Tim FerrissAll Things Ketamine — The Most Comprehensive Podcast Episode Ever with Dr. John Krystal
EVERY SPOKEN WORD
150 min read · 30,064 words- 0:00 – 3:08
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- TFTim Ferriss
Hello, boys and girls, ladies and germs. This is Tim Ferriss, and welcome to another episode of The Tim Ferriss Show. This is an episode I've wanted to record for several years. I've been asked many times, dozens of times, possibly hundreds of times, about ketamine, and this is intended to be the most comprehensive, in-depth coverage of ketamine in the podcast space. It is intended to be your one-stop shopping or at least your first stop in all things ketamine. We get deep in the weeds, so if you get lost at any point or start to drift because it's technical, just wait two to five minutes and we almost always explain things or shift gears. And the reason also that I wanted to do this episode is that I know friends who have averted suicide using supervised ketamine, and that is reason enough for me to want to put this together. My guest today is the incredible John Krystal. Dr. John Krystal is the Robert L. McNeil, Jr. Professor of Translational Research, Professor of Psychiatry, Neuroscience & Psychology, Chair of the Department of Psychiatry at Yale University, and the Chief of Psychiatry and Behavioral Health at Yale New Haven Hospital. Dr. Krystal is a leading expert in the areas of alcoholism, post-traumatic stress disorder, schizophrenia, and depression. His work links psychopharmacology, neuroimaging, molecular genetics, and computational neuroscience to study the neurobiology and treatment of these disorders. And he is very fluent, well-versed in many other things. But he is best known for leading the discovery of the rapid antidepressant effects of ketamine in depressed patients. He co-directs the Yale Center for Clinical Investigation, CTSA, NIAAA Center for Translational Neuroscience of Alcoholism, and Clinical Neuroscience Division of the National Center for PTSD. Dr. Krystal's a member of the US National Academy of Medicine, co-director of the Neuroscience Forum of the US National Academies of Sciences, Engineering, and Medicine, fellow of the American Association for the Advancement of Science, and editor of Biological Psychiatry, one of the most selective and highly cited journals in the field of psychiatric neuroscience. He's the co-founder and chief scientific officer of Freedom Biosciences, which you can find at freedombio.co, a clinical stage biotechnology platform developing next generation ketamine and psychedelic therapeutics that just recently emerged from stealth in August of 2022. One very important disclaimer. I'm not a doctor, nor do I play one on the internet. None of the content in this podcast constitutes medical advice or should be construed as a recommendation to use ketamine or psychedelics. There are psychological, physical, and sometimes legal risks with such usage. You have to be smart. You have to consult experts. Please consult your doctor before considering anything we discuss in this episode. And with all of that said, please enjoy my very in-depth, very wide-ranging, very nuanced, and I give that credit to Dr. Krystal, conversation with Dr. John Krystal. [upbeat music]
- 3:08 – 11:28
The challenges faced by John’s late father, Henry Krystal.
- TFTim Ferriss
Dr. Krystal, it is good to see you again. Thank you for making the time for this conversation. I really appreciate it.
- JKDr. John Krystal
Well, my pleasure.
- TFTim Ferriss
And I thought we would start with the personal. We're going to get into the scientific. I've been looking forward to this conversation for a long time, as I mentioned to you before recording, because I, I really think this will be an incredible resource for people. But I'd like to begin with some of your personal history. Could you please describe for people listening, and for me, your father and some of his bio and history?
- JKDr. John Krystal
My father was a psychiatrist and psychoanalyst named Henry Krystal, and h- he passed away a number of years ago. He was born in the town of Sosnowiec in Poland in 1925, and at, at the age of 14, was captured by the Nazis, who were rounding up the Jews in his area of Poland, and sent through a series of, uh, concentration camps. Importantly, you know, names people would probably recognize would be Auschwitz, Sachsenhausen, Buchenwald. And he survived the concentration camps, and he was the only member of his family to survive. So he was captured at the age of 14, and by 17, 18, when he came out of the, out of the camps, was a- alone in the world, essentially. He went to school, attained some schooling in Germany, and then came to the United States, where he had a, an aunt who put him up. And, and I grew up with stories of him sleeping in the cellar of her convenience store around the pickle jars that would spontaneously explode during the night-
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
... because for whatever reason, they were, uh, very potent. And, uh, he was able to get a scholarship to Wayne State University for college and then another scholarship to go to medical school. And, you know, along the way, he mastered English and, uh, you know, uh, settled into the United States. And he became very powerfully influenced by the chairman of the Department of Psychiatry at Wayne State University, whose name was John Dorsey, who h- had been analyzed by Freud, whose view of, of psychiatry was-- had to do with people em- embracing all aspects of themselves and becoming kind of integrated human beings and- And that that was a path towards both a healthy life and a, and a fulfilling life, uh, which was an idea that my father, uh, also not only embraced in his work, but embraced in, in, in his life. And ironically, my name is John, J-O-H-N, which is not commonly the name given to Jewish children, who are often named Jonathan instead. But I'm called John because I'm named after Dr. Dorsey, who was Irish.
- TFTim Ferriss
Mm.
- JKDr. John Krystal
So my dad became a psychiatrist and in his work evaluated people who survived the Holocaust for reparations to the German government. And this was both an incredibly meaningful task, but also one that was extremely challenging for many reasons. One is that he had to relive his own traumas in the process of working with the more than 1,000 people that he evaluated for reparations from the German government for their traumas. And the second thing was that he was in a nearly impossible position, which was that he was evaluating people for psychological damages related to their Holocaust experience. And this was in the, in the 1950s, 1960s, almost 30 years, 20 years before the diagnosis of a post-traumatic stress disorder existed. And what happened was that he and a colleague of his, his, Bill Niederland from New York, they developed this idea of survivor syndrome, of the psychological consequences of trauma that became one of the cornerstones, uh, along with the work of many others, such as Robert J. Lifton, for what became the diagnosis of post-traumatic stress disorder. And his work throughout his career about the-- trying to u-understand the roots of, of resilience and vulnerability and to develop treatments that would help people to manage the impact of psychological traumas, that was his life work and, and profoundly inspiring for me. I've always felt that there was no challenge that I could ever face, no obstacle that I could ever meet that was-- would ever match the challenges that my father's father faced in his life. And the kind of perspective that my dad brought to his own life challenges, his-- the way that he survived in the concentration camps, of recognizing and seizing opportunities that arose for him and, and realizing what was happening and, and seizing these kinds of opportunities which enabled him to survive, were also profound life lessons that in pursuing what one was working on, that you had to get outside of the constraints that the environment placed on you and recognize the nascent opportunities out there, no matter how out of the box and how unorthodox they were, in order to have a real impact. That was a key to my father's survival, but it was also a key for the way my father turned this process of evaluating people for disability pensions, turned that into the foundation for helping to open up the field of, of post-traumatic stress disorder and have a huge positive impact. So I have no doubt that my father's life experience and the way that he developed his career profoundly impacted me and my thinking and the things that I, I thought were important and, and what I ended up pursuing and the way that I'm pursuing them. The other thing about my father was he was profoundly curious-
- TFTim Ferriss
Mm
- JKDr. John Krystal
... and would read religions. He would read history. He would read s- neuroscience. He would read philosophy. He would pursue almost any field that he, that he thought had any relevance to what he was thinking about. And that perspective also was normally incredibly impactful for me and has influenced the way I approach everything that I do.
- TFTim Ferriss
Mm.
- 11:28 – 15:05
Was Henry’s work discussed around the Krystal dinner table?
- TFTim Ferriss
Thank you for sharing that, John. And it's, uh, part of the fabric of who you are also, these stories, and I had no idea of this background, of course. I mean, one of the great gifts that I get from these conversations is the excuse to do what would otherwise be very creepy in terms of due diligence on my f- [chuckles] friends or people that I know. And I'd love to ask you a bit more about your father. And I'm pulling from, in this case, a New York Times piece, which I, I believe was, you know, effectively upon your father's passing. And I'll just read a, a short section here that will lead into the question. So he, this is your father, "attributed the survival of some inmates to an almost childlike belief in their own indomitability." And then the quote is from your father. You know, "I feel that, quote-unquote, 'Healthy infantile omnipotence is the most important asset for dealing with life's stresses and potential trauma,' Dr. Krystal wrote in a chapter he contributed to Living with Terror, Working with Trauma: A Clinician's Handbook. [inhales] And I'll shorten this to end the quote with, "It is an emotional mainspring of extraordinary reserves. It provides a profound, unshakable conviction of one's invulnerability." Is that something that he ever discussed with you or fostered in you? I would love to, to hear anything that comes to mind.
- JKDr. John Krystal
First, I want to reassure you that he was, like, a normal person, and so, like, he would never talk about the omnipotent, uh, uh, interjected object at the dining room table.
- TFTim Ferriss
[laughs] Right.
- JKDr. John Krystal
You can imagine people have all kinds of ideas about what psychoanalysts talk about over dinner, and mostly-
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
... it was just bread and butter things. The second thing is that he believed that the parent-child interaction was fundamental to all human resilience, and in that kind of nurturing, supportive interaction lay the root of optimism. And having a sense that no matter what is happening around you, that there's still the possibility that things will work out okay is an enormous gift that comes out of this kind of nurturing developmental experience. And so much of what he dealt with in treating people who had been traumatized in psychoanalysis and in psychotherapy was the way that early life traumas disrupt that and create a feeling not of optimism and the potential for things to work out, but the opposite, that in the expectation that the world is a dangerous, threatening place and that failure lurks around the corner. And so creating the very constraints on creativity and motivation, deadening hope, deadening creativity, constraining opportunities, that people are putting this cage on themselves as a consequence of the disruption of the sense of safety and possibility that i- is a natural byproduct of a nurturing childhood experience.
- 15:05 – 23:35
What people frequently misunderstand about depression.
- TFTim Ferriss
Well, let's use that as a perfect leaping point to hop into some of the, you say, the salt and bread, the meat and potatoes [laughs] of some of the subjects that we'll cover. Because looking at, at your bio, just as an example, right? Dr. Krystal's a leading expert in the areas of alcoholism, post-traumatic stress disorder, schizophrenia, and depression. It sounds like a roll call for one of my family reunions. [laughs]
- JKDr. John Krystal
[laughs]
- TFTim Ferriss
And I certainly, if people are not aware, I'll just provide a little context, have experienced chronic, or let me call it repeated, but also a very severe depression throughout my life. It appears to be hereditary. And as you mentioned, there are people for whom despair instead of hope is a default setting or feels like a default setting, and there can be, say, a catalyzing event where in my lived experience, there might be a situation that provokes, or I should say, that I allow to provoke a feeling of despair, hopelessness. And then I'm able to observe the mindset and objectively perhaps think, "This shouldn't bother me so much. This is a failure of imagination. There are friends of mine, people I know, who would deal with this with complete equanimity," and then there's hopelessness about ever changing the mindset, and I think that is the scariest part. [inhales] So perhaps we could begin with just a, a brief discussion, doesn't have to be brief, about depression and perhaps what people underestimate, don't appreciate about depression, what you have come to realize perhaps as a clinician over many decades, just to set the table, as it were, for our discussion of different treatments, comparisons, ketamine, et cetera.
- JKDr. John Krystal
I think that people think that depression is like having a bad day. And everybody's had a bad day, and everybody's had a few bad days. And, and I think that some of the confusion about depression has to do with the way in which we use-- throw depression around as a term like, "I spilled my coffee and I'm depressed about that." Now, yeah, that is a disappointment, right? But that kind of experience isn't what we're talking about when we talk about depression. When we talk about depression, it's more about the experience that you're talking about. The way that depression can be a pervasive mode of being that invades every aspect of one's life and experience of the world. It affects the pattern of your thinking. In other words, instead of, as you say, instead of seeing the world as a mixture of risk and opportunity, you see the negative in everything that you engage. It affects the way you make judgments. Instead of being able to make judgments based on reasonable risk/reward kinds of decisions, everything's colored by the negativity. What people often don't appreciate about depression is that it goes beyond sadness. For many people, it can be a complete blunting of emotional experience, and people describe sometimes the loss of feeling. One of the people that we treated with ketamine said that she was just amazed to have feelings again after her depression began to lift. People often describe feeling blue when they're depressed because the contrasts in the world, their visual experience of the world is as if the, the normal contrasts are blunted and, and colors seem duller and, and things that are exciting and rewarding seem blander and a kind of sapping of life's essence. This kind of depression is associated with a loss of energy, a loss of concentration, difficulty sleeping, waking up early in the morning, tossing and turning, and difficulty relaxing and feeling comfortable. Being overcome with pervasive, intrusive, recurring thoughts on negative things like, "I'm a terrible person. I let people down," over and over and over, ruminating on these negative, horrible ideas. And I mentioned a sapping of energy, loss of appetite, decreased interest in activities, a kind of withdrawal. This state was deemed by the Greek Hippocratic doctors as, as a kind of fundamental negative mode of being that they l- thought was connected to black bile, which in Greek had the name melain for black, chole for bile.
- TFTim Ferriss
Huh.
- JKDr. John Krystal
And then has been known as melancholia or black melancholic depression ever since. And there's another kind of depression that we also see, which is people who have the capacity to see good and bad but who cannot constrain the way in which they react. So something good happens, they can react in a normal way to it, but something bad happens to them and they spiral downward in a very negative way out, out of beyond their control to despair and hopelessness and, uh, extreme distress. That is not the typical profile of traditional melancholic depression but is a kind of reactive depression, so that there... One of the things that we appreciate about depression is that it can be a very heterogeneous things, that there's a whole array of different kinds of depression, and we're just at the early stages of, uh, sorting that out. But one thing that's really important for people to understand that they often don't understand is the medical part of depression. And when I say medical part, is that, that we understand, yes, medical depression is a state of emotional experience, and yes, it's a altered way of brain function, but it's a brain function of an embodied brain. In other words, depression is a state that affects your entire body. Medical factors like inflammatory processes in the body related to obesity, cardiac disease, arthritis, asthma, a variety of things that cause inflammation in the body increase your risk for depression. And if you have depression, it makes inflammation worse, and that means it makes all of those medical illnesses where inflammation is a process worse. And so that if you have untreated depression, on average, it shortens your life, not by suicide. It still shortens your life by about five years.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
And if you have depression in the context of, of medical illnesses, it makes the medical outcomes worse. Not only the psychological outcomes, but the medical outcomes worse. So medi... depression is a disorder of the spirit, if you will, the brain, but also the whole body. And, and that's one of the reasons why, number one, it's one of the most disabling conditions that we have in the world, and two, it's from a medical point of view, it's also urgently important that people are treating their depression.
