependent.
1:30:23
If we give it in isolation, then it doesn't reopen.
1:30:29
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.
1:30:53
Unless we understand it from our context, we won't be able to readily adapt them, I think.
1:30:58
Tim Ferriss: 100 percent.
1:30:58
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.
1:31:15
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.
1:31:31
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.
1:31:42
And I appreciate you saying what you just said.
1:31:49
If you flash forward in your mind, I recognize there's some imagination and speculation required here, 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?
1:32:19
I'm pulling that number out of nowhere.
1:32:19
But I'm curious to know 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. Dr. Gül Dölen: Yeah.
1:32:31
at least now you're pursuing research. Dr. Gül Dölen: Yeah. I think for me, if this ends up being true, then it's going to be a pretty big paradigm shift for neuropsychiatric treatments because — let me just back up and say I have to give a little bit of credit to
1:32:52
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 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."
1:33:16
It's really this combination that's working."
1:33:23
That I think was a big shift in the way that the FDA wants us to test drugs in clinical trials.
1:33:32
I think that we're beginning to see more and more evidence that that context is really what matters.
1:33:39
For example, the clinical trials where context is 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.
1:34:10
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.
1:34:30
So while an inter-directed 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.
1:34:43
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.
1:35:04
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.
1:35:28
Tim Ferriss: 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?
1:35:46
Because if you have this less inter-directed, say, higher dose experience with a potential for these noetic qualities that you described, but rather you're following instructions, you are practicing skills using, potentially, VR, do you have any thoughts on how you design the study or what the minimum effective dose might look like? Dr. Gül Dölen: Yeah.
1:36:14
There are two questions in there, let me just pull them apart for a second.
1:36:18
The dose issue, our studies that we've done so far suggest that there's a pretty narrow dose response for reopening critical periods and that matches what we see in humans for the acute subjective effects.
1:36:28
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 open state.
1:36:42
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, less than a week.
1:36:53
Whereas if the window stays open for — if the acute subjective effects lasts 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.
1:37:02
In mice, that's four weeks.
1:37:08
In humans, that may translate to four weeks or four months. We're not sure.
1:37:16
And then psilocybin, MDMA, and LSD are in the middle there between those two extremes.
1:37:16
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.
1:37:27
So that dosing business, I think, 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 get less side effects and a shorter journey that will be easier to manage in a clinical setting. Again, what can you do? Nature is nature.
1:37:55
But I do think that it changes the model of how we approach these.
1:38:00
Rather than thinking of these as next generation anxiolytics or next generation anti-depressants or SSRIs, what we really need to be thinking of these as is more like surgery.
1:38:14
If you have a heart attack, you go and you have open heart surgery, it lasts for eight hours.
1:38:19
You have maybe two or three weeks afterwards where you are required to be on bedrest and take things easy. But then you're cured.
1:38:25
So who wouldn't rather be cured of a heart attack than have to be on a medicine for the rest of their lives?
1:38:32
I think most people see that as the major promise of psychedelics.
1:38:37
So in terms of the therapeutic approach, I think the way I'm framing this stroke trial is really I'm not worried about the fact that they're going to have to do a psychedelic.
1:38:51
Potentially, the maximum benefit is going to be from these long-acting psychedelics, because I think that 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.
1:39:11
We'll have to work out how to do them back to back to back.
1:39:11
But that's how I'm thinking about it there.
1:39:16
The second 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.
1:39:29
Actually, that's not how I'm imagining that this will work. Tim Ferriss: I got it.
1:39:36
It would be more sequential, not concurrent. It would — Dr. Gül Dölen: No, no, no.
1:39:40
It would be concurrent, but I would say it's not going to be practice-based.
1:39:42
One of the things that I would want to emphasize is part of the reason that I paired up with Steve Zeiler and John Krakauer at Hopkins is that their approach for treating stroke during the normal one, the critical period is already open, is that they've said, "Well, most of the physical therapy that patients receive is very goal directed.
1:40:15
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."
1:40:23
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 goal undirected to kind of play, wandering, don't care if I fall down a million times.
1:40:48
I mean, there's this great idea that children, when they're learning how to walk, will walk the equivalent of seven football fields in an hour.
1:40:56
Now the only time I've ever seen an adult do that is on MDMA.
1:41:03
They will just dance and they don't care if they look like fools.
