#625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever

Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever | Brought to you by Athletic Greens http://athleticgreens.com/tim all-in-one nutritional supplement, Helix Sleep http://helixsleep.com/tim premium mattresses, and Allform http://allform.com/tim premium, modular furniture. Dr. John Krystal https://medicine.yale.edu/profile/john_krystal/ is the Robert L. McNeil, Jr., Professor of Translational Research; Professor of Psychiatry, Neuroscience, and Psychology; Chair of the Department of Psychiatry at Yale University; and 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. He is best known for leading the discovery of the rapid antidepressant effects of ketamine in depressed patients. He directs/co-directs the Yale Center for Clinical Investigation (CTSA), NIAAA Center for the Translational Neuroscience of Alcoholism, and Clinical Neuroscience Division of the National Center for PTSD (VA). Dr. Krystal is a member of the U. S. National Academy of Medicine; co-director of the Neuroscience Forum of the U. S. National Academies of Sciences, Engineering, and Medicine; Fellow of the American Association for the Advancement of Science (AAAS); and editor of Biological Psychiatry, one of the most selective and highly cited journals in the field of psychiatric neuroscience. He is the co-founder and Chief Scientific Advisor of Freedom Biosciences https://www.freedombio.co/, a clinical-stage biotechnology platform developing next-generation ketamine and psychedelic therapeutics that recently emerged from stealth in August 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. Please consult your doctor before considering anything we discuss in this episode. Please enjoy! * This episode is brought to you by Helix Sleep http://helixsleep.com/tim! Helix was selected as the #1 overall mattress of 2020 by GQ magazine, Wired, Apartment Therapy, and many others. With Helix http://helixsleep.com/tim, there’s a specific mattress to meet each and every body’s unique comfort needs. Just take their quiz—only two minutes to complete http://helixsleep.com/tim—that matches your body type and sleep preferences to the perfect mattress for you. They have a 10-year warranty, and you get to try it out for a hundred nights, risk-free. They’ll even pick it up from you if you don’t love it. And now, Helix is offering up to 200 dollars off all mattress orders plus two free pillows at HelixSleep.com/Tim http://helixsleep.com/tim. * This episode is also brought to you by Athletic Greens https://www.athleticgreens.com/tim. I get asked all the time, “If you could use only one supplement, what would it be?” My answer is usually AG1 https://www.athleticgreens.com/tim by Athletic Greens https://www.athleticgreens.com/tim, my all-in-one nutritional insurance. I recommended it in The 4-Hour Body in 2010 and did not get paid to do so. I do my best with nutrient-dense meals, of course, but AG https://www.athleticgreens.com/tim further covers my bases with vitamins, minerals, and whole-food-sourced micronutrients that support gut health and the immune system. Right now, Athletic Greens https://www.athleticgreens.com/tim is offering you their Vitamin D Liquid Formula free with your first subscription purchase—a vital nutrient for a strong immune system and strong bones. Visit AthleticGreens.com/Tim https://www.athleticgreens.com/tim to claim this special offer today and receive the free Vitamin D Liquid Formula (and five free travel packs) with your first subscription purchase! That’s up to a one-year supply of Vitamin D as added value when you try their delicious and comprehensive all-in-one daily greens product. * This episode is also brought to you by Allform http://allform.com/tim! If you’ve been listening to the podcast for a while, you’ve probably heard me talk about Helix Sleep