- 23:35 – 30:22
Why partial response and non-response occur commonly in psychiatry.
- TFTim Ferriss
One thing you and I spoke about a little bit before recording that I'd love for you to touch on is perhaps the, the high frequency with which you have observed partial recovery and not full recovery or partial treatment and not full treatment. Perhaps if, if you could just speak to that.
- JKDr. John Krystal
So psychiatry has struggled with what to do with partial response and non-response for all psychiatric disorders. And I'm embarrassed to say that there is a strain of a history in psychiatry when patients didn't get better that they blame the patient. In other words, they would say things like, "Well, the patient wasn't adequately engaged in treatment. They didn't engage in psychotherapy. They weren't a good psychotherapy candidate. They didn't blah, blah, blah." And while it's true that people engage in treatment with varying levels of motivation and understanding and things like that, we would never say for a heart attack, for heart disease, "Well, you know, they had a heart attack, but they, you know, they weren't very motivated to be in treatment, so what could we do?" We would never say that. We would always say, "Well, let's look at the illness. Let's try to optimize the treatment, and if people aren't responding, let's do something about that." That the field of psychiatry hasn't always taken ownership for the fact that our treatments don't always work as effectively as we'd like them to be. Now, there are some underlying reasons why that tends to happen a little bit more in psychiatry than in some other aspects of medicine. One of them is that there's just inadequate support for psychiatry mental health treatment generally. So it's a scarce resource, and people often essentially take what they can get. And that speaks to the inadequacy of our national approach to making sure that people have access to effective healthcare. A second thing is we don't measure outcomes in clinical practice in any kind of routine way. In other words, if you have a heart attack, then you get scans, and they measure the EKG, the electrical activity of your heart. Maybe you have a stress test. Maybe you have an echocardiogram to measure the ability of your heart to contract. Well, where are those tests in psychiatry? Those tests, to the extent that we have them, are basically brief questionnaires that people can complete to give us some semi-quantitative idea about how people are doing. But those outcome measures aren't routinely applied in clinical practice. And so that as a field, when we look at our healthcare systems, there's no data on outcomes for the clinical interventions or much less data on outcomes. Some healthcare systems like the VA have started to embed clinical ratings into clinical care. But it's not a situation where the field has been held accountable for the outcomes. And the field hasn't been held accountable for outcomes. The insurance companies have not been held accountable for the outcomes. The country has not been held accountable for outcomes. And that has been particularly problematic for depression for a number of reasons. One of the reasons is the invisibility of inadequate responses. So what can happen is that people will start treatment. Maybe they start treatment with psychotherapy, and maybe the treatment is somewhat helpful for them, but it hasn't worked entirely. And then maybe they then add a medication to the psychotherapy, and maybe that medication is somewhat helpful, but not entirely. But the person has gone from an eight out of 10 to a five out of 10. So they're substantially better than they started off, but they're substantially symptomatic and in ways that take a toll on them, their social relationships, their work productivity. So why is it invisible? It's invisible because both the doctor and the patient have worked really hard over a long period of time to get to the point where they're only a five. And there is justifiably a sense of accomplishment and investment in that new status quo. But what there is though is a failure to say, "Have I exhausted all possible outcomes to go from a five out of 10 to a two out of 10?" And the answer is in most cases, the possible outcomes have not been explored. And this is really important. We have to keep pressing because not only is there a possibility of adding another kind of treatment that would be making the patient better, but there is also the possibility that we might need to remove a medication that's interfering with resilience and recovery. The other thing is that we are in a country which has restricted the availability of certain what are so-called gold standard or definitive treatments. And one of those would be electroconvulsive therapy. Now, electroconvulsive therapy we know is somewhat controversial in areas. It's obviously a treatment that has both medical and in some cases cognitive risks for patients. On the other hand, what's often appreciated and one of the reasons I mentioned the medical risks of depression is that depression when untreated has medical and cognitive risks at all that have to be balanced against the risks and benefits of these treatments. But the number of sites that administer electroconvulsive therapy has been progressively decreasing in this country, which means that access to this treatment has become progressively limited even though for people who fail to respond to multiple different kinds of medications, electroconvulsive therapy is sometimes the only treatment that
- 30:22 – 33:26
From the serotonin hypothesis to “what’s really exciting” about antidepression research.
- JKDr. John Krystal
will work.
- TFTim Ferriss
So let's, if you're open to it, John, give people also a preview of maybe some, some light at the end of the tunnel. We're going to talk more about some of the biological bases or perhaps mistaken hypotheses about biological bases of depression. But could you give us just a, a preview of, as it stands today, what excites you about some of the findings related to ketamine as compared to other treatment modalities? And then I'm gonna come back to, uh, and perhaps this will be part of your answer, but limitations of the serotonin hypothesis, right? Which has been pervasive. Certainly it has become in, on, on some levels a hypothesis that even laypeople will throw around very casually. But I would love to know what excites you about ketamine and sort of variants thereof.
- JKDr. John Krystal
If you don't mind, I might track the historical story-
- TFTim Ferriss
Let's do it
- JKDr. John Krystal
... because it's really takes us from the serotonin hypothesis to what's really exciting. And I told you this before, and I really believe it, that this is the most exciting scientific time in the entire history of the field of psychiatry, that we have been operating in some ways in the dark with not a very good understanding of what's happening in the brain for the last 60 years. And, and the sunlight is really just beginning to penetrate into, to our understanding of the brain in ways that are relevant to thinking about the biology and treatment of depression and, and other kinds of issues. So, so the serotonin story, the serotonin hypothesis really emerged from the appreciation of the effectiveness of antidepressant medication treatments. You know, the first, the first antidepressant that we had, which was discovered in 1957, which makes it one year older than I am [laughs] was a drug called a monoamine oxidase inhibitor, a drug that prevented the breakdown of, uh, norepinephrine and serotonin, two chemicals ha- that have been implicated in depression. And it's a great story because the first monoamine inhibitor given to depressed patients was given accidentally because it was a treatment for tuberculosis, and they discovered that the tuberculosis patients, their tuberculosis was getting better, but so was their depression.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
And that's how they discovered that first antidepressant. Then they discovered through a similar, a little bit accidental path, the tricyclic antidepressants, then much later in the 1980s, the SSRIs, which are like the tricyclic antidepressants, but act in a more narrow and specific way in the brain to block serotonin
- 33:26 – 35:02
How monoamine oxidase inhibitors reduce symptoms of depression.
- JKDr. John Krystal
reuptake.
- TFTim Ferriss
John, before we move on, and I don't wanna throw us off track, so we're at tricyclic and then we're gonna move forward in the chronology, but I'm so curious. Could you just briefly explain the mechanism by which MAO inhibitors improve or s- I should say reduce symptoms of depression? What is actually happening there?
- JKDr. John Krystal
So the way that monoamine oxidase inhibitors work is by an inhibiting an enzyme called monoamine oxidase, which is involved in the breakdown, uh, the metabolism of the chemicals norepinephrine and serotonin. And so when you give a monoamine oxidase inhibitor, you raise the level of serotonin and norepinephrine in the synapse, the space between nerve cells, and you increase the stimulation of the receptors for those, those chemicals. And in that way, they're a little bit like the SSRIs, which instead of preventing the breakdown, they prevent cells from taking up out of the synaptic space these same chemicals. The monoamine oxidase inhibitors also release a bit norepinephrine and serotonin so that they release a little bit and they prevent the uptakes. They're actually powerful antidepressant, and they have some side effects and risks that have limited their use in modern clinical practice. But in the era in which I trained
- 35:02 – 37:23
MAOI Side effects and risks.
- JKDr. John Krystal
were very commonly prescribed.
- TFTim Ferriss
What are the main risks and side effects? And this is tying into something that's, uh, been recently on my mind, which I'll, I'll bring up in a second, then we'll hop back into the chronology. I won't lose track.
- JKDr. John Krystal
Sure.
- TFTim Ferriss
But what were the side effects and, uh, what are some of the risks of those monoamine ec- oxidase inhibitors?
- JKDr. John Krystal
As you recall, these monoamine oxidase inhibitors cause a form of release of norepinephrine and serotonin and prevent their breakdown. So anything that independent of the m- drug increased the release of norepinephrine and serotonin had the potential to produce massive increases in norepinephrine and serotonin in the body. And so the problem you get in if you have a massive increase in norepinephrine is you can get big increases in blood pressure that can, can be life-threatening.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
And if you get a big increase in serotonin, you can develop something called a serotonin syndrome, which can also be very serious medically. It raises body temperature and creates a stress on the system. And the thing was that the kinds of things that most commonly were a problem is that there's a compound in aged cheese, in wines, in lots of really gr- things that people really enjoy eating that has... These kinds of foods have a lot of tyramine. And so people would like Be on a monoamine oxidase inhibitor and have several glasses of Chianti with a cheese pizza with lots of cheese on it, aged cheese, and then their blood pressure would go through the roof. And some people would even, you know, have a, a negative, a really bad complication like a stroke or something like that. That happened vanishingly, extraordinarily rarely. And plus these medications can interact with certain medications. A particular worrisome interaction was they're involved with the metabolism of meperidine or Demerol. And so there, there was a famous case in New York of someone who was on a monoamine oxidase inhibitor, uh, who was then given Demerol in the emergency room and then, and then died from the interaction.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
So they're really great drugs, but you'd have to, have to be a little careful
- 37:23 – 40:29
When Western medicine duplicates centuries-old shamanic wisdom.
- JKDr. John Krystal
with them.
- TFTim Ferriss
So the reason I'm doing some digging on this is... Well, there, there, there are several reasons. The first is that there's a, there's a collection of presentations from a symposium called ESPD 50, which investigated specifically a monoamine oxidase inhibitor called harmine. And the reason they were looking at harmine is because harmine, harmaline, and, uh, I believe there's at least one other monoamine oxidase that we've identified exist in the Banisteriopsis caapi vine, which is one of the two typical ingredients in ayahuasca. And the reason-
- JKDr. John Krystal
And the reason-
- TFTim Ferriss
... that I bring it up is that for a long time, for simplicity, I'll just say Western scientists largely dismissed the vine and ascribed to it one purpose, and that was to render the NN DMT found in chacruna. They're the leaves of this shrub orally available so that people could have these visionary experiences. Lo and behold, a number of things are true or appear to be true. One is that the vine itself and these monoamine oxidase inhibitors, which should not be a surprise to you at all, it wouldn't be, have in and of themselves therapeutic effects, including increasing brain-derived neurotrophic factor or BDNF. [laughs] So that's part one. Part two is, and I did not realize this, but you were just discussing aged cheese, wine, and the tyramine content and the contraindications that can come of that. Well, some, again, for simplicity, Western scientists have also dismissed what are sometimes referred to as dietas or preparatory diets related to ayahuasca consumption. And for hundreds and thousands of years at least, so we believe, given some of the carbon dating that has been done in places like Chile, although with different compounds, but sort of, um, outcome related, there are restrictions. There are food restrictions that include cheese and [laughs] uh, fermented products. I don't know the tyramine content of fermented foods-
- JKDr. John Krystal
Yeah
- TFTim Ferriss
... but certainly alcohol prohibitions, and these have been, and still are by many people dismissed as pure superstition. Well, it turns out that jungle biochemists who have had the opportunity to run trial and error for f- [laughs] at least a few hundred years may have figured out a few things. Which is not to say there aren't tremendous amounts of superstition in many of these traditions. There are. But I do find the duplication on these two [laughs] lists to be notable. So that's, that's why, that's why I bring it up. So to come back to the, the chronology-
- JKDr. John Krystal
Yeah
- TFTim Ferriss
... you went from the MAO inhibitors to tricyclic antidepressants, and then we're, we were moving closer to present day, if you wouldn't mind
- 40:29 – 45:03
How pre-imaging neuroscience of the ’80s was like Ptolemaic astronomy.
- TFTim Ferriss
continuing.
- JKDr. John Krystal
So my colleagues, the people that I trained with and, and have had my career with, in particular my mentor, Dennis Charney, with whom we did the first ketamine study, you know, they spent their careers trying to figure out what was the role of these chemicals, serotonin and norepinephrine, in depression and, and antidepressant treatment. And this was an era of really clever, creative psychopharmacology research. It's before CAT scans, before MRI, before fMRI, before PET scans, before any of that. And they had to use pharmacology and measuring neuroendocrine responses and behavior as a way to try to figure out what was going on in the brain.
- TFTim Ferriss
So just to pause for a second. So for people who may not know the acronyms, we're talking about basically a lack of imaging. So you have an inability to look inside the brain, so you're trying to... It's, if I'm hearing you correctly, you're trying to infer what is happening inside by observing what is happening outside. Is that a fair way to put it?
- JKDr. John Krystal
So the brain is perhaps the most complex structure in the entire universe, and you're trying to draw inferences about what's happening in certain connections by whether when you give a drug, does the cortisol level go up? Does the prolactin level go down? Does it... Like, so it's really rough and ready neuroscience, and it's a little bit like Ptolemaic astronomy in the sense that you have no understanding about really how the universe is constructed, and yet remarkably, the Ptolemaic astronomers could build elaborate explanatory systems to explain how the planets were moving in relation to each, each other. And that's really where psychiatry was, you know, in the '80s. And, and this was the leading edge of mechanistic research. In other words, the first, in some ways, kinds of mechanistic research going on in psychiatry. And what they figured out in building on the work of an alum, a graduate of our, our department who, who moved to McGill, Claude de Montigny, they developed a strategy for depleting the body of serotonin. It builds on the idea that tryptophan, which is the precursor for serotonin, is an essential amino acid. So if you deplete the body of free tryptophan, then the body, all over the body, you can't make any more serotonin, and you can drop the level of serotonin in the blood and in the body and in the brain. So-- and we could use that technique. Pedro Delgado really led the, the clinical projects in those days. You could use that technique to ask first the question, which is such a fundamental question but had not yet been answered, is serotonin necessary for the antidepressant effects of Prozac, right? Couldn't be a more basic question, but we didn't know.
- SPSpeaker
Yeah.
