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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. “Source of pain. And so that you live the life of a person who didn't have pain and you discovered that when you did that, you didn't have pain.”

    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. “Tension on pain and makes us vulnerable to blowing the pain out of proportion. It's not that we don't feel the pain more intensely, but we feel the pain more intensely because our attention tends to get drawn in such a focused way to it. So I think that there are many levels and many potential ways the neuroplasticity part of it, the depression and anxiety, cognitive part of it, the ability to engage a variety of strategies to suppress the pain signals through relaxation and other kinds of techniques. So I think chronic pain is like depression or PTSD in that it's often useful to think about being resilient to the pain as opposed to making whether or not you have it or not. So I think one of the things that you're describing is that ketamine helped you to be resilient in the face of a potential”

    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. “I don't know that I can explain six months, but what I can't say is so the first thing you said, which was that your whole body adapted to having pain in your knee. And you changed the way that you moved in ways that were probably sparing acute pain, but were probably a burden and maybe not good for your overall health. The second thing I would say is that there's a close tie between depression and anxiety and pain. And a lot of what we're managing when we're managing pain is our emotional response to the pain. And if you tone down the depression and anxiety, then you discover that the pain is actually much more manageable because anxiety and depression focuses our attention.”

    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. “Tree tree people with catamine have ketamine in their system when they undergo the knee replacement, the chances that they're going to develop this nagging, long lasting pain in neuropathic pain goes down. So it's very common to have a drug like ketamine given during an operation like that to reduce the development of neuropathic veins. So it can be used to treat pain and to prevent 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

  5. “and restoring sensitivity to the opiates so that people don't need to use so much opiates to control their pain afterwards. And the third thing that ketamine can do that's really interesting is prevent the sensitization of pain pathways. So let's say you're going to have a knee replacement and you know that when you have a knee replacement you know you're going to do some things to the nurse to make it possible to replace the knee and that there's a risk for some chronic pain related to that knee replacement. As you know, because you just said it, that ketamine interferes with neuroplasticity and while the ketamine is in your system can interfere with the encoding, the neuroadaptations associated with memory and so produce some temporary memory impairment. Well, it does the same thing for learning in the pain pathway.”

    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. “Maybe in the 90s, I think in the late 90s. And what they found is that you could prevent the development of tolerance to the anti-pain effects of opiates by co-administering ketamine or an NMDA antagonist. I think they used a different one, intermittently during the exposure to opiates. And so one of the big problems, as you know, with opiates, very helpful for controlling pain for many people. But if you have neuropathic pain, old sports injury, back pain, and you get that kind of chronic grading nerve pain, sometimes people will be on opiates for a long time and they're not really getting much benefit from those drugs. NMDA antagonists can be a path for reducing the pain that can't be reduced by the opiates.”

    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. “Yeah. And the answer is yes. And this is actually, there are two kind of interesting parts of this. One is the NMDA receptors are in the pain pathways. It's in the spinal cord. The NMDA receptors are in the spinal cord and involved in transmitting the pain messages up to the brain. And they're in the higher executive pain centers like in the thalamus, very dense in the thalamus. And so it both can reduce the experience of pain and it can reduce how much pain is upsetting to you. So in both ways, ketamine can be helpful via its action in blocking the NMDA glutamate receptors. And it's now being already used commonly in pain centers for the treatment of pathological pain. There's another part of ketamine that from the pharmacology point of view is extremely interesting. And this goes back to the work of Keith Trujillo and who to a kill.”

    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. “Japan by Kenji Hashimoto and some other groups. So there's interest in Arkadamine in how it should be dosed and what it would be like. It's still kind of getting sorted out. But it's really important to understand that there's a way to use our academine that's not that different than the way we currently use S-Kadamine, and then there's a way to use R-Ketamine that's some kind of lower dose treatment that if it works, would be working through some other pathway that we don't yet understand.”

    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. “What if archetamine works through some other target? Maybe it doesn't work through the NMDA receptor, in which case you might be able to get some kind of effectiveness at a low dose that doesn't produce dissociative effects. You know, that would be, if it really is just as effective as escapamine and doesn't produce a prediction liability and doesn't produce dissociative effects and doesn't have other medical effects, that would be super. The problem is If archetamine is working by some other mechanism, what is it? How does it work? Does it have any of the properties that we ascribe to recemic RS ketamine at lower NMDA receptor occupancy? And the answer there is we have no idea. So as our ketamine gets developed, it has shown effectiveness in animal models, in studies in general.”