mattresses, which I’ve been using since 2017. They also launched a company called Allform http://allform.com/tim that makes premium, customizable sofas and chairs shipped right to your door—at a fraction of the cost of traditional stores. You can pick your fabric (and they’re all spill, stain, and scratch resistant), the sofa color, the color of the legs, and the sofa size and shape to make sure it’s perfect for you and your home. Allform http://allform.com/tim arrives in just 3–7 days, and you can assemble it yourself in a few minutes—no tools needed. To find your perfect sofa and receive 20% off all orders, check out Allform.com/Tim http://allform.com/Tim. * [07:30] The challenges faced by John’s late father, Henry Krystal. [14:44] Was Henry’s work discussed around the Krystal dinner table? [18:10] What people frequently misunderstand about depression. [25:53] Why partial response and non-response occur commonly in psychiatry. [32:15] From the serotonin hypothesis to “what’s really exciting” about antidepression research. [35:08] How monoamine oxidase inhibitors reduce symptoms of depression. [36:41] MAOI Side effects and risks. [40:14] When Western medicine duplicates centuries-old shamanic wisdom. [43:13] How pre-imaging neuroscience of the ’80s was like Ptolemaic astronomy. [47:24] The reason for depression isn’t as simple as a lack of serotonin. [49:42] The change in perspective that illustrated ketamine as a potential therapy. [54:35] From first studies to overcoming skepticism. [1:02:39] How ketamine went from “horse tranquilizer” to antidepressant candidate. [1:18:46] The dose makes the difference. [1:23:02] What is dissociation, and is it an essential part of ketamine’s healing process? [1:37:32] Recommendations for optimal treatment of a close friend (frequency, duration, psychotherapy, etc.). [1:50:42] Reducing the potency of maladaptive memories. [1:56:15] Best dosage practices. [2:03:23] I. M. vs. I. V. [2:04:55] Common in-session side-effects (and remedies). [2:09:19] What my ketamine experience was like. [2:12:41] Optimal settings. [2:18:05] Ketamine risks. [2:30:22] Decreasing the opportunities for abuse and addiction. [2:37:28] Enantiomers: r-ketamine vs. s-ketamine [2:44:19] How effective is ketamine for chronic pain relief? [2:52:28] Why might the durability of relief outlast the presence of ketamine in the body? [2:56:12] What is s-methadone? [2:57:31] Does s-ketamine have the same abuse potential as r-ketamine? [3:00:46] Opiate receptor interaction with ketamine and other compounds. [3:05:56] What is Salvinorin A? [3:07:05] Exploring the ups and downs of optimizing ketamine with rapamycin. [3:23:28] Ketamine doesn’t have a lot in common with other psychedelics. [3:26:47] The effect of ketamine and other hallucinogens on the thalamus. [3:29:57] How important is the role of brain-derived neurotrophic factor (BDNF)? [3:32:20] BHB, ethanol-free alcohol, and exercise vs. depression. [3:35:31] Ketamine’s impact on sleep, and the potential dangers of too much exercise. [3:37:27] What John anticipates for the future of ketamine research and application. [3:41:51] Giving credit to the pioneers of the field. [3:43:21] Parting thoughts. * For show notes and past guests on The Tim Ferriss Show http://tim.blog/podcast, please visit tim.blog/podcast https://tim.blog/podcast/?utm_source=podcast&utm_medium=podcast&utm_campaign=podcast-description. For deals from sponsors of The Tim Ferriss Show http://tim.blog/podcast, please visit tim.blog/podcast-sponsors http://tim.blog/podcast-sponsors Sign up for Tim’s email newsletter (5-Bullet Friday) at tim.blog/friday https://go.tim.blog/5-bullet-friday-1/. For transcripts of episodes, go to tim.blog/transcripts http://tim.blog/transcripts. Discover Tim’s books: tim.blog/books http://tim.blog/books. 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• 0:00Tim Ferriss?