- JKDr. John Krystal
So what Pedro did was to deplete the body of serotonin using this tryptophan depletion technique, which involved giving all the other amino acids, tryptophan restricting, and then giving all the, uh, other amino acids to drive protein synthesis and use up all the free tryptophan, so it couldn't be used to make serotonin, dropping the serotonin levels and producing a brief relapse of depression. And so you could show that the antidepressant effects of drugs like Prozac depended on the ability of the brain to, in, on an ongoing way, to have a, a big supply of serotonin, right? And that was really important, and it really supported mechanistic ideas that had already been underway in a series of pioneering laboratories around the country, including the laboratory of George Agajanian at Yale, that at neuroadaptations associated with serotonin synapses really underlay the antidepressant effects as an initial and on, in some ways, ongoing mechanism of action for the SSRI antidepressants like Prozac. But when you depleted serotonin in healthy people, you did not make them depressed.
- 45:03 – 47:32
The reason for depression isn’t as simple as a lack of serotonin.
- SPSpeaker
Mm.
- JKDr. John Krystal
So there had been an idea floating around that depression was a manifestation of a pure deficit in serotonin. Lower serotonin, you get depressed. Take a Prozac, you get undepressed. We knew that idea was wrong right from the start because you take a tablet of Prozac, you do not get undepressed from a single tablet of Prozac. It can happen. It's extraordinarily rare. Doesn't-- and it usually doesn't last when that occurs. But the world is really complicated, and I'll-- and maybe we'll come back to it, and what's complicated is that serotonin does have a lot of acute effects in the brain, and a single dose of Prozac does change some things. So for example, Catherine Harmer at the University of Oxford in the United Kingdom has done a large number of studies to show that some of the negative biases that people have when they're depressed go away, at least transiently, with a single dose of Prozac.
- SPSpeaker
Hmm.
- JKDr. John Krystal
So it's not that there aren't some acute effects and that those effects aren't related to, to depression. It's just that this simple-minded idea that low depression, low serotonin equals depression, normal serotonin equals a healthy life, that idea is-- we knew pretty much from the start couldn't possibly, uh, be true as it was initially suggested. The other thing I'll say just before moving on, because there's a tendency to want to make the world simple. Either it's all serotonin or it's no serotonin. But as I said, would the most complex structure in the universe really work in such a simple-minded way that it had to be everything or nothing? Probably not. And there are brain scan studies in depression involving positron emission tomography, the work of people like Ramin Parsa and, and others, that do find some changes in the regulation of certain serotonin receptors that may be intrinsic to the biology of, of depression. So I'm not in any way arguing for a really simple-minded, uh,
- 47:32 – 52:57
The change in perspective that illustrated ketamine as a potential therapy.
- JKDr. John Krystal
idea of depression. But I do want to highlight that these, these monoamine depletion studies were a conceptual crisis, like the philosopher Thomas Kuhn would say. You come to a point where you have a body of theory, and then you have a single experiment which in a fundamental way challenges the idea that this idea that depression is simply a disorder of the very primitive and very few number of serotonin cells that live in a very primitive part of the brain, the midbrain and a little bit of the brain stem, that these primitive cells could be the cause of this pervasive syndrome of cognitive behavioral, um, et cetera, et cetera, impairment probably was... You know, just that idea itself was probably flawed from the start. But like all conceptual crises, it was incredibly stimulating in terms of creative thought about what the alternative ideas about depression were. And, and so in those days when these experiments were going on, Dennis Charney, who was the-- my, now my boss [chuckles] as well as my collaborator, his office was upstairs on the ninth floor. He had a really good view of Long Island Sound, and I had a l- little office on the eighth floor. And, you know, I would go up at the end of the day and we would talk about science and all the things that are going on. And we wrestled with this. This is one of the things that we wrestled with a lot. If it wasn't serotonin, simply, what could it be, right? And the answer was that we came to was, let's turn the brain on, on its head. Gosh, that's a really weird turn of phrase.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
But let's turn this problem upside down. If depression isn't a disorder of these really simple and few serotonin cells in the brain, then maybe it's an, a disorder that has a major part of its biology in the parts of the brain that are responsible for regulating emotion, for processing reward, for making plans, for interpreting the world. In other words, the higher cognitive centers like the cortex, cerebral cortex, and the higher emotional centers in the limbic system. And there was a profound consequence of that small conceptual shift because the cortex and the limbic system are predominantly driven by different chemical messengers than serotonin and norepinephrine. Serotonin and norepinephrine tune and, and modulate the activities of the higher brain centers. But it pulled us to think about the intrinsic circuit mechanisms of the cortex and limbic system and to try to approach those circuits directly with pharmacology.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
These higher brain centers predominantly use two neurotransmitters, glutamate, which accounts for something like ninety percent of the synapses of the brain, right? The main information highway of the brain, ninety percent of the synapses, the main excitatory driver for brain activity. And GABA, which is the main inhibitory transmitter of, of the cortex. The function of the cerebral cortex and limbic system is essentially a dynamic tension, like yin and yang, between factors driving excitation and the magnitude of excitation and the timing of excitation and the spatial dispersion of activity in the brain and GABA balancing inin- inhibition. And we thought, well, gee, how can we tap into signaling through the main information highway of the brain? And it's really remarkable, isn't it? Serotonin is maybe a couple of percentages of the synapses in the brain. Glutamate is ninety percent. Psychiatry had been studying depression for fifty years by that point, put all of its chips on serotonin and norepinephrine, the two percent.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
And completely ignoring the ninety-eight percent of the other mechanisms in the brain. So we thought, "Well, let's try that." So by that time, I had been studying for at least five years. I had been studying ketamine to try to understand its role in synaptic signaling in disorders, problems, cognitive processes, behavior, other things related to schizophrenia. And we thought, "Well, we can use ketamine to probe the integrity of glutamate synaptic signaling. That's been what I've been working on for the last five years. Let's bring that into testing depression."
- 52:57 – 1:01:33
From first studies to overcoming skepticism.
- JKDr. John Krystal
And we designed a study, and we gave ketamine to depressed patients. And ketamine did transiently produce some, you know, cognitive impairment and some changes and things like that, lasted, you know, an hour or so. And then those effects went away. And, you know, we saw nothing special. Ketamine has the same kind of effects in depression as it does in healthy subjects. And then the day, test day wore on. And within a couple of hours, people said, "You know, I'm feeling a little better." We thought, "Right. You're feeling a little better. Great. Fantastic." And then we sent them home. And then we called them the next day. "Did you have any bad effects from your ketamine exposure? W- d- do you have any hangover? Do you have any lasting effects? Did you sleep okay the night before?" And they said, "You know what? My depression's all better."
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
And we said, "What?"
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
Uh, okay. We know that these kinds of things happen. You know, you give somebody a glass of tea and the next morning a cup of coffee, a, uh, really good croissant, and the next day they really feel better, fantastic. But that, you know, we don't really-
- TFTim Ferriss
Can't rely on the croissant effect. [laughs]
- JKDr. John Krystal
Exactly. But it happened over and over and over in this pilot study. And it really-- we didn't really know exactly what to make of it. And we started sharing the findings with people. And, you know, science is just wonderful because the dominant mode of interaction in science is skepticism. So We would present these data and we'd say, "You know, people got a dose of ketamine and the next day they were, uh, several of them were better." And they'd say, "Right." You know, skepticism overall. And it took a long time for other groups to even try to replicate that ketamine finding. We presented the first results for the first time in 1997, and the first paper of a study that tried to replicate those ketamine effects came out in 2006. And that was because Dennis Charney had moved to NIMH. He had built a program. He and Husseini Manji and Carlos Zarate designed and executed a study to replicate the initial finding. And you know what? They found basically exactly what we found. And then more and more groups started to replicate that work and found the same thing over and over again. And people started to believe it. And you know, something really remarkable happened, which is that I started to give talks and I would describe how we gave ketamine as this research procedure, and, uh, it produced these antidepressant effects, and now what we need are definitive trials 'cause we really... You know, we have preliminary evidence, but we really need definitive trials. And then psychiatrists would tell me from the audience, "What are you talking about? I've already started using ketamine in my clinical practice, and I'm having great results." And I would, like, go pale, and I would freeze, and I would say, "Well, it's still an experimental procedure. We don't have enough evidence to really adopt it yet in clinical practice." But that's really what happened, which is somewhere in between '97, I guess, the first presentation, and the early 2000s there, I started to hear about its use already in clinical practice, which doctors can do because it's an FDA-approved drug. And the other key turning point, I think, for the field came in 2010 with the work of my late colleague, Ron Duman. And Ron was just an incredibly incredible trailblazing scientist, remarkably brilliant and, and talented neuroscientist, and a wonderful person and colleague and friend. And he did this study in collaboration with George Agajanian. Now, for those in the psychedelic world, you may be familiar with that name. But, but George Agajanian and Danny Friedman, who was his mentor, around 1960, 1958, 1959, 1960, the early 1960s, did some of the first studies to implicate serotonin signaling in the mechanism of action of psychedelic drugs.
- SPSpeaker
Hmm.
- JKDr. John Krystal
And George was the first person, the first physiologist to record the activity of serotonin nerve cells in the brain, and showing that psychedelic drugs changed the activity rate of these serotonin neurons, giving one of the first neural signatures of psychedelic drugs in the brain as well. So it's really kind of life goes full circle in a way that, that George Agajanian and Ron Duman together showed that if you give a dose of ketamine to stressed animals, that it produced rapid and profound biochemical, electrophysiological, and structural change in the brain within 24 hours. And, and this builds on an idea that really came first from the pioneering scientist Bruce McEwen, who was just a, another wonderful person and, and scientist who was based at the Rockefeller University, that if you stress animals, severe stress over a period of time, long period of time, that not only do they have behavioral changes, but that those behavioral changes are associated with the loss of the syn- synaptic connections in the brain. That the n- circuits involved in the regulation of cognition and mood lose a small percentage of the synapses, but enough to have profound functional and behavioral consequences. Stress-related behaviors, impairments in cognition, difficulty solving problems, uh, difficulty regulating emotions, et cetera. All of these behavioral changes that we associated with the emergence of stress-related changes in animals and depressions in people, that that loss of connections between nerve cells in the brain are a part of that series of events. And that within 24 hours of a single dose, these brain connections could go back. What a profound new way of thinking about what we're doing in the brain. And one of the things that's maybe a subtle point, but to me profound, is I view depression treatment as about thinking about how we restore behavioral and emotional resilience and how we can tap into the brain's intrinsic capacity for resilience to promote behavioral resilience. So what we've done by giving a single dose of ketamine, an innate-- uh, is we're not making random new connections in the brain. That would be a bad thing. The brain is not a chaotic structure, and we don't wanna make random connections because that would make things worse in theory. I mean, that's what you get with epilepsy, a growth of inappropriate connections in, in parts of the brain. What we do is overcome whatever intrinsic resistance there is to recovery in the brain to of give a brief pulse of ketamine and enable a restoration of the brain's intrinsic capacity to develop and maintain structural connectivity. And we think that is a part of the story [lip smacks] of how ketamine works in the brain. And that, that insight happened around 2010, and that was really fundamentally important i-i-in terms of driving the whole field forward and helping to reduce a lot of the skepticism about ketamine as a
- 1:01:33 – 1:18:49
How ketamine went from “horse tranquilizer” to antidepressant candidate.
- JKDr. John Krystal
treatment.
- TFTim Ferriss
So looking at the timeline, I just wanna recap a little bit, and then I have several questions because I love the history of science, and I feel like one of the best ways to try to hone oneself, not speaking for myself because I'm just a tourist, but [chuckles] to prepare the mind for future discoveries, to examine past discoveries. So let me just lay out a few things for folks. Number one is timelines. So animal studies in the early 1990s suggest there might be antidepressant effects. I'm gonna come back to that. 1997, your first presentation of results. 2000, first paper is published. 2006, publication of the first replication, big deal. That was in treatment-resistant depression. And then we may come back to this, but 2019, FDA approval of esketamine. So my question to begin is related to Ron Duman and the animal research with ketamine. So for people who really have no history on ketamine, and I want you to fact-check this and, and correct me if I get anything wrong. But ketamine is a dissociative anesthetic. It is widely used, very inexpensive. It is partially so widely used because it does not at least normally suppress respiration. So you find it being used in military capacities in the field, in veterinary medicine, but it's not a horse tranquilizer per se, which is, I think, what some people, uh, believe. But it is used in medicine, and it is one of the World Health Organization's most essential medicines. I mean, this is a pervasive anesthetic. How did Ron or others involved with the animal research even choose that as an intervention to begin with?
- JKDr. John Krystal
So first, I have to tell you about a cartoon that I saw about ketamine related to its use as a horse tranquilizer [laughs] which is the cartoon says, I think related to the abuse of ketamine. It says, "Ketamine," and it's got a picture of a horse. "Just say neigh." N-E-I-G-H.
- TFTim Ferriss
[laughs] That's good. [laughs]
- JKDr. John Krystal
At the time that I was studying ketamine, I was interacting, you know, regularly with this broader group of people at y- Ron Duman was at Yale, George Aghajanian at Yale, Eric Nestler, Dennis Charney, obviously my collaborator and mentor, and many other people. So one of the things that was really striking was when I was... when we had made this finding with ketamine and, and shared the results with Ron, I had the feeling that Ron thought that it was more important than we did. He would say, "This is like the most important finding in 50 years." And we would say, "What?" And so he was really highly motivated to try to understand how ketamine worked, and his own research was in the area of the basic neuroscience of stress and antidepressant activity. He showed, for example, he was the first to show that antidepressants stimulate something called neurogenesis, which is the birth of new nerve cells in the hippocampus in animals. And, and there's been some work to show that that might happen in, in human brain as well. And he was one of the pioneers of studying the role of, 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, he was in some ways uniquely situated to discover this profound structural change. And they didn't... What was really important about the work is they not o- not only did they describe the profound structural change, but they m-mapped the molecular signaling mechanisms that you alluded to about nerve growth factors engaging a fundamental mechanism for resilience in the brain, these gr-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, if you had a brake and then you had another brake that you stepped on to relieve the brake instead of stepping on the gas pedal, that's what ketamine is like in the brain.
- TFTim Ferriss
Hmm. Hmm.