1:41:09
They don't care if they're not good dancers. It's not goal-directed.
1:41:09
They're just enjoying the play of doing the motion.
1:41:14
What I like about Steve and John's approach to motor rehabilitation without psychedelics is that their virtual reality system that they've built is very much capitalizing on this non-goal directed, play-like behavior.
1:41:30
And I think that's going to be the key.
1:41:37
So I think if we can get people on psychedelics plus put them in this motor play context, then we can maximally recapitulate the conditions that we learn how to do motor function when we're developing as children.
1:41:51
Tim Ferriss: Speaking of fun, I want to go back in time to Bears Lab at MIT.
1:42:00
This is from Spectrum News, reading a section of this.
1:42:09
"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,' he used to say.
1:42:14
Dölen decided that if she was indeed going to give up a life of science, she would go out on her own terms."
1:42:23
Could you unpack that last sentence?
1:42:23
Were you considering giving up a life of science?
1:42:29
Then how did that lead to octopuses?
1:42:29
Because it seems like that focus then opened up Pandora's box in the most positive way.
1:42:39
I want to go back and do a little bit of postmortem on what exactly happened.
1:42:50
So please, if you wouldn't mind, just tell the story of that period. Dr.
1:42:56
Gül Dölen: When you start your own lab, you get a bunch of money.
1:43:01
That startup package is great to get you started, hire some people buy some equipment, get your lab established without having to worry too much about the funding.
1:43:14
When I started my lab, I got a nice startup package.
1:43:14
I immediately got a couple of private foundation grants which were very helpful to help me establish the lab.
1:43:26
But you really can't, in academia, survive unless you can also get funding from the NIH.
1:43:36
These big NIH grants, in my career, in my lifetime, have gotten harder and harder to get.
1:43:43
It used to be that people who were young and had a lot of creative ideas had much higher success rates than people who were older and just redoing the same experiments with the different — whatever, very conservative rinse and repeat type of experiments.
1:43:56
Over my scientific career, I have seen that situation essentially reverse.
1:44:02
So people over the age of 65 are getting most of the NIH grants, junior people are really struggling.
1:44:10
There have been some attempts to correct that, but they just haven't worked.
1:44:17
It's just incredibly difficult to get funding.
1:44:17
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 — once I have all of the results that are going to make a cool Nature paper, I write a grant on all of the boring experiments that I didn't do it for that paper but that I think that the reviewers might ask me for, and I package that together and I send that to the NIH.
1:44:52
That's how conservative my grants really are when I applied to NIH funding.
1:44:52
And that's been successful.
1:44:59
But there was a moment a few months before the octopus paper, before we even did that experiment, where I was just beginning to feel like I'm not going to make it.
1:45:07
I applied to the NIH 17 times before I got my first NIH grant. Tim Ferriss: Wow! Dr.
1:45:19
Gül Dölen: I think part of it was because Iwas proposing these crazy ideas that people were like, "There's no critical period for social behavior." What?
1:45:25
"Nobody's ever going to use psychedelics clinically." What? "No, that'll never work.
1:45:31
Oh, you made those mice — too bad you didn't use them for the experiment that I would've used them for.
1:45:37
You're just a junior person.
1:45:42
You have no established track record.
1:45:42
No, no, no, no, no, no, no, no."
1:45:42
I was feeling really demoralized and I was like, "I can't do this."
1:45:48
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.
1:45:54
That's what I had worked so hard for as a graduate student, as a postdoc, as a medical student.
1:46:01
That was the dream that I was sold.
1:46:08
I was pretty devastated by how many rejections I got.
1:46:08
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 I'm out as soon as I…" My department was very supportive.
1:46:24
They were like, "You'll get there, you'll get there, you'll get there. We'll cover you.
1:46:27
Don't worry, don't fire anybody. You're good."
1:46:31
But still, it's a blow to your ego if you can't convince your peers at the NIH to give you that money.
1:46:39
So going out on my own terms, I was just like, "Look, one of the creative — I've always wanted to do study evolution.
1:46:45
I've always wanted to do something to do with marine neuroscience.
1:46:51
I have this opportunity to look at what happens to this behavior in an octopus.
1:46:51
I'm just going to go for it and it'll be fun."
1:47:00
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'd tell him we were planning to do this octopus stuff, and he'd be like, "Gül, what are you doing?
1:47:21
We hired you to cure autism.