  This episode is brought to you by Helix Sleep. Helix Sleep is a premium mattress brand that provides tailored mattresses based on your sleep preferences. Their lineup includes 14 unique mattresses, including a collection of luxury models, a mattress for big and tall sleepers, that's not me, and even a mattress made specifically for kids. They have models with memory foam layers to provide optimal pressure relief if you sleep on your side, as I often do and did last night on one of their beds. Models with more responsive foam to cradle your body for essential support in stomach and back sleeping positions, and on and on. They have you covered. So how will you know which Helix mattress works best for you and your body? Take the Helix Sleep quiz at helixsleep.com/tim and find your perfect mattress in less than two minutes.

• 0:42Tim Ferriss?

  Personally, for the last few years, I have been sleeping on a Helix Midnight Luxe mattress. I also have one of those in the guest bedroom, and feedback from friends has always been fantastic. They frequently say it's the best night of sleep they've had in ages. It's something they comment on without any prompting from me whatsoever. Helix mattresses are American-made and come with a 10- or 15-year warranty, depending on the model. Your mattress will be shipped straight to your door, free of charge. And there's no better way to test out a new mattress than by sleeping on it in your own home. That's why they offer a 100-night risk-free trial. If you decide it's not the best fit, you're welcome to return it for a full refund. Helix has been awarded number one mattress by both GQ and Wired magazines.

• 1:23Tim Ferriss?

  For you, my dear listeners, Helix is offering up to $200 off of all mattress orders and two free pillows. Go to helixsleep.com/tim. That's helixsleep.com/tim. Helix, H-E-L-I-X, sleep.com/tim. Or click the link in the episode's description. Helixsleep.com/tim. With Helix Sleep, better sleep starts now. This episode is brought to you by Allform. If you've been listening to this podcast for a while, you've probably heard me talk about Helix Sleep and their mattresses, which I've been using since 2017. I have two of them upstairs from where I'm sitting at this moment. Helix has gone beyond the bedroom and started making sofas.

• 2:06Tim Ferriss?

  They've launched a company called Allform, A-L-L-F-O-R-M, and they're making Premium customizable sofas and chairs shipped right to your door at a fraction of the cost of traditional stores. So I'm sitting in my living room right now and it's entirely Allform furniture. I've got two chairs, I've got an ottoman, and I have an L sectional couch. And I'll come back to that. You can pick your fabric. They're all spill stain and scratch resistant. The sofa color, the color of the legs, the sofa size, the shape to make sure it's perfect for you and your home. Also, Allform arrives in just three to seven days and you can assemble it all yourself in a few minutes, no tools needed. I was quite astonished by how modular and easy these things fit together, kind of like Lego pieces. They've got armchairs, love seats, all the way up to an eight-seat sectional, so there's something for everyone.

• 2:51Tim Ferriss?

  You can also start small and kind of build on top of it if you wanted to get a smaller couch and then build out on it, which is actually in a way what I did because I can turn my L sectional couch into a normal straight couch and then with a separate ottoman in a matter of about 60 seconds. It's pretty rad. So I mentioned I have all of these different things in this room. I use the natural leg finish, which is their lightest color, and I dig it. I mean, I've been using these things hours and hours and hours every single day. So I am using what I am sharing with you guys. And if getting a sofa without trying it in-store sounds risky, you don't need to worry. Allform sofas are delivered directly to your home with fast, free shipping, and you get 100 days to decide if you want to keep it. That's more than three months, and if you don't love

• 3:34Tim Ferriss?

  it, they'll pick it up for free and give you a full refund. Your sofa frame also has a forever warranty that's literally forever. So check it out, take a look. They've got all sorts of cool stuff to choose from. I was skeptical and it actually worked. It worked much better than I could have imagined, and I'm very, very happy. So to find your perfect sofa, check out allform.com/tim. That's A-L-L-F-O-R-M dot com slash tim. Allform is offering 20% off all orders to you, my dear listeners, at allform.com/tim. Make sure to use the code TIM at checkout. That's allform.com/tim and use code TIM at checkout.

• 4:11Tim Ferriss?

  At this altitude, I can run flat out for a half mile before my hands start to shake. Can I ask you a personal question?

• 4:18Speaker 01

  Now would be an inappropriate time.

• 4:22Speaker 02

  I'm a cybernetic organism, living tissue over metal endoskeleton.

• 4:34Tim 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

• 5:14Tim Ferriss?