- JKDr. John Krystal
So, so ketamine allows more glutamate release to happen in certain circuits of the brain. And it-- 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. So a pulse of glutamate is good. That stimulates a type of glutamate receptor that triggers the elevation of BDNF levels. It causes a local seepage of BDNF, the nerve growth factor, out of the nerve cells and s- activates signaling. And then a key way station And I'm g- gonna get a little technical because we, I know we're probably gonna come back to this point later.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
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 mTOR.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
And mTOR is an abbreviation for something really complicated, the mechanistic target of rapamycin. And it turns out that if you activate mTOR, then you activate all of the downstream mechanisms that lead to the regrowth and stabilization of these new synaptic connections. Now, this might be a good time to come back and think about a little bit about the complexity of the neurobiology of glutamate abnormalities in depression.
- TFTim Ferriss
I think we should do that, but I want to just follow up on what you said to ask -
- JKDr. John Krystal
Yeah
- TFTim Ferriss
... how did, how was the hypothesis formed at all that ketamine, instead of a million other interventions or, you know, pharmacological tools, might be useful for repairing the structural damage of stress or alleviating depression? Was it something that was observed in the field? For instance, one of the rumors that I've heard is that veterans who were administered this anesthetic seemed to experience less PTSD. That was somehow recorded in the field, and that led to hypothesis generation and, and use of ketamine. That seems pretty tenuous. I don't know if that's true. But how did it go from anesthetic to, of all the things we could choose, we're gonna mess around with ketamine?
- JKDr. John Krystal
First off, I love hearing stories about how I, I and, uh, Dennis came up with ketamine for depression.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
Which one of my... [laughs] Like, like people, uh, uh, you know, it's like, "Oh, that's a great idea." No.
- TFTim Ferriss
[laughs] Just to be clear, this isn't specific to you. It's just I, I, I'm so fascinated by the, the genesis stories of these things. I think they're important, so I'd love to hear the, the real story as opposed to the Santa Claus version.
- JKDr. John Krystal
So the real story is not related to depression at all. It's related to, to schizophrenia.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
So it so happens in the great cosmic universe of coincidence that a friend of my dad's in Detroit, friend of our... And, and his family was a friend of our family, and we went on vacation together. I remember inner tubing down a river in northern Michigan. I grew up in Michigan. Inner tubing down a river with his daughter. We were maybe 10 or 9 or 10 at the time. His daughter is now an, an end- uh, is named Joan Luby. Um, e- she's now an endowed professor and, and expert in child psychiatry at, at Washington University in St. Louis. Anyway, this fellow's name was, um, Elliot Luby, and in 1959, he published a paper that was the first time phencyclidine or Sernyl was given to a human being, and this happened at the Lafayette Clinic in Detroit, a, an entity, a building which no longer exists, unfortunately. An extremely, extremely generative place in its era. And he said that if you gave Sernyl, which, which was the company name for phencyclidine, PCP, angel dust, if you gave it to people, it produced something like schizophrenia in them.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
The thing was, that's 1959, and the mechanism, the fact that it blocked the NMDA glutamate receptor wasn't identified until the mid-1980s or r- in '83, '84. So it was this fascinating observation which couldn't go anywhere scientifically. But they did research, and this is gonna bring us to other topics that we'll probably talk about, in which they compared the effects of phencyclidine to the effects of LSD in people.
- TFTim Ferriss
Mm-hmm. Yeah. Good old psychomimetic. [laughs]
- JKDr. John Krystal
Yeah. It's just, 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.
- TFTim Ferriss
It's a great name, too. [laughs]
- JKDr. John Krystal
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 on 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, sang a bit of the Van Morrison song, Domino.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
May be familiar with. Anyway, unforgettable to me because Ed became a very dear friend and colleague, uh, over the years. But Ed was the first to give ketamine to animals and humans.
- TFTim Ferriss
Hmm.
- 1:18:49 – 1:23:14
The dose makes the difference.
- JKDr. John Krystal
so m- our path in our institution, my path was the development of a research program on glutamate psychopharmacology, developing circuit and mechanistic hypotheses. One of my collaborators in those days was a pharmacologist named Bita Moghaddam. 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 and psychosis related to schizophrenia.
- TFTim Ferriss
Mm.
- JKDr. John Krystal
You know, that line of research has its own story because we began using the ketamine administration as a platform for trying to id- identify novel alternatives to antipsychotic medication for the treatment of schizophrenia. And, and that has had its own life and story, and maybe someday we'll, we'll talk about that. But one of the things Bita 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 to study cognition, it released glutamate. If you give it at anesthetic doses, it depresses glutamate, and it's not antidepressant at, at those doses.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
And if you give it at even a little bit lower level, it doesn't stimulate the glutamate release.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
There's this tiny narrow window where it's producing dissociation psychosis and a number of the other effects that we're really interested in, where it works. And 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, you know, 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 of ketamine to who couldn't answer a lot of our questions, but he was holding onto the bed really tightly.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
And I said, "Well, that's interesting. Why were you holding onto the bed?" He said, "Well," uh, basically the, 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-
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
... and the, the outer planets, and he was afraid that if he let go of the bed, that he'd be cast adrift in outer space and, and not make it back. Well, that was really fascinating.
- TFTim Ferriss
Seems reasonable. [laughs]
- JKDr. John Krystal
Yeah. It was really, really interesting, but useless. I couldn't get him... He couldn't do any tests. He couldn't perform anything.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
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, have repeatedly been shown to be so in, 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 used 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, we administer it for 40 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 ketamine administration
- 1:23:14 – 1:39:42
What is dissociation, and is it an essential part of ketamine’s healing process?
- JKDr. John Krystal
for the treatment of depression.
- TFTim Ferriss
So John, may I interject for a second?
- JKDr. John Krystal
Sure.
- TFTim Ferriss
So I wanna talk about, I think we'll, we'll get to this pretty quickly, basically what you consider best practices in terms of format, dosing schedule, et cetera, for ketamine as applied to depression. And if you want to take the conversation somewhere else first, that's totally fine. But I would love to have you just translate an earlier definition, which was in more, let's just call it science speak for the layperson, and that is a definition of dissociation. And then whether that is a feature a- or a bug, whether that is important for the clinical outcomes or it is a side effect to be removed. And this is highly relevant to the broader conversation, including psychedelics, because there are many efforts and different camps, some who believe the, say, psychedelic effects are critical to clinical outcomes, and then those who view them as side effects to be removed. Could you define dissociation and then share your perspective on whether it is helpful, AKA desirable or undesirable in the, in the effects that we see, the antidepressant effects?
- JKDr. John Krystal
You know, sometimes I have started papers on dissociation and stopped because I would get hung up on what the definition of dissociation is.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
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. And those 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 and 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 these states of feeling disconnected and, and that things are not real to sensory distortions to what people know as a very traumatic 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 that 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 kind of neurobiological path to studying the neurobiology of dissociation and PTSD and that's a whole other kind of discussion which we can, we can come back to. So what about dissociation in the antidepressant effects of ketamine? This is really an interesting and complicated question because to really answer your question, you have to acknowledge-- I have to acknowledge that 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. And so 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, and so a lot of people say that the dissociative experience is a very meaningful experience for them, uh, particularly if there's some kind of guided experience to do that. And I have no argument with that whatsoever. Why not? In fact, that's great. But 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 1,000 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." You know, that, you know, these kinds of scary thoughts. "My, my organs are being m- replaced with machine parts."
- TFTim Ferriss
[laughs] That sounds unpleasant.
- JKDr. John Krystal
Yeah. You know, stuff like that. And that is not a productive insight and it's not healing.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
It's not important for them to even remember that after the ketamine has worn off. So I would say the dissociation is clearly not a necessity in terms of producing a-attitude change and things like that. I would also say that some people, they get the ketamine and... I once had a g-- treated a guy, or it wasn't a treat, it was a research study, but I gave him a dose of ketamine. He had come from a Mormon background. He had never had coffee, he'd never had tea, never had alcohol, never smoked, never used any drug. And, and he described ketamine as the most fun he ever had since he arrived at Yale. So it was like a rollercoaster of like doing all these things. 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 the dose at which they experience dissociative symptoms. The dose that produces therapeutic effects, the dose that produce dissociation overlap, so that if you're giving a dose of ketamine that is d- is not producing any dissociative symptoms, for some people it will mean you have underdosed the ketamine.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
I mean, there are s- exceptions to this in that some people are just not very sensitive to the dissociative effects of ketamine, but still get the antidepressant effects. And examples of those people are people who have a personal or family history of alcohol use disorder who seem to have a built-in tolerance to the effects of ketamine-
- TFTim Ferriss
Hmm
- JKDr. John Krystal
... as they do have a built-in tolerance, some of them, to the effects of alcohol. And that's another story we can get to if you want sometime [laughs] . But what my colleagues, Irina Estalrez and Sophie Holmes and, and the broader group of collaborators with the Yale PET Center did a study which I think is in- incredibly important and interesting related to the Neurobiology 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 with using a, a molecular tag for synapses. And so, okay, so there are the, these depressed patients who have reductions in synaptic density. Great. So that so far that could be relevant to translating the animal work to the human work. So you give a mixed group of depressed patients, some who have synaptic 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, et cetera, et cetera, the more hardcore depressed patients. They get a dose of ketamine. They get a s- an increase in synaptic density. And the more dissociative symptoms they get, the bigger the increase in synaptic density.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
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 deficits, that dissociative symptoms produced by ketamine can be a marker that you've gotten 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. 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, so dissociation in these two groups of patients during ketamine means two different things.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
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 regrowing. So what could it be, right?
- TFTim Ferriss
Mm-hmm. Mm-hmm.
- JKDr. John Krystal
So I'm gonna 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.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
Another kind of abnormality that we've seen in, in people with PTSD and depression, and that was published this year also from the first author who is a colleague, Chadi Abdallah, who's now at, uh, Baylor College of Medicine. Using a really newfangled, clever technical technique where w- 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's being released and how much metabolic activity is triggered, okay? So you can say glutamate-- uh, amount of metabolic activity per glutamate. It's a measure of the effectiveness of that s- 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 measure.
- TFTim Ferriss
So not necessarily... Sorry to interrupt. Not necessarily a deficit in synaptic density, but just a decreased efficiency.
- JKDr. John Krystal
Exactly.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
Another deficit. And 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. So maybe the reason that 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 Alison Nugent and Carlos Zarate They used another 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 of ketamine... Well, first, that that sensory evoked potential is 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, uh, if you give a single dose of ketamine to, to patients with depression, you'll discover that there are two groups, those who don't respond. 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, um, not structurally. And so what we take from these kinds of studies and others, like functional... F- 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 it r- and restores 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 'cause it directly emerges out of Ron Duman's work and, and Bita Moghaddam's work. We know a lot about the biology of the structural... restoration of structural connectivity, and we know much less at this point about how ketamine restores the efficiency of the network. But my sense is that both are probably contributing to the clinical effect.
- 1:39:42 – 1:54:05
Recommendations for optimal treatment of a close friend (frequency, duration, psychotherapy, etc.).
- TFTim Ferriss
So let me hop in for a second because I'm enjoying this so much and learning so much, and a few things come to mind for me. The first is that we're talking about the sort of neuroanatomical changes, or maybe not neuroanatomical, but the certain activity changes, in some cases structural changes, that you observe and the clinical outcomes that you see in different breeds of depressed patients, right? Those with lower synaptic density-
- JKDr. John Krystal
I wouldn't use that word, but, uh, I'd say-
- TFTim Ferriss
Well, [laughs] right
- JKDr. John Krystal
... subtypes.
- TFTim Ferriss
Subtypes, there we go. Right. Um, I feel like, uh, you know, [laughs] I'm kind of allowed to play it fast and loose since I fit into the broad category of someone who, who has treatment-resistant depression. [laughs] So I f- I feel like I can kind of sling loosely. But right. But you have different responses to different, different types of depression, and part of me wonders if their subjective experiences are also different. And just by way of analogy, I'll say I think that labels can be so reductionist that it's easy to run into confounding factors or to run into confusion, and this is true in many, many areas, not just psychiatry. And it... And I think about, for instance, cardiology and dealing with lipid markers that are out of whack and how, how brute force and nonspecific certain approaches are. High cholesterol, statins, right? Instead of automatically doing that, which can be a tool in the toolkit, determining if one is a hyperabsorber of cholesterol versus-
- JKDr. John Krystal
Right
- TFTim Ferriss
... a hyperproducer of cholesterol versus-
- JKDr. John Krystal
Right
- TFTim Ferriss
... fill in the blank. In which case, your first line approach might be, say, something like ezetimibe or Zetia instead of a statin, which could then be looked at later if the sort of clinical changes aren't achieved. And similarly, I could imagine that in a group of depressed, self-described depressed patients, even if they take an assessment, uh, like a... Not sure what the proper assessment would be, like a HAM-D or something like that, that the subjective experience, as you noted earlier in this conversation, for one of these subgroups could be anhedonia, right? So they have an inability to feel joy, but they're not stuck in a endless loop of perseverating negativity.
- JKDr. John Krystal
Mm-hmm.
- TFTim Ferriss
And again, I'm speculating here.
- JKDr. John Krystal
Yeah, yeah.
- TFTim Ferriss
But to then jump from that, I can imagine that for some people, perhaps those who also respond to the dissociative effects, or let me be clear, have a high correlation of positive improvements to achieving those dissociative effects with dosing, that maybe they're the ones who have this self-hatred on endless loop and the dissociative effects have impart some of the subtraction of that, so they feel what it is like to exist without that loop playing endlessly. And this is one of my... And I am such a tourist, so I, I, I wanna dive into this further with you. But having gone through a five infu- well, it was supposed to be six, I ended up doing five infusion sequence myself, I was struck by how you can experience what it is like to not have a loop or a repetitive thought pattern, and that sometimes that subjective experience, putting aside that there are certainly other things happening in the brain, can feel tremendously therapeutic even in the moment. Versus, say, perhaps those who had positive outcomes but didn't seem to need the dissociative effect. I'm simplifying here. Perhaps just didn't have that loop issue. It was, it, it presented differently for them. These are just thoughts that are occurring to me as we're talking, and we're gonna dig into all sorts of this. Let me ask, if I may, just because I think people are, are chomping at the bit for this, and then we're gonna go in a bunch of different directions. If you had, say, close friend ended up working with you or a doctor you trust in a clinical capacity with treatment-resistant depression, what would the formatting, dosing, et cetera, look like, might it look like for that person? Recognizing that maybe it's, you know, mgs per kgs or weight-
- JKDr. John Krystal
Yeah, yeah
- TFTim Ferriss
... dependent or whatever. But what might it look like? Because before we started recording, and also based on what you said perhaps 10, 15 minutes ago, there's a response curve where too little doesn't do the trick, too much also doesn't seem to do the trick. There's this Goldilocks-
- JKDr. John Krystal
Yeah
- TFTim Ferriss
... narrow dosing window. But also there are all these other questions. Intravenous versus intramuscular versus something else. Is, is there therapy during the session or only before and after, right? So could you speak to sort of what that friend with someone who's highly competent with perhaps your input, what that experience of ketamine might look like?
