YouSaid · the spoken record

Dr. John Krystal

lines on the record
207
first
2022-09-29
most recent
2022-09-29
sittings or episodes
1
sources
podcast

Every line below is reproduced as it was said and linked to the record it came from. Nothing here is summarised or generated. Directory · Search · Corrections

  1. “But people are welcome to contact, we have the interventional psychiatry service at Yale New Haven Hospital, Doctors Ostrofen, Santa Cora, my office, or in most cities, most universities nowadays have academine service and a place where you can get connected. So the availability of ketamine programs is growing, and those are the places that I know of, but I'm sure there's some better centralized information source.”

    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. “If you're interested in the S ketamine and ketamine treatment generally, Jansen has a number of a lot of information on their website about Sketamine.”

    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. “Not ready to be built into recreational practice. And let me just say it's been an extraordinary pleasure to hang out and chat, so I really appreciate the time.”

    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. “Well, Tim, first, let me thank you for the opportunity to chat about this stuff. You know, I think ketamine and S kadamine are really extraordinarily important treatment advances. And depression is so terrible and that it's really important for people to know that there's hope out there. And even if the hope for them doesn't come from escape or from ketamine, there are still other things that can be done and that treatment can be very helpful and it's really important to get connected if you're struggling and don't give up. The second thing I'd say is I really appreciate the way that we've talked about it today. These are drugs every drug has a risk. You have to take them seriously. You have to give them the respect that they need in terms of making sure that if you're exposed to them, you're using them in the right way in a way that doesn't put you at risk.”

    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. “Yeah, Roland has been just a tremendous leader in this space and one of the very first pioneers. You know, there have been a number of pioneers, names who we've forgotten, who in their own way pioneered this science going back to the 1960s people like Daniel Friedman, Danny Friedman, and Sasha Shulgin and Mark Geier, and Dave Nichols and so on and so on and so on. But Roland has really been instrumental in moving this work forward and just a wonderful contributor and pioneer in the field.”

    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. “without getting the psychedelic effect. And so some people, like my friend Roland Griffiths, would say that's the wrong idea in the first place, that the psychedelic effects in the context of embedded in psychotherapy adds to the intrinsic antidepressant effect that you would get just by triggering synaptic growth and doing things like that. And others would say, Well, it certainly would be a lot easier to use these drugs to take them and to prescribe them if they didn't produce these psychedelic effects.”

    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. “Advantages as well. Well, a receptor is like that. Most receptors, including the serotonin 2A receptor, which is the target in the brain, can signal via two mechanisms. One pathway is sometimes called the traditional pathway or canonical pathway involves internal substrates that have names like cyclic AMP or phospholipase, different kinds of signaling mechanisms, but particularly the cyclic AMP dependent pathway. And then the other gas pedal signals by a compound called beta restin. And the idea is that different effects are mediated by these different signaling pathways. And if you could just selectively step on one gas pedal as opposed to the other, that maybe you can get the antidepressant effects of psychedelic drugs.”

    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. “Different downstream mechanisms and the work of Brian Roth and David Olsen now each of them have been associated with different pharmaceutical companies and other people are pursuing this. And the idea is imagine you're driving a car and instead of the car that we're used to it has two gas pedals and if you step on one gas pedal maybe you have you drive the electric motor And if you step on the other gas pedal, you drive the internal combustion engine. And there are situations where you're driving where it's much better to drive the internal combustion engine. Like there are no charging stations, but there are gas stations and you want to fill up. And we all know about that charging anxiety that comes with an electric vehicle. The other gas pedal gives you electric power and that has all kinds of”

    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. “So I think within five to ten years the current generation of NMDA receptor antagonists subtype antagonists, at least the one subtype selective group called the NR2B antagonist, the R acadamine, and some of the combination therapies with ketamine. I think that will settle out and will know whether there's meat on those bones. I think in parallel In the psychedelic space, there are certain key concepts that we're just getting into that will play out over the next five at most ten years before we have a good sense of how helpful they are. And probably the best known and in some ways perhaps the scientifically strongest foundation is the idea that psychedelics can signal at the same receptor via 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

  10. “In a pretty dose related way, increasing exercise up to reasonably high levels, particularly in the context of team exercise can be very helpful for depression, it is possible to engage in such extreme exercise that you lose the protective or at least some of the protective effects of exercise. And we don't really know if that's a product of the exercise or who is the people who are choosing to exercise at those very extreme levels, the stress that they're under. But the idea that you say about raising BDNF and other beneficial effects of exercise And the possibility that that would synergize with antidepressant treatment, which also raises SSRIs also raise BDNF in the brain, and as does academine and psychedelics.”