  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 Cristel. Dr. John Cristel is the Robert L. McNeil Jr., Professor of Translational Research, Professor of Psychiatry, Neuroscience, and Psychology, Chair of the Department of Psychiatry at Yale University, and the Chief of Psychiatry and Behavioral Health at Yale New Haven Hospital. Dr. Cristel 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

• 5:55Tim Ferriss?

  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, NIAA, Center for Translational Neuroscience of Alcoholism, and Clinical Neuroscience Division of the National Center for PTSD. Dr. Cristel's a member of the U.S. National Academy of Medicine, co-director of the Neuroscience Forum of the U.S. 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.

• 6:39Tim Ferriss?

  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,

• 7:19Tim Ferriss?

  very wide-ranging, very nuanced, and I give that credit to Dr. Crystal, conversation with Dr. John Crystal.

• 7:30Tim Ferriss?

  Dr. Crystal, it is good to see you again. Thank you for making the time for this conversation. I really appreciate it.

• 7:37Speaker 01

  Well, my pleasure.

• 7:39Tim 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 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?

• 8:05Speaker 01

  My father was a psychiatrist and psychoanalyst named Henry Crystal, and he passed away a number of years ago. He was born in the town of Sosnowiec in Poland in 1925, and 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 concentration camps. Importantly, you know, names people would probably recognize would be Auschwitz, Sachsenhausen, Buchenwald. And he survived the concentration camps.

• 8:44Speaker 01

  And he was the only member of his family to survive. So he was captured at the age of 14. And by 1718, when he came out of the camps, was alone in the world, essentially. He went to school, attained some schooling in Germany, and then came to the United States where he had an aunt who put him up. 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 because, for whatever reason, they were very potent.

• 9:24Speaker 01

  And he was able to get a scholarship to Wayne State University for college, and then another scholarship to go to medical school. And along the way, he mastered English and 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 had been analyzed by Freud, whose view of psychiatry had to do with people embracing all aspects of themselves and becoming kind of integrated human beings,

• 10:08Speaker 01

  and that that was a path towards both a healthy life and a fulfilling life, which was an idea that my father also not only embraced in his work, but embraced in his life. And ironically, my name is John, J O H N, which is not commonly the name given to Jewish children, who often named Jonathan instead. But I'm called John because I'm named after Dr. Dorsey, who was Irish. So my dad became a psychiatrist, and in his work evaluated people who survived the Holocaust for reparations to the German government.

• 10:53Speaker 01

  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 more than a thousand 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 1950s, 1960s,

• 11:36Speaker 01

  almost 20 years before the diagnosis of post-traumatic stress disorder existed. And what happened was that he and a colleague of his, Bill Nederland from New York, they developed this idea of survivor syndrome, the psychological consequences of trauma, that became one of the cornerstones, along with the work of many others, such as Robert J. Lifton and others, for what became the diagnosis of post-traumatic stress disorder. And his work throughout his career about the trying to understand the roots of resilience and vulnerability and to develop treatments that would help people to manage

• 12:22Speaker 01

  the impact of psychological traumas, that was his life work 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 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, the way that he survived in the concentration camps of recognizing and seizing opportunities that arose for him and realizing what was happening and seizing these kinds of opportunities, which enabled him to survive,

• 13:06Speaker 01

  were also profound life lessons that in pursuing what one

• 13:12Speaker 01

  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 post-traumatic stress disorder and have a huge positive impact.

• 13:56Speaker 01

  So I have no doubt that 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 thought were important 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 and would read religions. He would read history, he would read neuroscience, he would read philosophy, he would pursue almost any field 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

• 14:40Speaker 01

  I approach everything that I do.

• 14:45Tim Ferriss?

  Thank you for sharing that, John. And it's 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 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

• 15:14Tim Ferriss?

  New York Times piece, which I believe was effectively upon your father's passing. And I'll just read 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, "I feel that, quote unquote, 'healthy infantile omnipotence is the most important asset for dealing with life stresses and potential trauma,' Dr. Crystal wrote in a chapter he contributed to Living with Terror, Working with Trauma: A Clinician's Handbook." And I'll shorten this to end the quote with, "It is in an emotional mainspring of extraordinary reserves.