1:47:21
What is this octopus stuff? What?"
1:47:26
And I'd just be like, "Look, you've got to back off.
1:47:26
This is what I want to do.
1:47:33
This is what's going to make me feel like science is fun.
1:47:33
I'm doing it not in a goal-directed way, in a playful, just out of curiosity.
1:47:40
I just want to know what happens."
1:47:48
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 have fun with it.
1:48:00
Tim Ferriss: So you, I wouldn't say bet the farm, but you were willing to go out in a blaze of glory and meaning just focusing on fun and trying to break new ground. It worked.
1:48:15
How do you think about, if you do, preserving that type of willingness?
1:48:15
Maybe the octopus work bought you a golden ticket to now continuing to do work that is not rinse and repeat, but perhaps — I'm just spinning a story here.
1:48:34
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.
1:48:45
How do you think about risk taking moving forward? Dr. Gül Dölen: Yeah.
1:48:45
First of all, I don't want to oversell how big of a risk it was for me to do that experiment.
1:48:53
We were already working on MDMA, we already had reasonable response from nature about the MDMA critical period experiment.
1:49:06
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.
1:49:13
Then a collaborator was like, "Whoa!
1:49:19
We have seven octopuses that we can lend you for a week."
1:49:19
And I was like, "Come on down."
1:49:26
He flew down, he slept on my couch.
1:49:26
We stayed up until two o'clock in the morning every night just doing it, mad scientists, because we had to send the octopuses back by the end of the week.
1:49:33
It was just like this mad scientist fun time.
1:49:38
So how do I preserve that?
1:49:38
Well, I guess part of, I think, the reason that we as scientists are seeing less and less of that crazy stuff is really the funding.
1:49:58
Just to give a sense of this, I think this is a really missed point, especially with tech.
1:50:07
In the '50s and '60s, the NSF, the National Science Foundation, and the NIH were funding all kinds of crazy stuff that they just never thought would ever be useful or have a goal.
1:50:18
They were just funding it.
1:50:18
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."
1:50:36
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 vets.
1:50:55
So I think this non-goal directed, curiosity-based science, it doesn't show any usefulness for 40, 50 years.
1:51:04
It takes that long for something meaningful to come out of that discovery-based, curiosity-based science.
1:51:11
And I think that the way that funding constraints and the way that the tech and — even private foundations are very goal-oriented.
1:51:19
It's like, "Well, how can we sell this? How can we market this?"
1:51:28
And the private foundations have names like Cure Autism Now.
1:51:36
They're very goal-directed.
1:51:36
I think that that kills the motivation or the impetus to just do the weird stuff that's just for fun and curiosity.
1:51:46
I would say every person who becomes a scientist at one point or another had that as their motivation.
1:51:53
The strain of the funding crisis is essentially what has forced people to get more and more and more conservative.
1:52:01
So I don't think I'm unique for wanting to just see what happens when you give octopuses MDMA.
1:52:09
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?"
1:52:22
It resonated with people, and I just think it mostly gets beaten out of us because of funding constraints.
1:52:34
Tim Ferriss: Is there any solution there?
1:52:34
I mean, if you could wave a magic wand, are there any structural changes that would help to alleviate that?
1:52:40
I'm just wondering if anything comes to mind aside from just, "Come on, guys. Come on.
1:52:45
We need the exploratory stuff, the weird stuff.
1:52:45
Otherwise, we're not actually investing in the long-term serendipity that has produced all of these world changing technologies."
1:52:57
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? Dr.
1:53:08
Gül Dölen: Well, I would say that this is venturing off into politics, which is a hobby, not my area of expertise.
1:53:17
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, we collected a lot more taxes.
1:53:35
Today, we give away more in tax breaks than the entire discretionary budget back to big corporations as incentives and tax breaks.
1:53:40
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.
1:54:13
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.
1:54:30
They came because the United States for years understood that this was an investment for the way way future.
1:54:37
So I think changing our tax structure to reinvest in the future of science, it's either going to happen or it's not.
1:54:46
It's going to move to other countries and places like China that are investing in science and technology in this non-goal directed, “just throw money at it and eventually something cool will pop out” attitude.
1:55:00
I mean, that's just my two cents.
1:55:00
I hope I didn't insult half your audience, but — Tim Ferriss: No. Dr.
1:55:10
Gül Dölen: — that's what I think.