    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. “Yeah, it does affect sleep. It's probably one of the ways that alcohol intoxication, particularly at high levels, affects sleep is by blocking NMDA glutamate receptors. And there's some EEG sleepy EEG studies showing reduction in sleep quality after getting ketamine. And so when that data was reported, there were some people who thought, well, maybe the disruption in sleep is actually contributing to the antidepressant response because for so many people, the full antidepressant response doesn't really appear until at least one night of sleep after ketamine, but we don't really know the answer to that yet. To come back to exercise, exercise shows dose related antidepressant effects. And my colleague and I actually analyzed, my colleague led the study, Adam Chakrud, and this remarkable data about how”

    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. “One of the things it does in the depotentiated synapses, the less efficient synapses, when the BDNF levels goes up, it tends to drive more receptors for glutamate to the synaptic surface. In other words, it tends to make the neuron more receptive to glutamate. So that in that way compensating for the earlier deficits in synaptic efficiency. And it tends to be involved in the regrowth of the synapses via the mechanisms we just talked about, that MTOR is a part of.”

    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. “And that is a nerve growth factor or a growth factor that seems to involve the interface of neurons and glia with the surrounding circulatory system. And if you block The short name for it is Vejef. At least that's what people call it. If you block Vejef, you can reduce the antidepressant effects of most antidepressants, just like if you block BDNF, you can block the action of most antidepressants. But BDNF does seem to be really important. It's a key thing. It affects raising BDNF affects both the synaptic efficacy, and it affects the synaptic number. And it affects the synaptic efficacy.”

    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. “There are a whole family of neurotrophic factors in the brain, and when the different neurotrophic factors have tended to be studied, there has been some indication that other neurotrophic factors may also be involved in the antidepressant effects of ketamine and psychedelics, and in fact the antidepressant effects of SSRIs and other antidepressants. And one of them called vasoendothelial growth factor.”

    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. “effect on micro circuits and regrowth of synapses, and that's encouraging as a potential foundation for the way people think about the potential therapeutic effects of psychedelics.”

    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. “and glutamate output triggering the downstream neurotrophic effects and triggering the regrowth of inanimal models, the triggering the regrowth of the synapses that had been lost. The key thing that we don't know yet in terms of and so we see evidence hints of efficacy in the Imperial College study and in the studies done at Hopkins and some of the other trials and a little bit of a stronger signal in the compass data that's been released in the press releases but we do not yet have data in the treatment resistant depressed population and there are a lot of reasons why we have different populations being studied for the different agents but to make a long story short even despite all the differences in the clinical data at the basic science level we do have this kind of common”

    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. “In the cortex, catamine is relieving inhibition and thereby increasing activation in the psychedelics are driving autonomously excitation, again creating a new message. And so that difference has been one of the reasons that people have thought that ketamine sensory experiences tend to be more distortions of sensory experience. In other words, the walls are breathing in and out. My arm is now a foot longer than it used to be, things like that, whereas, oh look, there's a shining, glowing orb in the middle of the room that wasn't there previous, you know, from the psychedelic, right? A fully fledged hallucination. So in that way, they're not exactly the same in terms of the microcircuit, but they both have as a common property this increase of excitability, increase.”

    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. “So, what I'm going to say about ketamine and the hallucinogens and the psychedelics, if you will, are going to be complementary at each stage of information processing. Ketamine is relieving inhibition in the thalamus, in other words resulting secondarily in excitation and hallucinogen psychedelics are stimulating thalamic neuronalact the output of the thalamic neurons. So you have sensory information coming in and the ketamine is distorting that message to the cortex and psychedelics are creating a new message to the cortex. And similarly.”

    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. “You do activate inputs to the cortex from the thalamus. You really disinhibiting them, and you're inhibiting the inhibitory nerves, the gava nerve cells. So you're locally reducing the degree of inhibition and you're increasing a little bit the excitatory input.”