- JKDr. John Krystal
The first thing is the choice of s-ketamine versus intravenous ketamine, and it's really, 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, then getting the medication intranasal is a huge benefit. And, 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.
- TFTim Ferriss
Mm.
- JKDr. John Krystal
And that can be a problem for some people, and s-ketamine can be given intranasally, and that's really-- can be given in more settings. It makes it easier to give it in different kinds of settings that might be-
- TFTim Ferriss
Mm
- JKDr. John Krystal
... more congenial, and has all kinds of other implications.
- TFTim Ferriss
And for the sake of our hypothetical, let's say this person is not averse to needles, so IV or intramuscular is okay.
- JKDr. John Krystal
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 s-ketamine. And because of the fixed milligram dose of s-ketamine, it's recommended that you start at fifty-six milligrams of s-ketamine and then work your way up, if you tolerate that, to eighty-four milligrams. And that means that for many people, they're gonna 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 they, 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 ketamine as a treatment because they want the rapid response, that there's a little bit of an advantage for getting the full dose of ketamine intravenously. It's a theoretical advantage. Whether it's a real clinical advantage, still e- early to say because we don't, we don't really have good head-to-head data. It's mostly derived from comparison of secondary data, secondary analyses. But for some people, there may be an advantage of the intravenous dose.
- TFTim Ferriss
I'd love for you to also just speak to the cost differences, uh, potentially. Um-
- JKDr. John Krystal
Yeah. So the s-ketamine is a little bit expensive medication. It's about six hundred a, a treatment. Maybe, you know, depending on where you're getting your treatment, can be, can be more. But it's usually covered by insurance or in- at least in, in many places covered by insurance, so it's more of a cost for the overall health system than it is often for the individual. Uh, but sometimes it's the individual who's paying out of pocket, and ketamine is obviously generic and much less expensive.
- TFTim Ferriss
So let's say they are suffering from acute depression, maybe suicidal ideation. I mean, putting aside the other precautions they might be taking in such a situation, but let's just say it's acute depression. They're looking for rapid antidepressant effects. What then? What does the... How many sessions over what period of time? What does a session itself look like? I would just love to, to know what's the, the current state of the art without some of the forward-looking stuff. We'll get to what the future might look like, but just as it stands right now, if someone wanted to go to a clinic today.
- JKDr. John Krystal
Well, I think that 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, 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. A lot of people will do short-term course, six treatments, 10 treatments, 12 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, 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, um, 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 ketamine so that there's not an interaction there. So some people will just do a course and, and then they'll be done, but others will need ongoing, some kind of ongoing maintenance treatment to sustain the benefit.
- TFTim Ferriss
Now, with someone who, again, friend of yours that you refer to a clinician you trust, would you in such a case tend to lean towards the four weeks of two times a week, then one time a week, or would you tend to lean towards... And again, uh, we said this in the introduction, or I will have recorded this by the time this comes out [laughs] , this is not medical advice. This is for educational purposes only. So obviously speak to your own general practitioner or physician before considering anything like this. But would you tend to lean towards four weeks, two times a week, and then the, the sort of tapering, so to speak, not tapering, but the greater distribution after that, or the more perhaps aggressive higher frequency per week? And then what does an individual session, what might an individual session look like in terms of duration, milligrams per kilogram, psychotherapeutic wrapper, if one?
- JKDr. John Krystal
So there's very limited data comparing modes of ketamine 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 masked ketamine treatments, in other words, three consecutive days or, 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. So in my view, for treatment-resistant depression, this is a, a pretty good strategy. The question about how to wrap psychotherapy around this is really an interesting one. And, and there are some important points to make about ketamine generally before going into the wraparound treatment because i- in my view, ketamine is an intervention and it's part of an overall treatment. In other words, it's really important that somebody is thinking about the overall wellbeing of the patient, providing support, providing oftentimes psychotherapy, and thinking about how the other medications that patients are taking are interacting with the ketamine, and looking out in a big picture way for the overall wellbeing of patients. Ketamine is an 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, and that these sessions can both potentially extend and, and augment the effectiveness of ketamine. Such, uh, paper by Sam Wilkinson here at Yale suggests that.
- 1:54:05 – 1:59:58
Reducing the potency of maladaptive memories.
- JKDr. John Krystal
But there's also this interesting question about what do you do during the ketamine 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 Harpas Rotem 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 concern that treatment would in some way rob them of their trauma memories and, 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, and oftentimes they believe that, that the trauma memories are a burden, but in some ways valuable to them. And, 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, with the ability to achieve things in life and, and they don't interfere with quality of life. So If you activate a trauma memory or an alcohol or say for alcohol use disorder 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. 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 w- about what I'm talking about, about the broader psychotherapeutic context for, for ketamine, which is that there's an overall treatment process and then there's the intervention and what we can reasonably expect from it. But there is a sign that not only craving for alcohol, but actually alcohol consumption may be reduced, uh, from a, an initial preliminary study conducted by a group in London. Ravi Das is the, uh, the lead author on that paper. It was in Nature Communications a few years ago. And people are trying to develop that into a treatment for alcohol use disorder.
- TFTim Ferriss
Quick question on that. Is that independent of the content of the session? In other words, is that a pharmacological effect or is that in combination with, say, bringing up maybe early trauma that they attribute their alcohol use disorder or alcoholism to?
- JKDr. John Krystal
So this is one of the kind of really interesting byproducts of ketamine 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. And we think that every time you activate a memory, you put it, that memory into a somewhat labile state. In other words, you can strengthen the impact of that memory-
- TFTim Ferriss
Mm-hmm
- JKDr. John Krystal
... 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, and the whole narrative starts to be integrated in your life like a bad habit and, and your, 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 it a little bit more. And you are using it over and over and over, and those alcohol-related memories have more and more power in the way you think and the way you act.
- TFTim Ferriss
Mm.
- JKDr. John Krystal
And so by interfering with neuroplasticity and preventing that strengthening process, you actually weaken 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 PTSD. And particularly relevant to PTSD because in a large... for its kind, a large study that we published this year with about 50 patients in the group where we compared standard dose ketamine to a lower dose ketamine to a placebo in people with military-related PTSD. We found that there was a robust antidepressant effect, but a really weak and, and didn't quite meet statistical significance effect on core PTSD symptoms. So it may be that if you want just the antidepressant effect, you can just give a dose of 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-
- TFTim Ferriss
Mm-hmm
- JKDr. John Krystal
... of the ketamine infusion to, to get the full benefit. And that seems to be different than major depression, where a lot of people or 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.
- 1:59:58 – 2:07:18
Best dosage practices.
- TFTim Ferriss
John, we've been talking about best practices. Let's get into some of the nitty-gritty of dosing because it seems like too little doesn't do the job, too much also counterproductive on some levels. What are the milligrams per kilogram best practices to achieve that, let's call it optimal or at least land in the narrow therapeutic window?
- JKDr. John Krystal
We have the most information for a 40-minute intravenous in- infusion.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
And so the 40-minute intravenous infusion dose that we most commonly use is 0.5 milligrams per kilogram. And there-- I'm told that there are some people who are very unresponsive to the 0.5 milligram per kilogram dose, and I've heard that there are some cases wh- where you would go to 0.6 or 0.7 and can sometimes get a good effect. But 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. It... 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 less side effects and, and still get some efficacy. So it's a really narrow range. I mean, i- if you think about almost any medication that you take, you take aspirin. People take two aspirin, right? So it would be as if, if you went down to one aspirin, you get no effect, and if you took two aspirins, it would knock you out. So with-
- TFTim Ferriss
Mm
- JKDr. John Krystal
... 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 0.5 milligram per kilogram intravenous dose. 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 traditional antidepressant dose of ketamine is doing.
- TFTim Ferriss
So let me ask a few follow-up questions. Well, actually, let me just maybe explain for folks [laughs] if, uh, my audience is, as I imagine, a lot of Yanks, meaning Americans. So kilogram, roughly 2.2 or maybe exactly 2.2 pounds. So for me, again, this is not perfect math, I weigh about 170, 175. Let's just call it roughly 80 kilograms, something in that range. For the 0.5 milligrams, so half a milligram per kilogram of body weight, what is the rate of infusion? So if we're talking about a 40-minute IV, is it equally distributed? In other words, is each minute, the first minute, second minute, 13th minute, 40th minute, the same amount, or do you front load in some capacity a bolus so that a larger percentage of the total is administered in the earlier phases of administration?
- JKDr. John Krystal
It depends really whether it's a clinical or research procedure. So wh- 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, a, a longer period of time where the brain has a steady exposure for ketamine, where we can really do brain imaging studies or te- psychological testing and things like that. When you get a bolus of ketamine, it's like jumping into a cold pool of water. And one person told me he felt like he was rocketed out of the universe-
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
... when he got a big bolus of, right up. Because y- you get the full effects within about, about 30 seconds or a minute of the infusion.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
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 disorienting for people. People tend to like that a little better.
- TFTim Ferriss
So is it from a clinical outcome perspective... And just as a, as an example for folks, because bolus may be a fancy word. If we say hypothetically, since it's a 40-minute IV, for the sake of making the math simple, let's say somebody weighs 40 kilograms. So they're getting .5 milligrams per kilogram, so that would be 20, if I'm not screwing this up, 20 milligrams [laughs] total, right? One option would be the .5 milligrams every minute for 40 minutes. And if it were a bolus, uh, certainly there are some clinics I've observed who might administer 20 or 30% of that total in the first handful of minutes. So my question is, for you, putting the patient comfort aside, which may be a silly thing to do, but if we put patient comfort aside, let's just say getting rocketed into a different universe or out of the universe [laughs] is acceptable. If you're looking at clinical outcomes with depressed patients, do you think there is a difference between the, the continuous administration, the wading into the pool, versus the bolus in the beginning? And if you do use a bolus for a clinically depressed patient, what does that potentially look like, just as a percentage of the total over what period of time in the beginning?
- JKDr. John Krystal
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.
- TFTim Ferriss
Mm-hmm, mm-hmm.
- JKDr. John Krystal
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.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
What is different is that if you took the infusion rate and doubled it, and so you said, "We're gonna give you the same," and I think my math is correct, 80 kilograms, half a milligram per kilogram would be 40 milligrams. I'm gonna stick to my math.
- TFTim Ferriss
You should be right. You should be right. You should be right. [laughs]
- JKDr. John Krystal
If you took those 40 milligrams and you infused them over 80 minutes, then y- you would get the same total dose, but the peak blood level would be half.
- TFTim Ferriss
Right, right.
- JKDr. John Krystal
And as far as we can tell, that would be more like giving a lower dose. I don't think that would be as effective.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
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.
- 2:07:18 – 2:08:52
I.M. vs. I.V.
- TFTim Ferriss
Is the choice for IV over, say, intramuscular injection, which is another, let's just call it common means of administration-
- JKDr. John Krystal
Yeah
- TFTim Ferriss
... at least by some therapists or facilitators, clinics, et cetera. What are the upsides and downsides of that? Is it simply less predictable, less trackable, the, the sort of pharmacokinetics are more erratic, and therefore for a scientific context, it makes more sense to do IV? What are the pros and cons of one versus the other?
- JKDr. John Krystal
As far as I can tell, the main pro of I.M. 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.M. injections, typically people get the entire injection at once, and that's not optimal for everybody. Because sometimes when people get upset during a ketamine 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. But once you've given the dose intramuscularly, you can't take it back.
- TFTim Ferriss
[laughs] Yeah, once you've hit the golf ball, you can't un-hit the golf ball. [laughs]
- JKDr. John Krystal
Exactly. So then you're counting on the person being able to ride out whatever side effect they get from the medication.
- 2:08:52 – 2:13:34
Common in-session side-effects (and remedies).
- TFTim Ferriss
And what are some of the side effects in session, and how do you mitigate those side effects? For instance, when I had my own experience with a series of infusions, it was standard operating procedure to give, I think it was eight milligrams or so of Zofran, so for sort of anti-nausea.
- JKDr. John Krystal
Right.
- TFTim Ferriss
So nausea does appear to be quite common for folks, but it can be attenuated with some type of medication beforehand. What are some of the more commonly observed side effects in session, and post-session for that matter? And how do you attempt to address some of those?
- JKDr. John Krystal
The one that's probably most disturbing to people is nausea. Nobody likes to get nauseous. Nobody likes to vomit, that I know of.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
So the Zofran, which 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. Uh, I don't know if it was for you, but that, for some people, that is the experience that they describe, and the Zofran 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, 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, a drug like propranolol, 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, the side effect of dissociation or s- transient psychosis or cognitive impairment. And the main way we manage that when we're administering the drug intravenously is by stopping the infusion.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
We can stop an infusion. Within 30 minutes, a 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 r- 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 gonna be okay and that this isn't gonna last. Because one of the things that can happen during a 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.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
So what we do before we give anybody ketamine is spend a, a fair amount of time telling them what ketamine effects could be like, preparing them so they're not surprised when it happens. And then when it does happen, say, if they happen to have a prominent feeling of, uh, unreality or changes in environmental perception or perception of their body, we tell them, "You remember before the session, we, we talked about how you might have these kinds of effects? Well, it's happening."
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
"And it's gonna go away."
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
And most people find that very comforting because they kind of knew it was gonna happen all along, and, and you tell them, "This is what we're talking about," it does change their frame of reference.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
But they usually tolerate it pretty well.
- TFTim Ferriss
[laughs] That makes me remember a sign that at one point was inside a yurt at Burning Man, which was associated with something called Zendo, which is sort of peer support, harm reduction, mostly related to psychedelic use. So if people are having a difficult psychedelic or drug experience, their friends will bring them to this yurt where there will be sober sitters and volunteers and managers and so on to look after them. And [laughs] I don't think they have it there anymore, but there used to be a sign, huge sign on the wall where everybody could see it, that said, "You took drugs, and the good news is they're working." [laughs]
- JKDr. John Krystal
[laughs] Exactly.