    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. “Strategy will be followed one strategy says our ketamine has a different binding profile at NMDA receptors and other targets. And so the ratio of its affinity for NMDA versus these targets is different than eschetamine. So if we bring Retamine up to the same dose as esketamine, the same comparable occupancy of NMTA receptors, maybe it'll be a little bit more tolerable. The alternative idea 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

  11. “That we studied was a mixture of R and S. And when people say s ketamine, which is the version of ketamine that was developed by Jansen Pharmaceuticals, that's the S isomer, which is more potent at blocking the NMDA glutamate receptor. The idea being cadamine has a more potent and less potent blocker. Let's develop a treatment that blocks the NMDA receptor more potently. logic goes something like, then we can give less total dose, and maybe that'll be safer in terms of side effects or better in terms of tolerability. The alternative idea, which is being developed in relation to R ketamine, is still, I'd say, from where I sit, which is a bit at a distance from the archetamine, is one of two strategies. And it's not clear to me which”

    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. “So when people say ketamine these days, they're talking about the mixture of the R and the S molecules. I see. So the standard”

    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. “In three-dimensional space, they actually occupied them in ways that couldn't be one where you couldn't superimpose one on the other. They're actually turning in opposite directions. And that turns out to make a big difference because aramine is somewhere between three and five times less potent in its ability to block what we perceive to be, what we think is the primary target of ketamine in the brain, which is the NMDA glutamate receptor. And it's a really complicated story, too complicated for us to go into in detail. But the reality is that there are at least four subtypes of NMDA glutamate receptors and ketamine binds with a little bit different affinity to each of the four types of the NMDA receptors. The fact that there's that differential affinity for ketamine has been taken up by the pharmaceuticals industry where you have different companies developing alternatives to ketamine that target just a subtype of the NMDA glutamate receptor to block. And that's a whole”

    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. “But secondly, you said something which is extremely important, which is that what really counts for these molecules binding to the nooks and crannies is the three-dimensional space. So what you couldn't portray is that when you overlaid the two hands in a way that made the sequence of the molecules in the two isomer similar, was that in one case the first carbon might be sticking into the plane, but in the other case the carbon was sticking out of the plane. And so that when you saw the actual structure”

    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. “Of exposure to the drug, and then they tend to develop heavier versions of alcohol or ketamine self-administration. Those self-administrator PCP and other substances from that class.”

    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. “What's interesting is that there are some drugs abuse like cocaine that animals. Know And humans seem to like as well. But ketamine is more like alcohol. So there are some strains of rodents that naturally consume alcohol or naturally consume ketamine, but generally speaking, you have to kind of gradually introduce them to alcohol or decetamine. And then they can become compulsive alcohol consumers or ketamine consumers just like humans. And it's bad. And the animal models vary between very patient escalation of alcohol or ketamine, and you give it to them at times when they're most active, like in the dark and the rodentomycin rats are more active in the dark. And you give it a little bit and you take it away and then the animals will, when you give them access again, they'll drink a little more, take a little more. And so they go through bouts.”

    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. “Abuse is the greatest risk associated with ketamine. Ketamine has been around since the sixties, its medically safe and well tolerated by most people when given in the way in which it's given for treatment. We don't see much evidence of persisting medical risk. The only persisting medical risk is when people are exposed to ketamine in the context of the persisting medical risk that we can't prevent is the one when people are developing addictions. So we want to think about ways to broaden the pool of people who would be considered for ketamine and maybe to take advantage of the fact that treating depression is good for addiction just like treating addiction is good for depression, so providing an avenue for the safe treatment of these patients is we think is really important.”