• 15:54Tim Ferriss?

  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, I would love to, to hear anything that comes to mind.

• 16:10Speaker 01

  First, I want to reassure you that he was like a normal person. And so like, he would never talk about the omnipotent interjected object at the dining room table.

• 16:21Tim Ferriss?

  Right.

• 16:22Speaker 01

  You can imagine people have all kinds of ideas about what psychoanalysts talk about over dinner, and mostly it was just pretty much bread and butter things. The second thing is that I think about is that he believed that the parent-child interaction was fundamental to all human resilience. And that in that kind of nurturing, supportive interaction, lay the root of optimism. And that having a sense that no matter what is happening around you, that there's still the possibility that things will work out okay.

• 17:04Speaker 01

  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

• 17:47Speaker 01

  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 is a natural byproduct of a nurturing childhood experience.

• 18:11Tim Ferriss?

  Well, let's use that as a perfect leaping point to hop into some of the, say, the salt and bread, the meat and potatoes of some of the subjects that we'll cover. Because looking at your bio, just as an example, Dr. Crystal's leading expert in the areas of alcoholism, post-traumatic stress disorders, schizophrenia and depression. It sounds like a roll call for one of my family reunions. 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

• 18:51Tim Ferriss?

  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.

• 19:35Tim Ferriss?

  And I think that is the scariest part. So perhaps we could begin with just 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.

• 20:07Speaker 01

  So 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 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 it's not, that kind of experience isn't what we're talking about when we talk about depression. What we talk about depression is more about the experience that you're talking about. The way that depression can be a pervasive mode of being that invades every aspect

• 20:52Speaker 01

  of one's life and experience of the world. It affects the pattern of your thinking. In other words, instead of, as you say, 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...

• 21:29Speaker 01

  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. And 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 normal contrasts are blunted and colors seem duller 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,

• 22:13Speaker 01

  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 a kind of fundamental negative

• 22:58Speaker 01

  mode of being that they thought was connected to black bile, which in Greek had the name melon for black, cholia for bile, and then has been known as 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...

• 23:32Speaker 01

  React in a normal way to it, but something bad happens to them and they spiral downward in a very negative way, beyond their control, to despair and hopelessness and extreme distress. That is not the typical profile of traditional melancholic depression, but is a kind of reactive depression. One of the things that we appreciate about depression is that 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 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.

• 24:15Speaker 01

  And when I say medical part, is that, that we understand, yes, medical depression is a state of emotional experience, and yes, it's an 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.

• 24:59Speaker 01

  And that means it makes all of those medical illnesses where inflammation is a process worse. If you have untreated depression, on average, it shortens your life, not by suicide, it still shortens your life by about five years. And if you have depression in the context of medical illnesses, it makes the medical outcomes worse, not only the psychological outcomes, but the medical outcomes worse. Depression is a disorder of the spirit, if you will, the brain, but also the whole body. And that's one of the reasons why, number one, it's one of the most disabling conditions

• 25:43Speaker 01

  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.

• 25:54Tim 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 you could just speak to that.

• 26:17Speaker 01

  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 heart attack, for

• 27:00Speaker 01

  heart disease, well, you know, they had a heart attack, but 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

• 27:45Speaker 01

  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

• 28:28Speaker 01

  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.

• 29:11Speaker 01

  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.

• 29:55Speaker 01

  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...

• 30:10Speaker 01

  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.

• 30:53Speaker 01

  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.

• 31:34Speaker 01

  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 will work.

• 32:15Tim Ferriss?

  So let's, if you're open to it, John, give people also a preview of maybe 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 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 going to come back to, and perhaps this will be part of your answer, but limitations of the serotonin hypothesis,

• 32:55Tim Ferriss?

  which has been pervasive. Certainly, it has become, 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.