- TFTim Ferriss
Just a
- 2:13:34 – 2:16:52
What my ketamine experience was like.
- TFTim Ferriss
big reminder. Now l- let me share a few things from, from my experience, which I am sure, just to be clear, format-wise diverged quite a bit from what, uh, you are describing in terms of best practices, duration of IV, et cetera. And I chose a clinical setting for a number of reasons, and I think we'll come back to a few of them. One was I wanted to make it as inconvenient as possible for me to use ketamine. So we're gonna... We'll come back to that.
- JKDr. John Krystal
Yeah. The second-
- TFTim Ferriss
The second was I really Wanted to standardize the experience and have the versatility that IV provides, which is not the case with hitting the golf ball with intramuscular injections. So I wanted to be able to, which I did ultimately, have the ability to dial up the rate of administration in the middle of, say, a therapy conversation with a therapist. And then at one point, I remember very, very [chuckles] clearly, dialed up the rate by about 20, 25%, and suddenly things got very strange, and there seemed to be a distinct lag between my thought, my mouth moving, and me hearing any sound, which makes it very hard to talk. It's kind of like having a delayed reverb on a microphone or a set of speakers when you're trying to talk. It's extremely challenging. And I remember saying, "John," that was the name of the technician or medic who-- a former medic who was administering [chuckles] the ketamine. I said, "John, things are getting a little bendy. Could you please dial back?" And he was able to dial back, and then I could resume the session. And I, I wanted that type of ability to experiment. The session itself, and this is where I'd love to hear a bit about the setting. The session itself, there was an intake process, and I was in a room sitting in a comfortable chair, recliner, effectively, big screen TV, and you got to choose your effectively, let's call it a nature video with scenes of nature with music overlaid. And I standardized on one redwood video [chuckles] bec- and, and I should say that was the first time I had ever watched a video in a, any type of clinical or serious setting with, with drug administration. So I found that in and of itself quite novel. We can come back to the pros and cons of that at some point. And my experience post-session was, and we were gradually escalating dose, I mean, starting well below, let's just call it the minimum effective dose that you're outlining, and then probably exceeding it by quite a bit by the end. And my experience after the session became a running joke with my girlfriend because I would always forget something at the clinic. I would leave my wallet. I would forget my phone. I would forget my backpack. I would come home. I'd put something somewhere, forget where it was, and it seemed like my short-term memory was just gone for a period of time. And
- 2:16:52 – 2:22:51
Optimal settings.
- TFTim Ferriss
that leads me to two questions. So number one, how common is that, that one experienced some cognitive deficit or short-term memory impairment for a period of time? And what does the actual setting look like in the clinical setups that you've supervised or observed? Is it in a blank room? Are they staring at the ceiling? Do they have eye shades on? Are they listening to music, et cetera?
- JKDr. John Krystal
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 setting. So in our clinic, which is led, co-led by, uh, Dr. Robert Ostroff and, uh, Gerard Sanacora, both experts in this work, it would look like a surgical recovery room with-
- TFTim Ferriss
Mm-hmm
- JKDr. John Krystal
... 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, it's more of a strange, in some way, a almost a communal experience. Not that people are wanting the communal experience per se, but, but it is a r- a very efficient way to, uh, deliver the treatment. One of the things about ketamine is that it distorts perception in exactly the way that you describe. 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, it is said by mentors of mine who worked the emergency rooms when, when you would get PCP and, and LSD intoxicated people come to the emergency room, that the management strategy was the opposite for those two medications. Because PCP, like ketamine, 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 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, and so you tend to have a little bit more stimulation in the emergency room setting with, with the psychedelics than you do with, with PCP.
- TFTim Ferriss
[chuckles] Is there... Let's see here. Well, actually, I think you answered the question. I was gonna ask you if, if cost and scale were no consideration, I suppose I didn't frame it this way. For the purposes of scaling, it makes perfect sense that you would want the least cost, the least, on some level, the least space required, least training, right? You don't want it to require a four-string quartet or something. But if cost and scale were no consideration, do you have any thoughts on how you might design the setting? Would it be any different? I understand the point that you made, which I think probably applies whether cost is a constraint or not, about minimizing inputs. But do you have any other thoughts on what that might look like?
- JKDr. John Krystal
It's an interesting question. My general, uh, 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.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
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. And the video mainly because not much happens. Describing a treatment where not much is happening during the infusion. If you're gonna reactivate trauma memories or if you're going to reactivate alcohol memories, that itself is gonna be a pretty engrossing intervention and, and probably will occupy a, a lot of the kind of sensory space of the infusion. It sounds like you had some version of that.
- TFTim Ferriss
[laughs] Yeah. Well, there [laughs] the problem with video... Well, one of the many potential complications with video is that n- not all content may provoke the warm and cozy feeling that you [laughs] may be seeking. So I remember watching for the first time this video, and it's like beautiful redwoods and rivers, kinda creepy... not creepy, but, like, minor tone melancholic music, which I didn't love. I didn't expect that or see that coming, but I was already kinda strapped to the seat and on the ride [laughs] so I couldn't, couldn't get off in the middle of Pirates of the Caribbean Disney World ride. So I was, I was in it. But [laughs] I remember at one point on a higher dose, there was this one scene that popped up out of nowhere, and it was just this, it was this fox, this little fox. It, it looked like maybe it was Patagonia or something like that. It was just sitting on this freezing cold beach. It was sitting on this sand, and it just looked miserable. It wasn't doing anything. I was like, "Why is this fox here?" It looked really unhappy [laughs] and that was not conducive to, uh, an optimal clinical experience.
- 2:22:51 – 2:35:57
Ketamine risks.
- TFTim Ferriss
Let's talk not about necessarily the side effects in session, but some of the risks of ketamine, and I'm gonna lead into that in a few ways. So one of the apparent pros, one of the apparent benefits of ketamine, as contrasted to some other drugs that people may have heard about on this podcast, let's just say ayahuasca as an example, there appear to be fewer contraindications for ketamine. I'd, I'd love for you to speak to that, but there appear to be fewer contraindications versus, say, ayahuasca plus SSRI could mean serotonin syndrome, possibly fatal. Certainly ibogaine with cardiac risk. People die from these things.
- JKDr. John Krystal
Right.
- TFTim Ferriss
In contrast to some of these very powerful psychedelics, and there are certain psychedelics, to be fair, psilocybin, LSD being two of them, that seem to have almost no identifiable LD50. From a physiological basis, they, they seem to be relatively low risk. Not true psychologically, perhaps. But ketamine, for me, has two huge advantages relative to many other psychedelics. Number one, there are legal options you can explore. That is non-trivial, right? Legal options you can explore, which means you can operate through, in many cases, regulated, vetted practitioners on some level. So the- there, there's a practitioner risk that to a certain extent you can remove if you're proactive about focusing on that. The second would be contraindication risk. However, one of the things I mentioned earlier I want to come back to, and that was I wanted to make it as inconvenient as possible for me to use ketamine.
- JKDr. John Krystal
Right.
- TFTim Ferriss
And the reason I decided to do that is... Well, there are multiple reasons. The first is, and most important, is that I had seen multiple friends, and there are at least a handful of friends right now I know of who will fit this description, who had decided to stop using one dissociative anesthetic, certainly at high enough doses, alcohol, and switch to using ketamine four or five nights a week. Alcohol without the hangover. And I found this very deeply concerning, and certainly new friends who are using ketamine hundreds of times a year in some cases. And these are also, to paint a full picture, experienced psychonauts with a lot of psychedelic experience. But psychedelics, and you see this in animal models as well, have a certain, for most people, self-regulating or self-limiting capacity. I mean, if you give LSD to a rat in a bottle, it hits it once, and it never touches [laughs] it again. Uh, so I would love for you to speak to some of the risks of ketamine, maybe outside of the lab or even inside of the lab, and how you think about mitigating some of those risks. If there's addictive potential, speaking to that. And out of my own personal curiosity, I, I would also be fascinated to know Is the behavior that I've seen in humans, the addictive behavior, also found in animal experiments, or is it, is it not?
- JKDr. John Krystal
So first, I think your point's really well taken, which is that 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? And to tell the truth, I have found that those risks are really quite limited. People have undersold [laughs] the addiction risk of ketamine in the, in the United States. But in some parts of the world, ketamine is known as a very significant commonly abused substance, often as an alternative to alcohol or sometimes as an alternative to cannabis. I have visited clinics where ketamine abuse was being treated, and these were really heavy users of ketamine. They were hospitalized in patient unit. They were persistently psychotic, and those psychoses didn't clear even after a time when they had stopped using the ketamine. And so ketamine abuse carries with it, uh, risks that have to be taken very seriously, all the way from drunk driving to really high-dose ketamine u- use. We said earlier that the typical therapeutic dose for an 80-kilogram man was about 40 milligrams. And in China and in, uh, Taiwan, I've met with people who were using eight grams a day intranasally and orally.
- TFTim Ferriss
[laughs] Holy cow.
- JKDr. John Krystal
So in other words, that's 8,000 milligrams. That's 100-fold or 200-fold times the dose, and they used it every day. One of the things that, 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, those are all kinds of effects that we hope to see and, and, and hopefully over time with treatment will become stabilized. And when we space the doses apart, we don't get tolerance to the effects of ketamine. We don't have to give higher and higher doses of ketamine. 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 i- in some way adapted in a positive way. Ketamine, 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 of ketamine. 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, 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 take it, you know, maybe if they were heading into a stressful 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 of ketamine. And some of these people, with the best of intentions and no interest whatsoever in, in developing a 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 were... who, who had the ability to take it whenever they, whenever they needed. And, and some of these people ended up taking it every day, and some of these people ended up taking it four, five, six times a day in order to maintain their equilibrium. And one of the things that, 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 when used in this compulsive manner as opposed to decreasing your symptoms of depression. And, 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, uh, 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 of ketamine for a long period of time, you have this risk of persisting psychosis. And as I mentioned earlier, that's particularly scary because these Persisting psychotic symptoms that you see with long, high dose, long-lasting ketamine use, they don't respond very well to antipsychotic medications, and those psychotic symptoms don't necessarily go away quickly when ketamine is, use is stopped. So ketamine is a drug that has to be given a lot of respect and, and treated with a way that recognizes that careful thought needs to go into protecting people from developing, uh, problems related to ketamine use. And, and 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, and that's a problem in terms of access to ketamine as an effective antidepressant because out of this 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, of, 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.
- TFTim Ferriss
Mm.
- JKDr. John Krystal
So you're cutting out a large group of, of people, and I believe, and I think others believe, that there's a need to really think about how, what the optimized way to treat these patients who have depression and, and comorbid substance use disorders. So one strategy is the strategy that was developed, uh, by the group in England that I, that I mentioned earlier, University College London, where they're trying to activate the drug memories during the ketamine infusion to try to, to counteract whatever aggravating effect ketamine might have on addiction, and in fact, have produced beneficial effects on, on, uh, drug craving. The biggest step is to limit the availability of ketamine to the clinic setting, and that, that protects people not only from developing, 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, 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 1,000 milligrams of it, or let's say they got, um, pills of ketamine that had a, a, 1,000 milligrams, because 1,000 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 1,000 milligrams might not be that much for someone who was just going to use it orally. But what if they gave that 1,000 milligrams to someone who was gonna dissolve it and, and administer it intravenously? Person can get high on maybe 10 milligrams.
- TFTim Ferriss
Yeah, or snort it.
- JKDr. John Krystal
Or snort it, exactly. So you've 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, when you give ketamine to people for home use, you have to really be, you know, thoughtful and careful about thinking about that. And there are a variety of interesting strategies to deal
- 2:35:57 – 2:43:25
Decreasing the opportunities for abuse and addiction.
- JKDr. John Krystal
with this. So for example, there's a company out there that's developing a intranasal delivery system to deliver controlled substances in a manner that has less risk.
- TFTim Ferriss
Wait, how do they decrease the risk with the nasal administration? Is it, like, a childproof lock that just locks it for a period of time, or how does it work?
- JKDr. John Krystal
It's sort of a more elaborate version where there's some external regulation of the dosing and external monitoring of the dosing, so the person only is able to use it to administer the ketamine at certain times.
- TFTim Ferriss
Mm.
- JKDr. John Krystal
It's not for 100% protection, but it, but for most people it would be very protective against the, the diversion of ketamine. Another strategy is to try to develop a ketamine that is less, got less abuse potential. So a company that, 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, it's an interesting idea.
- TFTim Ferriss
So on that last point, and we don't have to get into any specifics you don't wanna get into, but is it, is it by changing the ketamine itself, or is it by lowering the minimum effective dose required of ketamine by combining it with other drugs?
- JKDr. John Krystal
So there 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 a, a r- less abuse liability is using the opposite isomer. In other words, the mirror image of S-ketamine is called R-ketamine. And so they believe that 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, with ketamine. There's the strategy that Freedom is trying, which is combining an anti-addiction medication with ketamine to reduce-
- TFTim Ferriss
Ah. Interesting
- JKDr. John Krystal
... its, uh, abuse risk. So there are a variety of strategies that people are taking to try to reduce this risk because in s- in many ways, abuse is the greatest risk associated with the With ketamine. Ketamine has been around since the '60s. It's medically, uh, safe and well-tolerated by most people when given in the ch- in the way in which it's given for treatment. We don't see much evidence of, of persisting medical risk. The only persisting medical risk that we can't prevent is the one when people are developing, uh, addiction. So we want to think about ways to broaden the pool of people who would be considered for ketamine and, and maybe to take advantage of the fact that, that treating depression is good for addiction, just like treating addiction is good for depression.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
So providing an avenue for the safe treatment of these patients we think is really important.
- TFTim Ferriss
I wonder if there is a drug, and there may be, I just, I just don't know my, my biochemistry and my pharmacopoeia. But if there's a drug that would increase the nausea and other undesirable side effects of ketamine in between sessions, and therefore act as a biological policing function of sorts. Because I know these drugs exist for other things, for other compounds. But it's just, I'm allowing my mind to go wild with all the different options. I mean, there are a lot of different options here. Let me, let me come back to the, the animal model question for a second, or the animal testing model, because it's sometimes easy to forget that humans are not just really large mice. [laughs] In fact, we are quite different. Are addictive properties of ketamine observed in animal use or self-administration, or is that seemingly unique to higher primates or humans who have all of the [laughs] sort of attendant weaknesses of, l- let's just call it higher functioning [laughs] and neuroses and so on? Is the abuse witnessed in animals?