    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. “Are a variety of companies that are approaching a variety of different strategies to try to get to this point? So, for example, one company that believes that their version of ketamine has less abuse liability is using the opposite isomer, in other words, the mere image of Sketamine is called arcetamine. And so they believe that that version of ketamine might have less intrinsic abuse liability. There are other drugs that block the NMDA receptor that are being explored or being developed for the treatment of depression that may or may not have similar degrees of abuse liability with ketamine. There's the strategy that freedom is trying which is combining an anti addiction medication with kadamine to reduce. It's interesting. It's abuse risk. So there are a variety of strategies that people are taking to try to reduce this risk because in many ways”

    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. “Sort of a more elaborate version where there's some external regulation of the dosing and external monitoring of the dosing so they can, the person only is able to use it to administer the ketamine at certain times. It's not for 100% protection, but for most people it would be very protective against the diversion of ketamine. Another strategy is to try to develop ketamine that has got less abuse potential. So a company that I've been working with called Freedom Biosciences is trying to do just that by combining ketamine with a drug that might reduce its abuse liability to come up with a version of ketamine that has less abuse risk associated with it. And that's still early days with that, but it's an interesting 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

  20. “Or snorted, exactly. So you just given the person who maybe just got a few doses of oral ketamine all of a sudden maybe just got like 100 doses of intravenous ketamine. So the risks of diversion when you give ketamine to people for home use, you have to really be thoughtful and careful about thinking about that. And there are a variety of interesting strategies to deal with this. So for example, there's a company out there that's developing intranasal delivery system to deliver controlled”

    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. “might not be that much for someone who was just going to use it orally. But what if they gave that a thousand milligrams to someone who was going to dissolve it and administer it intravenously? Person can get high on maybe ten milligrams or store.”

    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. “effect Ketamine might have on addiction and in fact have produced beneficial effects on drug craving, the biggest step is to limit the availability of ketamine to the clinic setting and that protects people not only from taking more and more ketamine on their own but it also helps to limit the possibility that the ketamine that they're given would be diverted to others who wanted to use it for recreational purposes and That's really something that needs to be thought about really carefully because let's say a person got a bottle of ketamine that had a thousand milligrams of it or let's say they got pills of ketamine that had a thousand milligrams because a thousand milligrams might not be that many oral doses because your body metabolizes ketamine so rapidly that if you give it orally you have to give a lot and so giving a thousand milligrams”

    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. “concern about the addiction risk of ketamine or the risks of ketamine for people with addiction. A lot of programs that would otherwise be prescribing ketamine for the treatment of depression will exclude people who have these substance use disorders. And that turns out to be a lot of people who are depressed in the first place. So you're cutting out a large group of people and there's, I believe, and I think others believe that there's a need to really think about what the optimized way to treat these patients who have depression and comorbid substance use disorders. So one strategy is the strategy that was developed by the group in England that I mentioned earlier at the University College London and that is extended to, I think it's Manchester, but I may be wrong where they're trying to activate the drug memories during the ketamine infusion to try to counteract whatever aggravation.”

    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. “I mentioned earlier, that's particularly scary because these persisting psychotic symptoms that you see with high-dose, long-lasting ketamine use, they don't respond very well to antipsychotic medications. Those psychotic symptoms don't necessarily go away quickly when ketamine use is stopped. So ketamine is a drug that has to be given a lot of respect and treated with a way that recognizes that careful thought needs to go into protecting people from developing problems related to ketamine use. In the group that people worry about the most are people who have already not only depression but some kind of substance use disorder, whether it be alcohol use disorder, stimulants, opiates, things like that. And that's a problem in terms of access to ketamine as an effect of antidepressant because out of this”

    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. “In this compulsive manner as opposed to decreasing your symptoms of depression. And if you look at the brains of people who use ketamine very regularly, they have, rather than enrichment of synaptic connections, they tend to have loss reductions in white matter, you know, the marker of neural connections in the brain on MRI in parts of the brain. They tend to have impaired function of the brain with functional magnetic resonance imaging. They tend to have cognitive impairments, and those cognitive impairments tend not to resolve rapidly when ketamine use is stopped, but rather have a very slow response and in some cases there may be residual impairments in memory or attention. And then the most extreme cases for this group of people that are using extremely high doses academy for a long period of time, you have this risk of persisting psychosis.”