    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. “I think you capture the key point of convergence, which is these are structurally these drugs are not at all similar. Mechanism of action, these drugs are not at all similar. And where they converge, which is something you have to expect in the brain, which is this enormously complicated organ, that where they converge is how they perturb the effects of microcircuits. And microcircuit being a cluster of a small group of excitatory and inhibitory cells that are, you might say, the transistor, if you will, of the transistor radio. In other words, the lowest level that has the superordinate properties that you can study in relation to cognitive effects. So when you give a dose academine, you do two things, mainly, three things. One is...”

    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. “A treatment that's less burdensome for them. And if we can space out, avoid that period of time when people are getting more frequent infusions reduce the cost, we increase the safety, improve the tolerability, and we provide a greater flow through the clinics so that more people can get access to the treatment. So I think at every level, if we can, if there is truly a potential to realize here and if we can realize that potential, then I think a lot of people could benefit by that.”

    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. “Exactly, and enabling it to persist for a longer period of time. And one possible way this could play out, but it's certainly not by no means the only possible way, would be that Maybe the first time it lasts two weeks, and then maybe when you have repeated combinations of rapamycin and ketamine, maybe it can last longer and longer from there, which would be really great. And it would be great for a number of reasons. One is, as we say, and we keep coming back to both of us have tried to make the point that no treatment, no medication is without risk. Every medication and treatment has risk. And so we want to provide a treatment that has as few exposures to the drug as possible because that's a way of limiting risk. And it's a way of ensuring at the same time increasing the likelihood that people will stick out the treatment and it will increase the likelihood that people will get the treatment because it will cost less. So systems of care are more likely to adopt a less expensive treatment. People are likely to take”

    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. “This has been one of the most intriguing parts of the Kadami work, and it is again one of the most intriguing parts of the rapomycin work, which is that in both cases We're not trying to produce a chronic state of intoxication with ketamine, and we're not trying to produce a chronic state of exposure to rabomycin. We want the Zambonis to clean up the ice. We want the microglia to clean up the brain most of the time. What we want to try to do is to create an optimized environment so that in the time when these new synapses are particularly vulnerable to being engulfed that we've protected them and”

    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. “So first, Tim, this is an experimental procedure. It's not really not ready for prime time. The finding hasn't even been replicated yet. You know, this is what you do when you're trying to develop a new treatment and it's very preliminary data in some ways, even though it's a very robust finding. But it was just a single dose of rampomycin given with that single dose of academy. And that was what was so striking to us because rapamycin lasts a little longer than ketamine, but doesn't last two weeks. So really, the possibility that there's some synergy between the two treatments is really a possibility from the preliminary findings.”

    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. “Oral rapamycin. And we may have stumbled onto something by giving that dose. And what I mean by that is that we thought it should get into the brain at six milligrams. And we were pretty confident that it would get in the brain and would have some effect in the brain. But rapamycin turns out to be actively pumped out of the brain. And so the concentration that we achieved was probably kept quite low by this act of clearance mechanism. And so what we think we did was to stumble on a combination that was in a kind of sweet spot, high enough to interfere with gobbling up of the synapses, but not so high to interfere with the antidepressant effects. So it's a little bit of serendipity.”

    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. “We're really interested in developing this idea both from the point of view of academic research and I have a colleague that I've collaborated with for many years Tom Sue in Taipei who is doing a study looking at this combination and then we're developing a version of this idea one that we think may be optimized for use in the treatment environment within a company called Freedom Biosciences that I'm associated with.”

    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. “What we think is happening is that we might be preventing the microglia from gobbling up the newly created synapses. And so instead of lasting a couple of days, we get like a full course of treatment. How long does rapomycin extend the antidepressant effects academy? We don't know the answer to that because Since we didn't expect to see it, we only designed the study with a two week window of follow up, so we'll have to do, you know, longer studies to figure that out. But”

    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. “Exactly. Something like that. You know, I don't really know, and I don't think anybody does what's going on with the microglia, but it's really interesting to me that you have these two stress-related disorders, one like major depression, where you get a lot of cortisol in the body and the microglia tend to be activated in the brain, and you get the opposite pattern in PTSD where you don't tend to get so much cortisol chronically, and you don't tend to get so much microglio activation chronically. So we've stumbled onto something that we think is important, that's different in these disorders that we don't yet quite understand. But for the antidepressant effects academy,”

    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. “But in patients with post-traumatic stress disorder, we find both in patients while they're alive with pet scanning and in analyzing postmortem brain tissue that the microglia are suppressed. And I've been talking to colleagues about this and they think, well, maybe at one point they were activated, but maybe there's kind of in a burned out state, you know, an exhausted state.”