- JKDr. John Krystal
It's a great question. And what's interesting is that there are some drugs of abuse, like cocaine, that animals love.
- TFTim Ferriss
Love. [laughs]
- JKDr. John Krystal
And humans seem to like as well, right?
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
But ketamine is more like alcohol.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
So there are some strains of rodents that naturally consume alcohol and, or naturally consume ketamine. But generally speaking, you have to kind of gradually introduce them to alcohol or to ketamine, and then they can become compulsive alcohol consumers or ketamine consumers, just like humans. And-
- TFTim Ferriss
Hmm
- JKDr. John Krystal
... it's bad. And the animal models vary between very patient, you know, escalation of alcohol or ketamine. And you give it to them at times when they're most active, like in the dark. Uh, you know, the rodent, mice and 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 or take a little more. And so they go through bouts of exposure to the drug, and then they tend to develop more heavier versions of alcohol or ketamine self-administration.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
They'll self-administr- ketamine, they'll self-administer PCP and other substances from that class.
- TFTim Ferriss
I was speaking with an acquaintance who was commenting on a few subcultures, I w- I won't name them, but a few subcultures in the US that seem to use ketamine extensively as a drug of abuse. And he said, "If anyone claims they're not addicted to ketamine, ask if you can borrow their, look at their inhaler for a second, or their, their insufflator, their nasal applicator, and just stick it in your pocket and see how long it takes them t- to get really agitated and sort of insist on getting it back, like Smeagol from Lord of the Rings." And I will also just add one comment, which is, I think it is very dangerous for people to say or believe or assume, «I do not have an addictive personality, therefore this is not a risk,» because my feeling, based on all my experience, there is a molecule that will get you. There is a molecule that will get you. So I, I think an ounce of prevention is worth a pound of cure, for sure, in this instance. And many of my friends who are experienced psychonauts, at least a few of them, had no prior abuse history with, with any drugs outside of, in this case, ketamine.
- 2:43:25 – 2:50:33
Enantiomers: r-ketamine vs. s-ketamine
- TFTim Ferriss
So let's talk about, you mentioned the R-ketamine versus S-ketamine.
- JKDr. John Krystal
Right.
- TFTim Ferriss
And there are a lot of urban myths from avid consumers of ketamine as to the differences between these two. And who knows? Maybe they know what they're talking about. I think most of them are just bullshitting, frankly.
- JKDr. John Krystal
[laughs]
- TFTim Ferriss
But good at storytelling, and that's their new way of showing off, is talking about how deep their expertise in, in ketamine consumption goes as connoisseurs. But this is just a, a, a question that I'm sure I will embarrass myself in asking. So you're talking about R-ketamine versus S-ketamine. And is it right to say they're kind of mirror images? They're like enantiomers. Is that the word? I'm probably pronouncing it incorrectly.
- JKDr. John Krystal
You've got it. You got the lingo.
- TFTim Ferriss
All right. So just for people who are not looking at video. On the audio, what I'm doing is I'm holding up both of my hands open, palms facing me. So thumbs pointing different directions. A- another way to think of it would be like the state of Michigan [laughs] , the glove, flip it the other way. Okay. So we have these two mirror images, but then I'm thinking to myself, «Well, wait a second. Well, these are not 2D images. These are three-dimensional molecules. So if I rotated one of my hands 180 degrees, would they not be the same thing?» So I'm [laughs] just very confused-
- JKDr. John Krystal
Yeah. By the-
- TFTim Ferriss
... by this right and left-handed shorthand that is sometimes used to describe the differences in these two, because it fe- it, it, it seems like, well, if I had flipped one 180 degrees, you would have effectively the same molecule. the same series of hydrogen and carbons or configuration, would they not bind in exactly the same way? Could you just, uh, shed some light on that?
- JKDr. John Krystal
Well, first, I think you do a great job of portraying the R and S enantiomers.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
That was very impressive.
- TFTim Ferriss
Thanks.
- JKDr. John Krystal
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 thr- three-dimensional space. So what you couldn't portray is that when you overlaid your two hands in a way that made the sequence of the molecules in the two, in the two isomers similar, was that in one case, the first carbon might be sticking into the plane. But in the other case-
- TFTim Ferriss
Ah.
- JKDr. John Krystal
The carbon was sticking out of the plane.
- TFTim Ferriss
Right.
- JKDr. John Krystal
And so that when you saw the actual structure in three-dimensional space, they actually occupied them in ways-
- TFTim Ferriss
Yeah
- JKDr. John Krystal
... that couldn't be one where you couldn't superimpose one on the other. They're actually-
- TFTim Ferriss
Got it
- JKDr. John Krystal
... turning in opposite directions. And, and that turns out to make a big difference because R-ketamine is somewhere between three and five times less potent in its ability to block 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, too complicated for us to, 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. And the fact that there's that differential affinity for ketamine has been taken up by the pharmaceuticals industry wh- where you have different companies developing alternatives to ketamine that target a s- just a subtype of the NMDA glutamate receptor to block, and that's a whole other area that's being developed by the, by the pharmaceutical industry. But, uh, when we go back to R versus S-
- TFTim Ferriss
John, may I interrupt for one second?
- JKDr. John Krystal
Sure.
- TFTim Ferriss
So when people just say ketamine, is that a third molecular configuration versus R and S, or is it just a lazy shorthand that is omitting one of those?
- JKDr. John Krystal
So when people say ketamine these days, they're talking about the mixture of the R and the S molecules.
- TFTim Ferriss
I see.
- JKDr. John Krystal
So the standard, uh, ketamine that we studied was a mixture of R and S. And, uh, when people say esketamine, which is the version of ketamine that was developed by, uh, Janssen Pharmaceuticals, that's the S isomer, which is more potent at blocking the NMDA glutamate receptor. The idea being ketamine has a more potent and less potent blocker. Let's develop a treatment that blocks the NMDA receptor more potently, and the 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 R-ketamine, is one of two strategies, and it's not clear to me which strategy will be followed. One strategy says R-ketamine has a different binding profile at NMDA receptors and other targets. And so the ratio of its affinity for NMDA versus these, uh, targets is different than esketamine. So if we bring R-ketamine up to the same dose as esketamine, the same o- comparable occupancy of NMDA receptors, maybe it'll be a little bit more tolerable.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
The alternative idea is, what if R-ketamine works through some other target? Maybe it doesn't work through the NMDA receptor.
- 2:50:33 – 2:59:05
How effective is ketamine for chronic pain relief?
- TFTim Ferriss
So I have a f- a few things just to bookmark for folks or mention for folks, and then I have a question about other applications of ketamine, because I would be remiss if I didn't mention my own personal experience. But first, I just wanna talk about [chuckles] a bit of trivia. People should look up another piece of trivia, the origin, the etymology of the word trivia Three roads meeting. In any case, people should look it up. It's, it's pretty fun. Separately, I have read a theory, a description of a theory that has, has postulated that the origin of human tendency to alcohol abuse originates from [laughs] from our simian ancestors who would find fruit that was fermenting and consequently become somewhat intoxicated, but that it was an evolutionary driver. It was a, a fitness advantage for natural selection to be able to not just identify and find fermenting fruit, but to consume it and to be inclined to consume it. So I, I don't know if there's any scientific consensus or [laughs] acceptance of this, but relatively recently came on my radar, which I thought was at least interesting as a thought exercise. The, the application, potential application, uh, I'd like to get your two cents on the scientific support for this, that I experienced firsthand was going in for my series of ketamine infusions, which just as a, a comedic side note, in these intake questionnaires, they would always ask, you know, anxiety on a scale of one to 10. And I, I mean, starting from nothing, what I always do with these one to 10 questionnaires, because how the hell do you know? I... On some level. I mean, if it's, if, if it's a pain scale, I think it's a little bit easier, right? It's like, okay, one is, "I can't feel it," 10 is, "I need to go to the emergency room immediately." Okay, fine. But on the anxiety, I always choose five. If it's the first session for anything, I choose five so that I can go above or below on subsequent intake forms. And I was doing, I think it was three a week, and I was, I was coming in without any depression at the time, but I, I had a packed schedule of podcast recording. And so my anxiety kept going up over time because it was screwing up my ability to prepare for the podcast 'cause my short-term memory was vanishing. [laughs] And, and the, uh, the nurse practitioner said, "I've never seen anything like this. You just keep getting worse." And I'm like, "Well, it's not the full picture, but yeah, that's fine." However, what I did realize about a week after my two weeks of infusions, chronic pain that I'd had on my, the left side of my thoracic region of my back had completely vanished, and it remained gone for probably five or six months minimum. And it was the first time in my adult life that I had gone pain-free for that period of time with this, this thoracic carryover from a severe injury many, many years ago. Is there much published literature to support using ketamine, and I don't know if this... I would imagine it is related to NMDA receptors, to reboot or otherwise treat chronic pain?
- JKDr. John Krystal
The answer is yes. There are two kind of interesting parts of this. One is the NMDA receptors are, are in the pain pathways. They're, it, they're, 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, 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.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
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 Huda Akil 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, they're very helpful for controlling pain for many people. But if you have, like, you know, neuropathic pain, a old sports injury, back pain, or, you know, 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. And so NMDA antagonists can be a path for reducing the pain that can't be reduced by the opiates and restoring sensitivity to the opiates so that people don't need to use so much opiates to control their pain afterwards.
- TFTim Ferriss
Mm.
- JKDr. John Krystal
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 gonna do some things to the nerves to make it possible to replace the knee and, and, and that there's a risk for some chronic pain related to that knee replacement. As you know, because you've just said it, ketamine interferes with neuroplasticity and, and while the ketamine is in your system, can interfere with the encoding and the neuroadaptations associated with memory and so, uh, produce, uh, some temporary memory impairment. Well, it does the same thing for learning in the pain pathway.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
So if you pre-treat people with ketamine and have ketamine in their system when they undergo the, 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 a, an operation like that to reduce the development of neuropathic pain. So it can be used to treat pain and to prevent it.
- TFTim Ferriss
I mean, what I found most incredible about the experience was the durability of the pain relief. This is not a scientific explanation because I haven't done the proper homework to be able to speak to that, but it seemed like there are certain motor patterns that we learn to associate with pain, even if the mechanical dysfunction or damage has ceased to be an issue. Right now, m- in the case of my midback, there are actually some spinal issues, but let's just say you do a squat, you blow out your knee, and then for six months it hurts to squat. After that point, mechanically you're intact, but you have learned that a certain motor pattern is dangerous, and so your body delivers a learned pain signal in some capacity. It, it seems like, [sighs] at least to me, that there was, as you mentioned, a learned aspect to this that was over-sensitizing, and that that was rebooted or disabled with the use of ketamine. Maybe to use a different analogy or metaphor for folks, like imagine that if you got severely sunburned, after the sunburn had passed, you would retain a certain sensitivity to the sun, an oversensitivity as a, like, prophylactic learned precaution so that you would not get sunburned again. You know, something like that. It's not the best comparison, but you get the idea.
- 2:59:05 – 3:03:09
Why might the durability of relief outlast the presence of ketamine in the body?
- TFTim Ferriss
How do you explain the durability of the effects? Because the, the half-life of ketamine, it's long gone pretty quickly, but the pain relief, I mean, complete pain relief, it wasn't 10% better, it was 100% better, lasted at least six months, and that, that I found just staggering. How do you explain that?
- JKDr. John Krystal
[laughs] Well, that's a great question. I don't know that I can explain six months, but what I can say is... So the first thing you said, which was that your whole body adapted to having pain in, 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, and pain.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
And a lot of what we're managing when we're managing pain is our emotional response to the pain.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
And if you tone down the depression and anxiety, then you discover that the pain is actually much more manageable, because a- anxiety and depression focuses our attention 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. And so I think that there are many levels where, in many potential ways, the neuroplasticity part of it, the depression and anxiety, cognitive part of it, the ability to engage, um, uh, uh, a, a variety of strategies to suppress the pain signals of, 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.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
So I think one, one of the things that you're describing is that ketamine helped you to be resilient in the face of a potential source of pain and, and so that you lived the life of a person who didn't have pain, and you discovered that when you did that, you didn't have pain.
- TFTim Ferriss
Yeah, I like the comparison to PTSD. I mean, you can imagine, and this is getting into an entire different, uh, class of the [laughs] I guess it's not really a phenethylamine. That would be more MDA. But if we're looking at MDMA-assisted psychotherapy for PTSD, the memory is the same, right? The, the traumatic experience and the memory thereof may be the same, but it's how you contextualize it and relate to it that seems to contribute to the diagnosis or non-diagnosis of PTSD. It's not a perfect comparison, but certainly the sort of phenomenology, the, the subjective experience that is reported by many patients is that they were able to go back, revisit this memory that would normally be re-traumatizing or make them hyperreactive and produce this huge physiological response, and calmly engage with it as their present-day self, as sort of an observer to metabolize it such that it doesn't have that complete grip. It's not consuming for them afterwards. And just by comparison, in the same way that if somebody has acute pain, I know that when, when I've had acute pain in my midback, it dominates everything. I mean, it is, it is the background color of anything that is written upon it in my mind. And so to have that removed was just incredible.
- 3:03:09 – 3:04:31
What is s-methadone?
- TFTim Ferriss
Let's, uh, let's hop... We talked about r-ketamine. Here's one that I Don't know anything about, but it's, it's in some notes, so I would love to, uh, hear you describe in any capacity s-methadone. What is s-methadone?
- JKDr. John Krystal
S-methadone is yet another drug that blocks NMDA glutamate receptors, and is a drug that has some potential to treat depression. The other isomer of methadone is the methadone that we associate with opiate maintenance.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
So this is the inactive isomer of methadone, which works by blocking NMDA glutamate receptors. And, and there's some preliminary data that's encouraging for the treatment of depression. You know-
- TFTim Ferriss
Mm-hmm
- JKDr. John Krystal
... it's really important that, you know, 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, and it- it'll probably be the case with NMDA glutamate receptor antagonists that ketamine works for some people, and some people, they don't like the side effects. They, they go to another NMDA receptor antagonist, and maybe that one will work. So that- that's a drug that has some potential in that regard.
- 3:04:31 – 3:07:56
Does s-ketamine have the same abuse potential as r-ketamine?