• 33:13Speaker 01

  If you don't mind, I might track the historical story, because it really takes us from the serotonin hypothesis to what's really exciting. And I told you this before, and I really believe that this is the most exciting scientific time in the entire history of the field of psychiatry, you know, 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 the sunlight is really just beginning to penetrate into our understanding of the brain in ways that are relevant to thinking about the biology and treatment

• 33:53Speaker 01

  of depression and other kinds of issues. So the serotonin story, the serotonin hypothesis, really emerged from the appreciation of the effectiveness of antidepressant medication treatments. The first antidepressant that we had, which was discovered in 1957, which makes it one year older than I am. Was a drug called a monoamine oxidase inhibitor, a drug that prevented the breakdown of norepinephrine and serotonin, two chemicals 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.

• 34:36Speaker 01

  And they discovered that the tuberculosis patients, their tuberculosis was getting better, but so was their depression. And so that 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 reuptake.

• 35:07Tim Ferriss?

  John, before we move on, and I don't want to throw us off track, so we're at tricyclic and then we're going to move forward in the chronology, but I'm so curious, could you just briefly explain the mechanism by which MAO inhibitors improve, or I should say, reduce symptoms of depression? What is actually happening there?

• 35:29Speaker 01

  So the way that monoamine oxidase inhibitors work is by inhibiting an enzyme called monoamine oxidase, which is involved in the breakdown, 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 chemicals. And in that way, they're a little bit like the SSRIs, which instead of preventing the

• 36:09Speaker 01

  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.

• 36:24Speaker 01

  So that they release a little bit and they prevent the uptake. They're actually powerful antidepressants 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, were very commonly prescribed.

• 36:41Tim Ferriss?

  What are the main risks and side effects? And this is tying into something that's been recently on my mind, which I'll bring up in a second, then we'll hop back into the chronology. I won't lose track. But what were the side effects and what are some of the risks of those monoamine oxidase inhibitors?

• 36:57Speaker 01

  As you recall, these monoamine oxidase inhibitors cause a form of release of noradrenaline serotonin and prevent their breakdown. So anything independent of the drug increased the release of noradrenaline serotonin had the potential to produce massive increases in noradrenaline serotonin in the body. And so the problem you get in if you have a massive increase in noradrenaline is you can get big increases in blood pressure that can be life threatening. 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

• 37:39Speaker 01

  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 things that people really enjoy eating. 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 have a negative, a really bad complication, like a stroke or something like that. That happened

• 38:19Speaker 01

  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 was a famous case in New York of someone who was on a monoamine oxidase inhibitor, who was then given demerol in the emergency room and then died from the interaction. So they're really great drugs, but you'd have to be a little careful with them.

• 38:54Tim Ferriss?

  Just a quick thanks to one of our sponsors and we'll be right back to the show. This episode is brought to you by Athletic Greens. I get asked all the time what I would take if I could only take one supplement. The answer is invariably AG1 by Athletic Greens. If you're traveling, if you're just busy, if you're not sure if your meals are where they should be, it covers your bases. With approximately 75 vitamins, minerals, and whole food sourced ingredients, you'll be hard pressed to find a more nutrient dense formula on the market. It has a multivitamin, multi-mineral greens complex, probiotics and prebiotics for gut health and immunity formula, digestive enzymes, and adaptogens. You get the idea. Right now Athletic Greens is giving my audience a special offer on top of their all in one

• 39:37Tim Ferriss?

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• 40:15Tim Ferriss?

  So the reason I'm doing some digging on this is there are several reasons. The first is that there's a collection of presentations from a symposium called ESPD 50, which investigated specifically a monomine oxidase inhibitor called HARMINE. And the reason they were looking at HARMINE is because HARMINE, HARMALINE, and I believe there's at least one other monomine oxidase that we've identified, exist in the Benastereopsis copi vine, which is one of the two typical ingredients in ayahuasca. And the reason that I bring it up is that for a long time,

• 40:59Tim Ferriss?