    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. “So microglia tend to be activated under conditions of severe and persisting stress like you have in depression. The paradox, and I don't want to get us too distracted because frankly, I don't understand what we found. So I can't really explain it.”

    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. “So microglia are really interesting because they have different modes of function in certain circumstances they can promote nerve growth in the brain. Another circumstances when synapses get immunologically tagged, they can surround them and literally eat them up. And so, in fact, over development, there are certain programmed ways that synapses are eliminated and microglia are involved in that. But when you have inflammation in the brain, as you do in depression, microglia are involved, and we think they contribute to the initial deficits in synaptic density and depression. So one way that ketamine plus rapamycin.”

    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. “Which is a powerful immunosuppressant, are related to its ability to extend the antidepressant effects academy. And in particular, you may recall that I said that the antidepressant effects acetamine, at least in animals, seem to last about as long as the newly created synapses. And so we assume that as those synapses are being gobbled up, that the antidepressant effects are going away. So what is doing the gobbling up? It turns out that one of the critical mechanisms that gets engaged are the primary immune cells in the brain. And these, Tim, I think, are maybe your new favorite cells, the microglia?”

    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. “It seemed to us to be non-trivial, and it was also a little bit perplexing in the sense that we knew we were giving a drug that had the potential to block Emtor in the brain. And if MTOR activation was critical, then why didn't rapomycin block the antidepressant effects academy? And one of the ideas that we are wrestling with is maybe the immunosuppressive effects of rapamicin.”

    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. “Academy was about thirteen percent, and when they got the same people, the same depression, if they had gotten pre treated with rapamycin, their response rate was over forty percent.”

    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. “Now you'll recall from the animal studies, you may recall, that emtor activation was implicated in the antidepressant effects academy. And so we did a study to try to show that that was somehow involved in humans. We gave the highest dose of rapomycin, the MTOR blocker, that we felt would be perfectly well tolerated by everybody in the study. MTOR is an immunosuppressing drug, and that was in our mind as well for reason that I'm going to come back to in a little bit. So we gave rapamycin with ketamine. So in the same group of 20 patients with treatment-resistant depression, they completed one ketamine day where they got just ketamine, plus placebo, of course, and then the other day they got ketamine plus rapamice. And the remarkable thing was that the response rate at two weeks, when they got”

    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. “gets triggered when you give ketamine. Downstream one of the proteins that gets activated inside nerve cells that triggers the regrowth of those synaptic connections. And that protein is called emtor. And the drug we use to manipulate it is called rapomycin. It's a block of emptor.”

    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. “that that would be a reasonable thing to try to do. It's because when you give ketamine to patients in the long run, You can space out the treatments more and more. In other words, you start with giving it twice a week, then you go to once a week, then you go to every other week, and then eventually many people will get to every three weeks or maybe even every four weeks. So it suggests that there are some mechanisms that are triggered when we give ketamine or existing as a precondition for treatment-resistant depression that shortened the duration of the effectiveness academy. And so we've been interested in that question for a long time, and we did a study that really spurred our interest in this question. And it was led by at our site by my colleague Chaddy Abdullah. And what we did was to try to block a certain molecular switch that”

    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. “Let's start with the end, if you will. What do we really want in treatment? What would be the ideal antidepressant? The ideal antidepressant would be a drug that acted rapidly and lasted forever. We would call that basically cure. And we never use the word cure in psychiatry. We don't even think of the idea of cure. And that's partly because we don't really understand the brain well enough to really know how to completely undo the changes that we see there. So let's start just with the shortest version of that, which is what if we could take ketamine, which is a very, has a short duration of antidepressant effectiveness at the beginning, somewhere between, say, three and seven days, and make it last two weeks or a little bit longer. And you might say, well, why would you think that”

    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. “Yeah, inability to feel joy. And my brother, who's a psychiatrist, you know my family history. My father was a psychiatrist and psychoanalyst. My mother became a social worker. My brother is a psychiatrist. My cousin's a psychiatrist. I come from a genetically high vulnerability family for mental health professionals. My daughter's becoming a psychiatrist. My brother did a study as part of a consortium and gave a kappa opiate receptor blocker. In other words, the reverse of Salvinor, and looked at the effects on brain circuit activity and anhedonia in patients with depression and showed that you could Affect the reward circuit activation and reduce anhedonia in depressed patients with this kind of mechanism, a capa-obiet antagonist. And so people are actually interested.”

