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Dr. John Krystal

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2022-09-29

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2022-09-29

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1. “Extend and augment the effectiveness of catamine such a paper by Sam Wilkinson here at Yale suggests that. But there's also this interesting question about what do you do during the cadamine infusion? And I think that this question is particularly relevant when you're, in a way, treating the impact of maladaptive memories. What do I mean by maladaptive memories? I mean things like early life trauma, current traumatic experiences, addiction, which is a kind of reward learning, if you will. And what we have found in a study led by Ilan Harpaz Rotam is that if you activate trauma memories during the ketamine infusion, then the potency of those trauma memories is greatly reduced. You know, people with PTSD have a lot of concerns.”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

2. “Because, in my view, ketamine is an intervention and it's part of an overall treatment. In other words, that it's really important that somebody is thinking about the overall well-being of the patient, providing support, providing oftentimes psychotherapy, and thinking about how the other medications that patients are taking are interacting with acadamine and looking out in a big picture way for the overall well-being of patients. Ketmines and intervention embedded in overall treatment. And for many people, there's some kind of ongoing psychotherapy, and there's evidence that because ketamine increases the neuroplasticity of the brain, that there may be synergy between ketamine and other treatments that are given outside of the ketamine session. In other words, oftentimes sessions 24 hours after, and that these sessions can both potentially”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

3. “There is very limited data comparing modes of catamine administration. There was a small study that suggested that three times a week or modest study that suggested that three times a week is no better than two times a week in terms of the effectiveness or the duration of the antidepressant effects. So the twice a week startup tends to be the standard frequency. There are some people who think that mast ketamine treatments, in other words three consecutive days or multiple days in a row might produce more lasting benefit. I don't think we can conclude that yet from the evidence that we have. So we tend to do twice a week. In my view for treatment-resistant depression, this is a pretty good strategy. The question about how to wrap psychotherapy around this is really an interesting one. And there are some important points to make about ketamine generally before going into the wraparound treatment.”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

4. “Ten treatments, twelve treatments, and they'll do that course to get back to a remission of their depression. And some people are able to then just stay on their ongoing treatment. Usually people are in some kind of ongoing treatment before they come to ketamine. We don't stop their standard medications, basically. If they're taking a sedative medication during the day or an anxiolytic medication like a benzodiazepine, we'll ask them to hold it on the mornings that they get their academy so that there is not an interaction there. So some people will just do a course and then they'll be done, but others will need ongoing some kind of ongoing maintenance treatment to sustain the benefits.”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

5. “This is an evolving story, and when we're talking about ketamine for treatment resistant depression, it tends to be administered in many clinics without any attendant psychotherapy. So for example, people will come in, they'll get the ketamine, they'll hang around for another hour or two, and then head out. And they'll do that for the initial four weeks, at least four weeks. They'll do it twice a week. Most people after four weeks of twice a week will go to once a week, and if they tolerate that, eventually they'll go to once every other week, and after a longer term treatment several months, some people will go to every three weeks, sometimes as infrequently as once a month and be able to be maintained on ketamine after that. People will come in, do a short term course, six treatments.”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

6. “The cost differences est ketamine is a little bit expensive. Medication is about 600 treatment, maybe depending on where you're getting your treatment, can be more. But it's usually covered by insurance, at least in many places covered by insurance, so it's more of a cost for the overall health system than it is for the... But sometimes it's the individuals paying out of pocket, and ketamine is obviously generic and much less expensive.”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

7. “Ketamine as a treatment because they want the rapid response that there's a little bit of an advantage for getting the full dose acadamine intravenously. Is it theoretical advantage, whether it's a real clinical advantage, still early to say because we don't only have good head-to-head data, it's mostly derived from secondary comparison of secondary data, secondary analyses. But for some people, there may be an advantage of the intravenous dose.”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