    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. “Time and a stressful weekend, they would take an extra dose before the weekend. And maybe they were having a down day, they'd take an extra dose academy. And some of these people, with the best of intentions and no interest whatsoever in developing ketamine habit, found themselves taking it more and more frequently every day. These were people who were given bottles of ketamine to use at home and who had the ability to take it whenever they needed. And some of these people ended up taking it every day. And some of these people ended up taking it four or five, six times a day in order to maintain their equilibrium. And one of the things that happens if you take high doses of ketamine every day as opposed to lower doses of ketamine sporadically is that ketamine can increase your vulnerability to 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

  27. “higher and higher doses academy. And if anything, the fact that we can space it apart suggests that the brain has become more responsive or the brain's reaction to ketamine has in some way adapted in a positive way. When you use ketamine regularly, when you use it every day, it produces the opposite pattern of adaptations. Instead of becoming sensitized to the effects of ketamine and having the ability to give doses that are spaced farther and farther apart, you become tolerant to the effects academy. You need more and more ketamine to produce the same effects. And people tend to use the dose more and more frequently. So I've spoken to people who started using ketamine to self-treat their depression. They would take it once a month and that would initially hold them just fine. And then they'd take it maybe if they were heading into a”

    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. “One of the things that happens when you use ketamine every day is that its effects on the brain turn out to be the opposite of the acute effects. So when we give a dose and we let the brain react, the brain responds in ways that are helpful. We get regrowth of synaptic connections. We get potentiation of synaptic function. And in animal studies, there's some evidence that the inhibitory cells, which are sometimes atrophied in depressed patients, will come back to life and all kinds of beneficial effects happen. And while the effects of a single dose don't seem to be permanent, those are all kinds of effects that we hope to see and hopefully over time with treatment will become stabilized. And when we space the doses apart, we don't get tolerance to the effects academy. We don't have to give”

    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. “Hospitalized inpatient unit, they were persistently psychotic, and those psychoses didn't clear even after a time when they had stopped using the academy. And so ketamine abuse carries with it risks that have to be taken very seriously, all the way from drunk driving to really high-dose ketamine use. We said earlier that the typical therapeutic dose for an 80 kilogram man was about 40 milligrams. And in China and in Taiwan, I've met with people Eight grams a day intranasally and orally. So in other words, that's 8,000 milligrams. That's a hundred fold or 200 fold times the dose. And they used it every day.”

    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. “First, I think your point's really well taken, which is to think about a drug like ketamine. Most people gravitate to the risks that are the most flamboyant part of it. In other words, what's the risk of dissociation? What's the risk of a transient psychosis from single doses? To tell the truth, I found that those risks are really quite limited. People have underssold the addiction risk of Kadmin United States. But in some parts of the world, cadmium is known as a very significant commonly abused substance, often as an alternative to alcohol or sometimes as an alternative to cannabis. So I visited clinics where ketamine abuse was being treated, and these were really heavy users of ketamine.”

    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. “My general feeling about ketamine, like most clinical experiences, is that when the patient is comfortable and feels well cared for and supported, that outcomes tend to be better. So the whole setting that you describe, a really comfy chair, a really relaxing video that's not too stimulating, privacy and quiet is pretty close to an optimized setting. In the video mainly because Not much happens for, you know, that's describing a treatment where not much is happening during the infusion. If you're going to reactivate trauma memories or if you're going to reactivate alcohol memories, that itself is going to be a pretty engrossing intervention and probably will occupy a lot of the kind of sensory space of the It sounds like you had some version of 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

  32. “control of your perceptual world. So when you put the blinders on and produce sensory deprivation, you tend to augment the intensity of LSD. You're withdrawing the organizing effects of the sensory world. And so you tend to have a little bit more stimulation in the emergency room setting with the psychedelics than you do with PCP.”

    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. “Way to deliver the treatment. One of the things about ketamine is that it distorts perception in exactly the way that you described. So some groups try to keep the level of stimulation limited because the more intense the sensory input on ketamine, the more you get distortions of the experience. And it is said by mentors of mine who worked the emergency rooms when you would get PCP and LSD, intoxicated people come to the emergency room, that the management strategy was the opposite for those two medications because PCP, like ketamine, is a causes distortions of the input. So the more input that you get, the more distorted things become. But with LSD, there's almost like a battle for”

    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. “You know, I've seen all of the above in terms of settings, and we've always used blank rooms, partly because what we're trying to do is to make ketamine available to as many people as possible and have the most efficient settings. So in our clinic, which has led, co-led by Dr. Robert Ostroff and Gerard Santakora, both experts in this work, it would look like a surgical recovery room with a number of bays, and everybody has their own space. They're shielded from seeing other people by curtains and things like that. So they do have some privacy. But the doctors are moving and the nursing staff are moving from patient to patient to patient in the session. So it's more of a strange in some way almost a communal experience. Not that people are wanting the communal experience per se, but it is a very efficient.”