    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. “But what's so interesting is that it shuts down dopamine-related reward signaling and some reward processing in parts of the brain. And so as we think about things like mood and addiction, all of the systems that we've talked about end up being implicated, the NMDA glutamate receptor and synaptic connection, and the kappa opiate receptor is thought to contribute to some of the anhedonic symptoms of depression.”

    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. “But they don't, it doesn't block the dissociative effects. Now, Salvinorin, if you give it, Calvinoran is a very short-acting drug in humans. My colleague Cyril D'Souza and Mohini Ranganathan dosed Salvinorin. And you can get this very intense kind of psychedelic state in people that is relatively short-lasting. And what's interesting about Salvinorin is It's not such a positively euphoric experience as you get people uniformly rate, even if they don't like the experience, they still rate the ketamine experiences as euphorogenic, and they still rate a lot of the psychedelics.”

    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. “Do not, not at all. What we do is we tend to make a low dose of ketamine less pleasant for people. They get a little more anxious. They don't like it as much.”

    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. “An opiate receptor blocker. It blocks at low doses it preferentially blocks the mu opiate receptor, the morphine receptor. At higher dose, if you give a high dose, it also blocks the delta opiate receptor, which is the main target or amine target for the encephalins, endogenous opiates. And then if you give an even higher dose of naltrexone, you also block the kappa opiate receptor, which is the salvinorin receptor. If we give a pretty high dose of naltruxone and give ketamine, we don't change the dissociative effects of ketamine at all.”

    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. “Depending on the time frame, exactly. So as a result of our interest in this NMDA opiate interaction, we did a study where we gave people a high dose of naltrexone before we gave them a dose academy.”

    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. “The subjective effects of a low enough dose of ketamine are often described like similar to a glass of wine, and if you get your alcohol dose high enough, let's say it's been reported that you can get numbing distortions, impairments and cognitions, et cetera, et cetera, as we all know. And some of those effects are thought to be similar. In fact, we did a study where we gave ketamine to very experienced alcohol users who described the antidepressant dose of ketamine as similar on average to somewhere between six and ten drinks of alcohol.”

    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. “Let's backtrack and talk about these three or four compounds. First, alcohol. So alcohol is a ethanol, is a weak NMDA glutamate receptor antagonist. And that, we think, is a major contributor about why 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

  47. “I think it's both. I think there's been a tendency to be more concerned about the myoopiate receptor activity than the NMDA receptor antagonist activity. But in my view, that's a bit of a distraction because ketamine s ketamine is much more potent at NMDA receptors than at muopiate receptors. At least it's more potent, several fold to maybe tenfold somewhere in between there. But clearly we all know about addiction risks of opiates, but we want to make sure we don't underestimate the addiction risks of R ketamine, S ketamine, s methadone, whatever the NMD antagonist is. You know, the rate of ketamine abuse has been going up since the rate of ketamine use disorders has been going up since the about twenty eighteen or so in the United States, so we do want to be careful about that.”

    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. “So the animal data with archetamine have been pretty encouraging about abuse potential, but we don't have enough experience in humans to really be able to say. Sketamine, it's true that it's more potent at the NMDA receptor, it's also a little bit more potent at the mu opiate receptor than Retamine. And so there's been some discussion about the abuse liability of escetamine.”

    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. “Go to another NMDA receptor antagonist and maybe that one will work. So that's a drug that has some potential in that regard”

    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. “S methadone is yet another drug that blocks NMDA glutamate receptors and is a drug that has some potential to treat depression. So the other isomer of methadone is the methadone that we associate with opiate main. So this is the inactive isomer methadone, which works by blocking NMDA glutamate receptors. And there's some preliminary data that's encouraging for the treatment of depression. It's really important that we have many different drugs that block the SSRIs and it's been helpful to have a portfolio of medications because for one reason or another, one of the family of the SSRIs will be tolerable or will work or won't work for one patient versus another. And it'll probably be the case with NMDA glutamate receptor antagonists that ketamine works for some people and some people that don't like the side effects.”

    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