8. “So then there are some differences that favor the intravenous. One is that the intravenous dose is dosed on a milligram per kilogram basis, whereas there's a fixed milligram dose for the escetamine. And because of the fixed milligram dose of escapamine, some people start, it's recommended that you start at 56 milligrams of escetamine and then work your way up if you tolerate that to eighty-four milligrams. And that means that for many people, they're going to start on a dose which is not the maximally therapeutic dose for them, or maybe even an ineffective dose for them before they get to a therapeutic dose. And that means that for some people that they have to wait till they get to the higher dose to get much in the way of clinical benefit. So that is a subtle point, but if someone is getting to”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

9. “The first thing is the choice of S ketamine versus intravenous ketamine. And it's really not clear how they stack up against each other in terms of efficacy and tolerability. There's a clear difference in ease of use, which is if you're the sort of person who doesn't like needles, Getting the medication intranasal is a huge benefit. And if you're the sort of person who doesn't like sticking things in your nose, then getting ketamine intravenously would be a benefit. And that sounds like a trivial thing, but there are a lot of people who don't get a lot of treatment because they're afraid of needles. And that can be a problem for some people, and es ketamine can be given intranasally, and that's really can be given in more settings that might be more congenial and has all kinds of other implications.”

   2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

10. “We take from these kinds of studies in others, like fMRI studies and other things from ketamine is that ketamine has the ability both to increase the functionality of synapses, something that probably happens very rapidly within hours of ketamine administration, and for some people will be the bulk of their antidepressant response and restore synaptic connections. And that happens in a more delayed way and is involved in sustaining for many people the antidepressant response. And we know a lot about the mechanisms because it directly emerges out of Von Duman's work and Bitamogodam's work. You know a lot about the biology of the restoration of structural connectivity and much less at this point about how ketamine restores the efficiency of the network. But it's kind of my sense is that both are probably contributing to the Clinical effect.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

11. “cool technique called magnetoencephalography sort of like if you will eeg but with a magnetic signal rather than an electrical signal gets a little deeper into the brain a little higher sensitivity and what they showed is that you give a dose a ketamine well first that sensory evoked potentials the ability of a sensory input to activate the brain and you can measure that electrical or magnetic signature if you will using this technique that's a little bit blunted in depressed patients And if you give a single dose academy to patients with depression, you'll discover that there are two groups. Those people who don't respond don't show any change in the magnitude of this evoked response in the brain. But the people who do respond show an increase in the evoked response. In other words, the synaptic connections get potentiated functionally, not structurally, and so what...”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

12. “Exactly. Another deficit. So one of the ideas related to that is that probably that reduction in efficiency, efficacy is present more broadly in depression. And only a subgroup of the more severe chronic more treatment resistant depression have the reduction in synaptic density. you get some people getting better with depression when they get ketamine is for some people it's unrelated to the restoration of the synapses and it has to do with an increase in the efficiency or effectiveness of these synaptic connections what is the evidence to support that hypothesis a wonderful study conducted by allison nugent and carlosi they used another”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

13. “Using a really newfangled, clever technical technique where we can give a isotopically tagged infusion of acetate or glucose and then track its incorporation into a variety of metabolic intermediates in the brain. This technique allows us to measure two things. One is how much glutamate is being released and how much metabolic activity is triggered. So you can say amount of metabolic activity per glutamate. It's a measure of the effectiveness of that synaptic connection. How much is glutamate able to activate the brain? Lo behold, in some circuits, in the frontal cortex, there's a reduction in the effectiveness of synaptic efficiency in depression, in the frontal cortex. Pretty crude measurement.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

14. “So, what could it be? So I'm going to take a step back to point out that reduction in the density of synaptic connections in the brain isn't the only kind of glutamate abnormality that we have in depression. Another kind of abnormality that we've seen in people with PTSD and depression, and that was published this year also from the first author, was a colleague, Chadi Abdullah, who's now at Baylor College of Medicine.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