    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. “And then when it does happen, say if they happen to have promised. Well, it's happening, and it's going to go away. And most people find that very comforting because they kind of knew it was going to happen all along. And you tell them this is what we're talking about. It does change their frame of reference, but they usually tolerate it pretty well.”

    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. “Person is pretty much back to themselves, even if they get the full dose, the side effects usually don't last that long. And in my experience of administering ketamine a very large number of times, the main thing that's helpful is getting right up to people and talking to them so that they have a kind of visceral sense of your presence there and assuring them that they're going to be okay and that this isn't going to last. Because one of the things that can happen during ketamine infusion is that people lose the perspective that the drug is causing the change in their consciousness. And the best way to prepare people for that is remarkably to prepare them for that. So what we do before we give anybody ketamine is spend a fair amount of time telling them what ketamine effects could be like, preparing them so they're not surprised when it happens.”

    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. “And the Zafran works pretty well for that medically the side effect that people watch very carefully is blood pressure. So ketamine produces a small increase in blood pressure. And if you start with an elevation in your blood pressure before you get ketamine, it can boost your blood pressure up in a range where you wouldn't want it. So when that is a risk, we pre-treat people with a drug that blocks the beta adrenergic receptor drug like propanol, and that works pretty well. Those are the main side effects that we have to manage. People often think that the main concern is the side effect of dissociation or transient psychosis or cognitive impairment. And the main way we manage that when we're administering the drug intravenously is by stopping the infusion. And so we can stop an infusion within 30 minutes 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

  38. “The one that's probably most disturbing to people is nausea. Nobody likes to get nauseous, nobody likes to vomit that I know of. So this is our friend, who is an anti nausea medication, works pretty well for most people. And the nausea that you get with ketamine is a little bit like the spins that you get if you drink too much. I don't know if it was for you, but for some people that is the experience that they describe.”

    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. “So, as far as I can tell, the main pro of I am is ease. In other words, you go up to somebody, you give them an injection, and then it takes care of itself. You don't need an intravenous line. You don't need to wait around. And so in some contexts that's a little easier. But the main drawback is that with I injections typically people get the entire injection at once. And that's not optimal for everybody because sometimes when people get upset during acetamine infusion or if they get a headache or if they get nauseous or if they even start to vomit, we'll stop the infusion and hold it. And those side effects will go away on their own.”

    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. “If you took those 40 milligrams and you infused them over 80 minutes, Then you would get the same total dose, but the peak blood level would be half. That would be, as far as we can tell, that would be more like giving a lower dose. I don't think that would be as effective. And that's because we think that the antidepressant effects are kind of triggered by a relatively rapid change in glutamate synaptic function as opposed to a slower, smaller, more gradual effect in glutamate function.”

    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. “We don't have data to really inform us. But in theory, what we want to do is to get up to a certain occupancy of the NMDA glutamate receptor. And as far as I can tell, that's the critical thing. So if we get there quickly, or if we get there a little more slowly, so far it seems like both Have the potential to produce an antidepressant response. What is different is that if you took the infusion rate and doubled it, and so you said, we're going to give you the same, and I think if my math is correct, 80 kilograms, half a milligram per kilogram would be 40 milligrams. I'm going to stick to my math. That should be right.”

    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. “It depends really whether it's a clinical or research procedure. So when we do research with ketamine, we give a bolus and then a slow infusion to maintain that peak level of ketamine throughout the test period, because this gives us a longer period of time where the brain has a steady exposure for cadamine where we can really do brain imaging studies or psychological testing and things like that. When you get a bolus acadamine, it's like jumping into a cold pool of water. One person told me he felt like he was rocketed out of the universe when he got a big bolus right up because you get the full effects within about 30. Seconds or a minute of the infusion, whereas if you get the slow infusion in the traditional way, it's like wading into a pool. And so you gradually, gradually get the effects, and it's much less disorient”