1:55:10
Tim Ferriss: I don't think you've insulted half the audience.
1:55:13
I mean, I do think it's important to say that, I mean, the priorities of the government and nation state affect so many different components of life and the future of innovation in this country.
1:55:32
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.
1:55:52
Switching gears and just ask a few more questions.
1:55:52
Do you have any books that you have shared, recommended, or gifted the most to other people or recommended often to other people?
1:56:06
Any favorite books that come to mind? Dr. Gül Dölen: Oh, God.
1:56:06
How did we wander into this political sphere?
1:56:11
Probably the ones that I have gifted the most is a book called Invisible Women by Caroline Criado Perez.
1:56:18
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. It's just data.
1:56:36
It's like, "All right, well, here's how much it costs to keep ignoring women.
1:56:36
If you fix it, your city can save a million dollars a year."
1:56:43
It's all about the structural stuff.
1:56:43
It's not about your feelings about whether women deserve to be in the kitchen or not. It's not about that.
1:56:55
It's just here's how ignoring data about women's body sizes, women's travel patterns ends up costing society at large.
1:57:04
I think it's an excellent way of getting that.
1:57:04
Then the other book that I love the most, it's a very grandiose title.
1:57:11
It's called The Dawn of Everything: A New History of Humanity by David Graeber.
1:57:15
I actually love everything that guy wrote.
1:57:20
I started with this book called Bullshit Jobs, which — I was dealing with the bureaucracy of academia and feeling very frustrated.
1:57:28
I read that book and it was very cathartic, and then I just went down the rabbit hole and have enjoyed all the other books.
1:57:34
But The Dawn of Everything, 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.
1:57:47
Then the third one that I really love is The Immortality Key by Brian Muraresku.
1:57:59
I love that book so much.
1:58:02
I designed my entire Halloween decoration this year all around that book.
1:58:02
I sent pictures of it to Brian and he was like, "Oh, my God! You nailed it.
1:58:11
I've got to up my Halloween game."
1:58:11
So yeah, those are the three books that I would recommend. Tim Ferriss: Yeah.
1:58:18
The Immortality Key is the only of the three that I've read, but fantastic book.
1:58:22
Really, really exceptional.
1:58:29
It has made me want to try to meet archeo-chemists and have more conversations about recreating the elixirs of Midas and many others.
1:58:38
We'll see if I ever get around to that.
1:58:38
I'll have to maybe cut back on my podcasting to make time for that. Dr.
1:58:43
Gül Dölen: Well, I loved that book also because there's a — 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.
1:58:59
Definitely, next time I go to Turkey, I'm visiting Ephesus to try and figure out all those Hecate carvings and maybe take a little soil sample.
1:59:06
Tim Ferriss: Just a little soil sample.
1:59:06
Customs love soil samples.
1:59:12
Gül, this has been a wonderful conversation.
1:59:12
We've covered a lot of ground.
1:59:19
Is there anything else that you would like to add?
1:59:19
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? Dr.
1:59:31
Gül Dölen: God, I can't think of it.
1:59:31
I think this has been one of the most fun, meandering conversations.
1:59:36
I feel like we covered everything.
1:59:40
But 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 ground-shifting stories coming out and I would love to come back and share them with you. Tim Ferriss: Absolutely.
1:59:53
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.
2:00:08
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.
2:00:25
So thank you for doing the work that you do.
2:00:25
Is the best place for people to find your work dolenlab. org?
2:00:32
Is that where you would point people? Dr. Gül Dölen: Yes. Yes. Tim Ferriss: Perfect. Well, teşekkür ederim!
2:00:35
Thank you for taking the time today. Dr. Gül Dölen: Oh, wow! Excellent pronunciation. Ben teşekkürler! Tim Ferriss: Thank you. Yeah, I love Turkey. I love Turkey.
2:00:48
The language I'm fascinated with, that's a conversation for another time.
2:00:52
Very similar, grammatically, to Japanese, oddly enough, which is where I've spent more time.
2:00:57
But I really appreciate you taking the time today and being willing and so game to explore so many different subjects.
2:01:03
To everybody listening, we'll have links to the various terms, stories, people, names, books, et cetera that we discussed, including studies, in the show notes as always at tim. blog/podcast.
2:01:15
Until next time, experiment widely, be just a bit kinder to yourself and others than is necessary. Thanks for tuning in.