15. “What happens to them? They get dissociation too, but dissociation in those patients is unrelated to their clinical response. And if anything, it's not really so meaningful, but there's a little bit of a trend that the more dissociation they get, the less improvement they get. Not meaningful, but maybe it's there a little bit. So dissociation in these two groups of patients during ketamy means two different things. In one, it's a signature of clinical improvement, and another it's not. And what that highlights is really number one, ketamine is doing different things because the people who don't have synaptic deficits are still getting clinical improvement overall, but they're not getting clinical improvement that's related to the restoration of structural connectivity. They don't have that kind of depression. They don't have the deficits in synaptic density, and it's not revolving.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

16. “that dissociative symptoms produced by ketamine can be a marker That you've got enough ketamine into the brain and you're triggering the therapeutic antidepressant effects. But what about those other depressed patients, the other half of the patients with depression who are getting ketamine? They don't have synaptic deficits.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

17. “You give a mixed group of depressed patients, some who have symptomic deficits, others who don't have synaptic deficits, and you give them a dose of ketamine. What happens? This paper was from this same group published this year. It turns out that the people who have synaptic deficits, which are the more treatment resistant, the more severely ill, more chronically ill, etc., etc., the more hardcore depressed patients. They get a dose academy. They get an increase in synaptic density. And the more dissociative symptoms they get, the bigger the increase in synaptic density. And the bigger the increase in synaptic density, the greater their clinical improvement. Pilot data really preliminary, but very interesting. So it suggests that in people who have synaptic density, deficits,”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

18. “Did a study which I think is incredibly important and interesting related to the Nerbiology Academy which sheds light a little bit on dissociation, and that is they had previously reported that a subgroup of patients with relatively more severe depression had reductions in synaptic density. And they could show that with PET scans using a molecular tag for synapses. And so, okay, so there are these depressed patients who have reductions in synaptic density. Great. So far, that could be relevant to translating the animal work to the human work.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

19. “the dose at which they experience dissociative symptoms. I mean, the dose that produces the therapeutic effects, the dose that produces dissociation overlap. And so that if you're giving a dose of ketamine that is not producing any dissociative symptoms, for some people it will mean you have underdosed the ketamine. There are exceptions to this in that some people are just not very sensitive to the dissociative effects of academine, but still get the antidepressant effects. And examples of those people are people who have a person or a family history of alcohol use disorder who seem to have a built-in tolerance to the effects of ketamine as they do have a built-in tolerance, some of them, to the effects of alcohol. And that's another story which we can get to if you want sometime. My colleagues, Irina Estaldus and Sophie Holmes and the”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

20. “In terms of producing attitude change and things like that, I would also say that some people, they get the ketamine, and I once had treated a guy, or it wasn't a research study, but I gave him a dose academy. He had never come from a Mormon background. He had never had coffee. He had never had tea, never had alcohol, never smoked, never used any drug. And he described ketamine as the most fun he ever had since he arrived at Yale. So it was like a roller coaster of doing all these things. And so, I mean, it clearly has that part to it as well. So the question is, is dissociation telling us something important? And I think there are ways that it does on my side of the street, which is that, as I've mentioned, it just so happens that the dose of ketamine that is optimal for inducing the antidepressant effects is for many people.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

21. “Yeah, you know, stuff like that. And that is not a productive insight and it's not healing. It's not important for them to even remember that after the ketamine is worn off. So I would say the dissociation is clearly not a necessity.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

22. “I've seen a lot of people who get ketamine for treatment and a lot of people who just get ketamine. I've given well over a thousand doses of ketamine to people for whom it's not really that much of a meaningful experience. I've had people say things like, well, my parents scrimped and saved to send me to medical school and now I'm losing control of my thought processes during ketamine. I'm throwing away my parents' investment. These kinds of scary thoughts. My organs are being replaced with machine parts.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