    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. “Effects and still get some efficacy. So it's a really narrow range. I mean, if you think about almost any medication that you take aspirin, people take two aspirin, right? So it would be as if you went down to one aspirin, you get no effect. And if you took two aspirins, it would knock you out. So with the 40 minute intravenous infusion of ketamine, it's really a very narrow window where it really works. And this is really important because there are some preparations that are being developed that might be oral where the whole point of the treatment is to achieve a lower dose, not to achieve the kind of blood level that you get with the zero point five milligram per kilogram intravenous dose. And we don't know if those treatments are effective for various conditions or not really at this point. But whatever they're doing, they're not doing what 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

  44. “We have the most information for a 40 minute intravenous infusion. So the 40 minute intravenous infusion dose that we most commonly use is 0.5 milligrams per kilogram. And I'm told that there are some people who are very unresponsive to the 0.5 milligram per kilogram dose. I've heard that there are some cases where you would go to 0.6 or 0.7 and can sometimes get a good effect. People generally don't go much higher than that. And similarly, generally speaking, if you go much lower than 0.5 milligrams, for example, down to 0.2 milligrams, it's hardly effective for anyone. There are some people who are extremely sensitive to 0.5 where you can dial it down a little bit, maybe 0.4 milligrams per kilogram, and have a less size.”

    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. “Where a lot of people are a reasonably large number of people with not PTSD but major depression will have a major clinical response just to the pharmacologic effect of the drug, even if no Reactivating of memories happens during the infusion.”

    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. “The impact of those memories, and we think that that can be helpful. That's maybe relevant to some addictions, it may be relevant to BTSD, and particularly relevant to PTSD because in a large, for it's kind of large study that we published this year with about 50 patients in a group where we compared standard dose ketamine to a lower dose ketamine to placebo in people with military related PTSD, that we found that there was a robust antidepressant effect, but a really weak and didn't quite meet statistical significance effect on the core PTSD centers. So it may be that if you want just the antidepressant effect, you can just give a dose a ketamine to people with PTSD. But if you want the full-blown maximal impact on PTSD, you may have to activate the trauma memories in the context of the ketamine infusion to get the full benefit. And that seems to be different than major 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

  47. “And we think that every time you activate a memory, you put that memory into a somewhat labile state. In other words, you can strengthen the impact of that memory by rehearsing it in a negative way. And in fact, we think that's part of how PTSD develops. You have a negative trauma memory, you bring it up, you rehearse it, it gets more powerful, it has a bigger impact on your life. You do that over and over again in the whole narrative starts to be integrated in your life like a bad habit and your reaction and expectation of trauma becomes triggered every time that memory gets activated. The same thing is like an addiction. Use the alcohol you like it. Use it again. You like a little bit more. And you are using it over and over and over in those alcohol-related memories have more and more power in the way you think and the way you act. And so by interfering with neuroplasticity and preventing that strengthening process, you actually weaken.”

    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. “This is one of the kind of really interesting byproducts of kadamine in relation to other drugs like the psychedelics. So ketamine, because it blocks the NMDA glutamate receptor, blocks certain forms of neuroplasticity in the brain.”

    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. “memory during ketamine, you tend to reduce the potency of that memory. For a long period of time, surprising period of time after the event. And what we don't yet know is how it fits in the overall treatment of these folks in the sense that there are some signs that you can reduce the potency of a particular trauma memory so that you can talk about the worst event that ever happened and now it doesn't trigger a whole exacerbation of their PTSD symptoms, but it doesn't necessarily resolve the broader issues. And this is partly a bit about what I'm talking about, about the broader psychotherapy. And people are trying to develop that into a treatment for alcohol use disorder.”

    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. “That treatment would in some way rob them of their trauma memories and impede their overall ability to be advocates for the groups that they're often committed to. In other words, say combat veterans to their fellow combat veterans or rape survivors to other rape survivors. And oftentimes they believe that the trauma memories are a burden, but in some ways valuable to them. And I would want to reassure anybody who is in that kind of state that we're not talking about removing or deleting memories in any way, that all we're trying to do is to reduce the intensity of these memories so that they don't interfere with the ability to achieve things in life and they don't fear with quality of life. So if you activate a trauma memory or an alcohol, or say for alcohol use disorder,”

    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