  For simplicity, I'll just say Western scientists largely dismissed the vine and ascribed to it one purpose, and that was to render the NNDMT found in chacruna, there are 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 monoaminooccase 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 drive neurotrophic factor, BDNF. And that's part one. Part two is, and I did not

• 41:41Tim Ferriss?

  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 outcome related, there are restrictions, there are food restrictions that include cheese and fermented products. I don't know the tyramine content of fermented foods.

• 42:22Speaker 01

  Yeah.

• 42:22Tim Ferriss?

  But certainly alcohol, 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 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 lists to be notable. That's why I bring it up. So to come back to the the chronology, you went from MAO inhibitors to tricyclic antidepressants, and then we

• 43:06Tim Ferriss?

  were moving closer to present day, if you, if you wouldn't mind continuing.

• 43:12Speaker 01

  My colleagues, the people that I trained with and have had my career with, in particular, my mentor, Dennis Charney, with whom we did the first ketamine study. They spent their careers trying to figure out what was the role of these chemicals, serotonin and norepinephrine, in depression 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

• 43:56Speaker 01

  as a way to try to figure out what was going on in the brain.

• 43:59Tim 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, if I'm hearing you correctly, you're trying to infer what is happening inside by observing what is happening outside? Is that?

• 44:17Speaker 01

  That's right.

• 44:18Tim Ferriss?

  A fair way to put it?

• 44:19Speaker 01

  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? 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 other.

• 45:02Speaker 01

  And that's really where psychiatry was in the 80s. And this was the bleeding 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, building on the work of an alum, a graduate of our department who moved to McGill, Claude de Montagnier, 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.

• 45:43Speaker 01

  And you can drop the level of serotonin in the blood and in the body and in the brain. And we could use that technique. Pedro Delgado really led the clinical projects in those days. We 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? Couldn't be a more basic question, but we didn't know. 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 other amino acids to drive protein synthesis

• 46:27Speaker 01

  and use up all the free tryptophans 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 an ongoing way, to have a big supply of serotonin. 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 neuroadaptations associated with serotonin synapses really underlay the antidepressant effects

• 47:10Speaker 01

  as an initial and 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. 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 underpressed. We knew that idea was wrong right from the start. Because you take a tablet of Prozac, you do not get underpressed from a single tablet of Prozac. It can happen.

• 47:54Speaker 01

  It's extraordinarily rare, and it usually doesn't last when that occurs. But the world is really complicated, 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. So it's not that there aren't some acute effects and that those effects aren't related to depression.

• 48:38Speaker 01

  It's just that this simple-minded idea that low serotonin equals depression, normal serotonin equals healthy life, that idea is, we knew pretty much from the start, couldn't possibly be true as it was initially suggested. The other thing that 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

• 49:23Speaker 01

  work of people like Ramin Parsi and others, that do find some changes in the regulation of certain serotonin receptors that may be intrinsic to the biology of depression. So I'm not in any way arguing for a really simple-minded idea of depression. But I do want to highlight that 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

• 50:07Speaker 01

  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 brainstem, that these primitive cells could be the cause of this pervasive syndrome of cognitive behavioral, et cetera, et cetera, impairment. Probably was 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 so in those days when these experiments were going on, Dennis Charney, who was the

• 50:52Speaker 01

  now my boss, 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 little office on the eighth floor. 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? And the answer was, that we came to was, let's turn it on, let's turn the brain on its head. Gosh, that's a really weird turn of phrase, but yeah, let's turn this problem aside down. If depression isn't a disorder of these really simple and few serotonin cells in

• 51:37Speaker 01

  the brain, then maybe it's 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.

• 52:22Speaker 01

  Serotonin and norepinephrine tune 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. These higher brain centers predominantly use two neurotransmitters, glutamate, which accounts for something like 90% of the synapses of the brain, the main information highway of the brain, 90% of the synapses, the main excitatory driver for brain activity,

• 53:02Speaker 01

  and GABA, which is the main inhibitory transmitter 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, the magnitude of excitation and the timing of excitation and the spatial dispersion of activity in the brain, and GABA balancing and 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?