23. “So what about dissociation in the antidepressant effects academy? This is really an interesting and complicated question because to really answer your question, you have to acknowledge, I have to acknowledge, that I come from, I'm a translational neuroscientist and psychiatrist. I do work on trying to understand the most basic aspects of biochemistry, synaptic signaling, network function, computational modeling, whatever. There are aspects of engaging in treatment that are not so close to that. Like what did it mean to me to go through this experience? And so a lot of people say that the dissociative experiences are very meaningful experience for them, particularly if they're some kind of guided experience to do that. And I have no argument with that whatsoever. Why not? In fact, that's great.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

24. “These states of feeling disconnected and that things are not real to sensory distortions to what people know is a very dramatic aspect of PTSD, which are these flashbacks where people are completely absorbed in another state and lose touch with what's happening around them. And so one of the things that was exciting about the initial ketamine research was it was not only providing us a way a new way to think about the neurobiology of psychosis and cognitive impairments associated with schizophrenia, but it was also at the same time providing us with really the first pure neurobiological path to studying the neurobiology of dissociation in PTSD, and that's a whole other kind of discussion which we can come back to.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

25. “States of derealization and depersonalization as well as distortions in our perception of ourselves and the perception of the world as integrated are collectively what we tend to refer to as dissociative states because dissociation meaning disconnected from what's going on around us but really it's a much more profound and nuanced idea because you can have some distortion of dissociation in some dimensions and not others and it can be very nuanced. I got interested in dissociation because of working with Vietnam veterans with post traumatic stress disorder for whom dissociation is a complication or a part of the syndrome of post-traumatic stress disorder for many people. And it's a whole nuanced range of things from”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

26. “You know, sometimes I have started papers on dissociation and stopped because I would get hung up on what the definition of dissociation is. But our consciousness, our experience of the world, our sense of ourself in the world, our sense of our bodies, our sense of ourselves embedded in time. All of these things which people take for granted are constructions of our brain, active constructions. And when these fundamental aspects of the organization of consciousness are perturbed, we experience ourselves as disconnected from ourselves, in other words depersonalized, or in an artificial state, which is also called derealization. In other words, that you're in an altered reality.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

27. “We administer it for forty minutes to give us a time window where people are having the subjective effects of ketamine where we can test behavioral and cognition. That's why we had the slow infusion in the initial study. And we just imported that into depression, and that has become the standard treatment infusion paradigm for racemic academia.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

28. “Yeah, it was really, really interesting Useless. I couldn't get him. He couldn't do any tests. He couldn't perform anything. So, what that essentially did was create the upper bound of the dosing that we were using with ketamine. And then the lower doses just turned out to be completely ineffective and have repeatedly been shown to be so in single doses in antidepressant trials. So that's how we got to ketamine, and that's how we got to the dose of ketamine and the route of ketamine that we use in the treatment studies because what we did was to adapt the dose and the duration of administration like you could have said why 40 minutes well because ketamine is such a short acting drug.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

29. “You know, the Out of the Planets, and he was afraid that if he let go of the bed that he'd be cast adrift in outer space and not make it back. Well, that was really fascinating.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

30. “Basically, the dress, the blue in the dress of the interviewer had become outer space. The white polka dots in her dress had become planets and solar systems, and his bed was flying among the planets and the...”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

31. “Where it's producing dissociation psychosis and a number of the other effects that we're really interested in, where it works. And it turns out that that little narrow dose window is the dose range where it works for the treatment of depression. We just stumbled on that because it was optimal. You know, the thing was we couldn't give higher doses to people because we needed them to perform cognitive tests and be able to answer our questions. When we gave people much higher doses of ketamine, They would have pretty interesting experiences, but they couldn't answer any of our questions. So it wasn't any good for me as a research tool. I mean, I remember one person that we gave this higher dose acetamine to who couldn't answer a lot of our questions, but he was holding on to the bed really tightly. And I said.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

32. “To study cognition, it released glutamate. If you give it anesthetic doses, it depresses glutamate, and it's not antidepressant at those doses. And if you give it at even a little bit lower level, it doesn't stimulate the glutamate release. There's this tiny narrow window.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