- TFTim Ferriss
Hmm. Coming back to s-ketamine versus r-ketamine, and this is a simplistic question, but I'm wondering if s-ketamine is a more potent antagonist, if I am getting my terminology straight, does that mean that s-ketamine has at, at the same dose as r-ketamine more abuse potential? I'm wondering if, if one or the other appears to have or hypothetically should have more abuse potential.
- JKDr. John Krystal
So the animal data with r-ketamine have been pretty encouraging about a- abuse potential, but we don't have enough experience in, in humans to really be able to say. S-ketamine, i- it's true that it's more potent at n- at the NMDA receptor. It's also a little bit more potent at the mu opioid receptor than r-ketamine.
- TFTim Ferriss
Hmm.
- JKDr. John Krystal
And, and so there's been some discussion about the abuse liability of s-ketamine.
- TFTim Ferriss
That's because of the mu opioid receptor effect, or...?
- JKDr. John Krystal
I think it's both.
- TFTim Ferriss
Okay.
- JKDr. John Krystal
There's been a tendency to be more concerned about the mu opioid receptor activity than the NMDA receptor antagonist activity. But in my view, that's a bit of a distraction because a ketamine, s-ketamine is much more potent at NMDA receptors than at mu opioid receptors. At least it's more potent, right?
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
It's 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 NMDA antagonist is. You know, the rate of ketamine use disorders has been going up since the, uh, about 2018 or so in the United States, so we do want to be careful about that.
- TFTim Ferriss
Yeah, I wonder how, how much that is also correlated to just general increases in diagnosed. We have to be a little careful about assuming that all of these things are on an upswing. Not referring to ketamine abuse, but just because the detection or reporting or diagnosis can also become a trend in itself, right? If you develop better technology for scanning and identifying brain tumors, lo and behold, brain [laughs] tumors appear to be exploding, but it doesn't mean their prevalence wasn't the same beforehand. In any case, what I was gonna say is it, it seems like with the advent of social media and the sort of social proof approval culture that is so heightened by those tools, it just, it seems to me, and this is also just watching my audience, that the prevalence of just chronic anxiety, depression, certainly we saw during COVID a sharp increase in, in suicide hotline volume. I wonder if ketamine and maybe alcohol abuse are also correlated because people are just looking a way f- to numb themselves, to turn off certain feelings. I don't know the answer to that. But,
- 3:07:56 – 3:09:58
Opiate receptor interaction with ketamine and other compounds.
- TFTim Ferriss
you know, I wanted to mention one thing, which, which is the only other, apart from alcohol, and if I'm being honest, I don't really know how alcohol exerts its effects on the psyche and the subjective experience. But the only other dissociative that I have some familiarity with is Salvinorin A, which is a high-efficacy kappa-opioid receptor agonist. And I'm wondering to what extent the dissociative effects of ketamine are dependent on that opiate receptor interaction versus other receptors.
- JKDr. John Krystal
So 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.
- TFTim Ferriss
Huh. Okay.
- JKDr. John Krystal
And, and that we think is a major contributor about why the, the subjective effects of a low enough dose of ketamine are often described like similar to a glass of wine.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
And if you get your alcohol dose high enough, let's say it's been reported that you can get numbing, uh, distortions impairments in 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 6 and 10 drinks of alcohol.
- TFTim Ferriss
[laughs] It's quite, yeah, quite a few, depending on the timeframe. Yeah. [laughs]
- JKDr. John Krystal
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
- 3:09:58 – 3:14:34
What is Salvinorin A?
- JKDr. John Krystal
a dose of ketamine.
- TFTim Ferriss
Okay. Could you explain what naltrexone is? I mean, I, I know what it is, but yep.
- JKDr. John Krystal
An opiate receptor blocker. At low doses, it preferentially blocks the mu opiate receptor, the morphine receptor.
- TFTim Ferriss
Mm-hmm.
- JKDr. John Krystal
At higher dose, if you give a high dose, it also blocks the delta opiate receptor, which is the main target or a main target for the enkephalins, 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.
- TFTim Ferriss
Yep.
- JKDr. John Krystal
So if we give a, a pretty high dose of naltrexone and give ketamine, we don't change the dissociative effects of ketamine at all.
- TFTim Ferriss
You do not?
- JKDr. John Krystal
Do not. Not at all.
- TFTim Ferriss
Huh. Wow.
- JKDr. John Krystal
What we do is we tend to make a low dose of ketamine less pleasant for people. Then they get a little more anxious.
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
They don't like it as much. But they don't, it doesn't block the dissociative effects. Now, salvinorin, if you give it, it's a very short-acting drug in, in humans. My colleagues Cyril D'Souza and Mohini Ranganathan dosed salvinorin, and you can get this very intense kind of psychedelic state-
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
... in, in people that is relatively short-lasting. 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 euphoric genic, and they still rate a lot of the psychedelic-
- TFTim Ferriss
[laughs] Salvinorin A tends to be highly dysphoric. [laughs]
- JKDr. John Krystal
Exactly.
- TFTim Ferriss
Most people will say, "I never, ever in my life want to do that again."
- JKDr. John Krystal
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 a- 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, the kappa opiate receptor is thought to contribute to some of the anhedonic symptoms of depression.
- TFTim Ferriss
The inability to feel joy.
- JKDr. John Krystal
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. And, uh, anyway, so my brother did a study as part of a consortium and gave a kappa opiate receptor blocker, in other words, the reverse of salvinorin-
- TFTim Ferriss
Yep, yep
- JKDr. John Krystal
... 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-
- TFTim Ferriss
Hmm
- JKDr. John Krystal
... with this kind of mechanism, a kappa opiate an- antagonist. And so people are actually interested in the kappa opiate receptor blockers as potential treatments for some aspects of depression.
- TFTim Ferriss
Super interesting. Yeah, I will say, just to, to also put salvinorin A in context that more people may recognize, salvinorin A is isolated from a ethnomedical plant called Salvia divinorum. It's been used by indigenous populations, certain indigenous populations like the Mazatecs, for hundreds, probably thousands of years. And before you ever touch this stuff, go on YouTube and search smoking Salvia divinorum, and you will see dozens of videos of people who d- thought it was a good idea to set up a camcorder or a [laughs] iPhone before they did such a thing, and they will try to escape by running into walls, smashing through windows, flipping over couches, because they're so terrified [laughs] of this experience. So just, uh, the more you know, Smokey the Bear. Definitely think about it at least 37 times before you casually partake in, in any of these things. Okay. With that, thank you for providing all that context. So fascinating to me. Let's see here.
- 3:14:34 – 3:32:06
Exploring the ups and downs of optimizing ketamine with rapamycin.
- TFTim Ferriss
Going from risks of ketamine to alternatives to ketamine or complements possibly, right? Not necessarily replacements for, but depending on the subpopulation, what works and what doesn't work. Let's talk about ways to optimize ketamine. What are some of the means by which we might extend the efficacy, improve the safety? Wherever you wanna take that, what are some of the potential ways or future ways to go about optimizing ketamine?
- JKDr. John Krystal
Let's start with the end, if you will-
- TFTim Ferriss
Mm-hmm
- JKDr. John Krystal
... which is 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
- TFTim Ferriss
Mm-hmm
- JKDr. John Krystal
Right? We would call that basically cure. And we never use the word cure in psychiatry, and 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, the changes that we see there. So let's start just with, uh, the shortest version of that, which is what if we could take ketamine, which 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 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 shorten the duration of the effectiveness of ketamine. And so we've been interested in that question for a long time. And, and we did a study that really spurred our interest in this question, and it was led at our site by my colleague, Chadi Abdallah. And what we did was to try to block a certain molecular switch that gets triggered when you give ketamine. Downstream, one of the proteins that gets activated inside nerve cells that triggers the regrowth of those, uh, synaptic connections. That protein's called mTOR, and the drug we use to manipulate it is called rapamycin. It's a blocker of mTOR. Now, you'll recall from the animal studies that mTOR activation was implicated in the antidepressant effects of ketamine. And so we did a study to try to show that that was somehow involved in humans. We gave the highest dose of rapamycin, the mTOR blocker, that we felt would be perfectly well-tolerated by everybody in the study. Rapamycin is an immunosuppressing drug. And that was in our mind as well for a reason that I'm gonna 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 rapamycin. And the remarkable thing was that the response rate at two weeks when they got just ketamine was about 13%. And when they got the same people, the same depression, if they had gotten pretreated with rapamycin, their response rate was over 40%.
- TFTim Ferriss
I'm no scientist, but that seems non-trivial.
- JKDr. John Krystal
It seemed to us to be non-trivial. It was also a little bit perplexing i- in the sense that we knew we were giving a drug that had the potential to block mTOR in the brain. And if mTOR activation was critical, then why didn't rapamycin block the antidepressant effects of ketamine? And o- one of the ideas that we are wrestling with is maybe the immunosuppressive effects of rapamycin, which is a po- is a powerful immunosuppressant, are related to its ability to extend the antidepressant effects of ketamine. And in particular, you, you may recall that I said that the antidepressant effects of ketamine, 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.
- TFTim Ferriss
I'm fascinated by microglia. I just like saying it, too. But yes, microglia. Please continue.
- JKDr. John Krystal
Yeah. So microglia are really interesting because they have different modes of function. In certain circumstances, they can promote nerve growth in the brain. In another circumstance, when synapses get immunologically tagged, they can surround them and literally eat them up. 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 then we think they contribute to the initial deficits in, in synaptic density in depression.
- TFTim Ferriss
Are microglia correlated or is there a causal relationship between our subjective experience of stress and microglia activity?
- JKDr. John Krystal
Yes. 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, I don't understand what we found [laughs]
- TFTim Ferriss
[laughs]
- JKDr. John Krystal
... so I can't really explain it. 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, a- an exhausted state."
- TFTim Ferriss
Microglia are tired. [laughs] They're on the bench, out of the game. [laughs]
- JKDr. John Krystal
Exactly, something like that. You know, I don't really know, and I don't think anybody does what's, what's going on with the microglia. But it's, it's really interesting to me that you have these two stress-related disorders, one like major depression, where the, where you get a lot of cortisol in the body and the microglia tend to be activated in the brain. And then 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 microglia 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 of ketamine, 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, you know, like a full course of treatment. How long does rapamycin extend the, the antidepressant effects of ketamine? 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.
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
So we'll have to do, you know, longer studies to figure that out. But we're really interested in developing this idea, both from the point of view of academic research, and I have a, a colleague that I've collaborated with for many years, uh, Tom Hsu in, in Taipei, who is, uh, doing a study, uh, 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, uh, within a company called, uh, Freedom Biosciences that I'm, I'm associated with.
- TFTim Ferriss
Touching again on the rapamycin plus ketamine, certainly people can go on PubMed and search mTOR and ketamine, and there are a lot of... There's a lot to read. If you haven't published this, then of course, no need to, no need to get into it, or if you don't want to disclose it, that's fine too. But what was the, what was the dosage range that you decided upon, or maybe the s- precise dosage or protocol for the rapamycin that you determined or hypothesized would be well-tolerated?
- JKDr. John Krystal
Gosh, I think it's six milligrams.
- TFTim Ferriss
Six milligrams. Okay.
- JKDr. John Krystal
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 th- we, 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 active clearance mechanism. And so what we think we did was to stumble on a combination that was in a kind of a sweet spot, high enough to interfere with the gobbling up of the synapses, but not so high to interfere with the antidepressant effects. So a little bit of serendipity.
- TFTim Ferriss
Oh, I feel like a lot of science is, [laughs] uh, serendipity and knowing when to pay attention to it. Seems like that's one of the more exciting pieces of scientific discovery, is being able to spot those serendipities that matter. Let me ask, uh, actually just mention something. Please fact-check me if I'm not getting this correctly. But first, I want to emphasize what you said, and that is that rapamycin is an immunosuppressant, and at higher doses than we're discussing are used for, for instance, organ transplants and things along those lines. Was the frequency of administration of the oral rapa at five milligrams, was that once a week? Were you... Or less? Was it a one-time administration? How frequent in the intervention group? I don't know what the arms were in the study, but, uh, exactly. But how frequently would any one individual receive that rapamycin?
- JKDr. John Krystal
So first, Tim, I think the point that you make about this is a experimental procedure. It's not really not ready for primetime. 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, you know, it's very preliminary data in some ways, even though it's a very robust finding. But it was just a single dose of rapamycin given-
- TFTim Ferriss
Okay. Got it
- JKDr. John Krystal
... with that single dose of ketamine. And that was what was so striking to us because rapamycin lasts a little longer than ketamine, but it doesn't last two weeks. [laughs]
- TFTim Ferriss
Yeah.
- JKDr. John Krystal
So really, the possibility that there's some synergy between the two treatments is really a possibility from the preliminary findings.
- TFTim Ferriss
It's very exciting. It's very exciting. And the, the reason I ask is that for people listening, as you said, this is a powerful drug. You have to be very careful with it. You cannot just gobble this stuff like Tic Tacs and expect to turn out well. And My very primitive understanding is that if one were taking rapamycin as a monotherapy for, say, life extension, which is very, uh, I mean, I don't want to call it very speculative, but it's, it's certainly not main, uh, [chuckles] mainstream at this point, or for other purposes. My very cursory understanding is that you're, you're trying to have an effect on mTOR such that you trigger certain things like autophagy and sort of, uh, cellular cleaning and repair, but not so much that you bleed into, I think it's mTOR two territory, where you start to really experience the immunosuppressant effects because you then run the risk of, uh, greater likelihood of infection. If you become infected, greater severity of infection. You have to be very careful with it. So in any case, a fascinating, fascinating drug. In case people were wondering, rapamycin named after Rapa Nui, which is the native term applied to Easter Island, where the bacterium, I guess, was first isolated that relates to mTOR. Pretty fascinating stuff. But let me also just ask a novice question about microglia and glial cells. I assume they're related, but the description I read of the glial cells is that they're, in a sense, the connective tissue of the nervous system. They provide physical and metabolic support to neurons. How do you think about ensuring that the sort of Zambonis of the brain are able to do what they need to do while potentially inhibiting microglia enough to get these types of clinical outcomes that you're hoping for?
- JKDr. John Krystal
Yeah. This has been the, one of the most intriguing parts of the ketamine work, and it is, again, one of the most intriguing parts of the rapamycin 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 rapamycin. We want the Zambonis to clean up the ice.
Episode duration: 3:59:54
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