33. “And in 1997, she published a paper that showed that ketamine released glutamate in the brain at the very same doses that we were using, the equivalent of the very same doses that we were using to produce changes in cognition in psychosis related to schizophrenia. That line of research has its own story because we began using the ketamine administration as a platform for trying to identify novel alternatives to antipsychotic medication for the treatment of schizophrenia. And that has had its own life and story, and maybe someday we'll talk about that. But one of the things Beta found, which turned out to be profoundly important for the antidepressant story, was if you give it at the sub-anesthetic dose that we use,”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

34. “My path was the development of a research program on glutamate psychopharmacology developing circuit and mechanistic hypotheses. And one of my collaborators in those days was a pharmacologist named Betamokadam.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

35. “I felt like I just had to go out of the box. And this is where my father's legacy really had had a big impact. It's like, well, if you could do anything, what would you do? And it was like, well, I don't want to study these few cells contributing to dopamine or norepinephrine. I want to study the main information highway of the brain. Just a few years before they figured out that drugs like ketamine, PCP blocked this receptor for glutamate. And so what brought me to ketamine was really the effort to probe glutamate synaptic function in higher cortical circuits as a way of understanding the cognitive impairment's negative symptoms and other aspects of schizophrenia. So our path in our institution”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

36. “That's how I went into the field of schizophrenia research. And so I found myself as a new, completely inexperienced schizophrenia researcher setting up a research program related to the neurobiology and treatment of schizophrenia. And it happened to be just at that time that clozapine, which is an antipsychotic medication, that's a little bit more effective than other antipsychotics was introduced. And I've been raised studying monoamine pharmacology. That's what I knew. That's really what I had anticipated studying. I treated patients with clozepine and I thought it was a pretty good medication. But I didn't want my legacy after forty years of schizophrenia research to be that he figured out why closabine was a little bit more effective than other antipsychotic medications.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

37. “until landmark paper in 1979 from Steve and Suzanne Zukin. So it was darkness, right? It was like the Middle Ages of neuroscience. And so they had a brilliant insight, but they couldn't take it anywhere because there was no framework for it. So around 8889, joined the faculty in 88 at Yale. And I wasn't sure what I was going to do. And my boss said to me, Dr. Chinese said, Well, you can be the chief of the schizophrenia program or the deputy chief of the PTSD program. And I said, I like the idea being the chief.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

38. “They didn't know that it acted in a specific way in the brain. What that target was, they didn't yet know until the early 1980s that it was a glutamate receptor. They just didn't even know that there was a binding site for fence cycling.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

39. “Section of a paper in anesthesia journal. But really what happened was that this group of pioneers had an incredible tool, but no conceptual framework to use it to generate real deep scientific insight. And that's because they were 30 years ahead of the field. And it wasn't even known that there was a binding site for fencyclidine. first studies published in 1959. It wasn't even known that there was a binding site for fen cycladine.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

40. “There's a line in one of the first papers on ketamine, maybe the first paper that Ed Domino wrote, which was, when you give ketamine to humans, we notice that sensory information can get to sensory cortex unimpeded, but is altered or blocked in its transmission to association cortex. We call this dissociation and this process dissociative anesthesia or something like that. And wow, what a profound cast-off sentence, right? Buried in the discussion.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

41. “Was a fellow Corson who was working with him on some of those studies. So there's a line that I love Portentious lines in scientific literature. I think it's the last line in the Watson and Crick discovery of DNA where they say it has not escaped our notice that the elucidation of the structure of DNA may have relevance for the transmission of genetic traits or something like that, something unbelievably understated.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

42. “Unforgettable to me because Ed became a very dear friend and colleague over the years. But Ed was the first to give ketamine to animals and humans because it was a shorter acting, safer version of a small structural modification in the fencycladine chemical structure that made it possible to be shorter acting, more manageable, easier to control.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

43. “Yeah, my cousin, Tom, I apologize for mentioning his name, who was a medical student at the University of Michigan, brought me to sit in one of his classes when I was applying to medical schools. And it just happened to be Ed Domino. And my friends, my cousin and his friends, when Ed Domino came up to talk, saying a bit of the Van Morrison song Domino, which you may be familiar with. Anyway.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

44. “just unbelievably courageous and creative trailblazing psychopharmacology at a time when they just had no idea what was happening in the brain the neurobiology and in the early 60s Another trailblazing scientist also associated with that group was a guy named Ed Domino, who was a pharmacologist.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

45. “Extremely generative place in its era. And he said, If you gave Sernal, which was the company name for phencyclidine PCP angel dust, if you gave it to people, it produced something like schizophrenia in them. The thing was, that's nineteen fifty nine. And the mechanism, the fact that it blocked the NMDA glutamate receptor wasn't identified until the mid-1980s or 83-84. So it was this fascinating observation which couldn't go anywhere scientifically. But they did research, and this is going to bring us to other topics that we'll probably talk about In which they compared the effects of Encycladine to the effects of LSD in people.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

46. “So the real story is not related to depression at all. It's related to schizophrenia. So it so happens in the great cosmic Universe of coincidence that a friend of my dad's in Detroit and his family was a friend of our family and we went on vacation together. I remember intertubing down a river in northern Michigan. I grew up in Michigan, intertubing down a river with his daughter. We were maybe 10 or 9 or 10 at the time. His daughter is now named Joan Luby. She's now an endowed professor, an expert in child psychiatry at Washington University in St. Louis. Anyway, this fellow's name was Elliot Luby. And in 1959, he published a paper that was the first time fencycladine or Cernal was given to a human being. This happened at the Lafayette Clinic in Detroit, an entity, a building which no longer exists, unfortunately.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

47. “First off, I love hearing stories about how I and Dennis came up with Ketami for depression. It's one of my people. You know, it's like, oh, that's a great idea.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

48. “The elevation of BDNF levels, it causes a local seepage of BDNF, the nerve growth factor out of the nerve cells, And activates signaling. And then a key way station, and I'm going to get a little technical because I know we're probably going to come back to this point later. A key way station in the signaling of the nerve growth factor is a protein in nerve cells that's got the name mtor or m torque. And mtor is the mechanist, is called as an abbreviation for something really complicated, the mechanistic target of rapamycin. And it turns out that if you activate emtor, then you activate all of the downstream mechanisms that lead to the regrowth of these and stabilization of these new synaptic connections. This might be a good time to come back and think about a little bit about the complexity of the neurobiology of glutamate.”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

49. “Mechanism for resilience in the brain, these growth factors as a consequence of chemical communication in the brain. So although ketamine is a glutamate receptor blocker, one of the things that it does is block the excitation of inhibition, inhibitory cells. That's a really complicated. It's like if you had a break and then you had another break that you stepped on to relieve the break instead of stepping on the gas pedal, that's what ketamine is like in the brain. So ketamine allows more glutamate release to happen in certain circuits of the brain. You get a pulse, if you will, of glutamate, which is good for the brain, as opposed to sustained high levels of glutamate, which is toxic for the brain. The brain is really sensitive to temporal dynamics. That stimulates a type of glutamate receptor that triggers”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source

50. “Something called neurogenesis, which is the birth of new nerve cells in the hippocampus in animals, and there's been some work to show that that might happen in human brain as well. And he was one of the pioneers of studying the role of neurotrophic signaling in depression and its treatment. So his laboratory had all the pieces of the story about how nerve growth might be involved in antidepressant treatment. And so he was in some ways uniquely situated to discover this profound structural change. And what was really important about the work is not only that they describe the profound structural change, but they mapped the molecular signaling mechanisms that you alluded to about nerve growth factors engaging a fundamental”

    2022-09-29 · The Tim Ferriss Show · #625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever · IDENTIFIED FROM THE TRANSCRIPT · source