• 53:42Speaker 01

  Serotonin is maybe a couple of percentages of the synapses in the brain. Glutamate is 90%. Psychiatry had been studying depression for 50 years by that point, put all of its chips on serotonin and norepinephrine, the 2%, and completely ignoring the 98% 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'd 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

• 54:25Speaker 01

  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. And we designed a study, and we gave ketamine to depressed patients. And ketamine did transiently produce some cognitive impairment and some changes and things like that, lasted 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, we're on. And within a couple of hours, people said, you know, I'm feeling a little better.

• 55:10Speaker 01

  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? Do you have any hangover? Do you have any lasting effects? Did you sleep okay last, the night before? And they said, you know what? My depression's all better. And we said, what? And, 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 really good croissant, and the next day, they really feel better. Fantastic. But that, you know, we don't really, we didn't really think, you know, with the first-

• 55:55Speaker 01

  Can't rely on the croissant effects. Exactly. But it happened over and over and over in this pilot study. And 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, no, people got a dose of ketamine and the next day, they were, several of them were better. And they'd say, right. You know, skepticism overall.

• 56:34Speaker 01

  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.

• 56:50Speaker 01

  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 Hussani Manjy and Carlos Sarati 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 it produced these antidepressant effects.

• 57:35Speaker 01

  And now what we need are definitive trials because we really 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. It's not, 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

• 58:13Speaker 01

  presentation and the early 2000s that, that 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 incredible trailblazing scientist, remarkably brilliant and talented neuroscientist and a wonderful person and colleague and friend. And he did this study in collaboration with George Agagianian. Now, for those in the psychedelic world, you may be familiar with that name, but George

• 58:58Speaker 01

  Agagianian 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. 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 George Agajanian and Ron Dooman

• 59:41Speaker 01

  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 this builds on an idea that really came first from the pioneering scientist Bruce McEwen, who is just another wonderful person and scientist, who was based at the Rockefeller University, that if you stress animals, severe stress over a period of time, a long period of time, that not only do they have behavioral changes, but that those behavioral

• 1:00:21Speaker 01

  changes are associated with the loss of the synaptic connections in the brain. That the 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, 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 loss of connections between nerve cells in the brain are a part of that series of events.

• 1:01:04Speaker 01

  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 is we're not making random new connections in the brain. That would be a bad thing. The brain is not chaotic structure.

• 1:01:48Speaker 01

  And we don't want to 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 parts of the brain. What we do is overcome whatever intrinsic resistance there is to recovery in the brain to 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 of how ketamine works in the brain. That insight happened around 2010, and that was really fundamentally important in terms

• 1:02:30Speaker 01

  of driving the whole field forward and helping to reduce a lot of the skepticism about ketamine as a treatment.

• 1:02:39Tim Ferriss?

  So looking at the timeline, I just want to recap a little bit, and 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 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 going to come back to that. 1997, your first presentation of results. 2000, first paper is published. 2006, publication of the first

• 1:03:23Tim Ferriss?

  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

• 1:03:42Tim Ferriss?

  Animal research with ketamine. So for people who really have no history on ketamine, and I want you to fact check this 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 and veterinary medicine, but it's not a horse tranquilizer per se, which is, I think, what some people believe. But it is used in medicine, and it is one of the World Health Organization's most essential medicines. And this is a pervasive

• 1:04:21Tim Ferriss?

  anesthetic. How did Ron or others involved with the animal research even choose that as an intervention to begin with?

• 1:04:33Speaker 01

  So first, I have to tell you about a cartoon that I saw about ketamine related to its use as a horse tranquilizer, which is, it's, the cartoon says, and it's, 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.

• 1:04:55Tim Ferriss?

  That's good.

• 1:04:57Speaker 01

  At the time that I was studying ketamine, I was interacting regularly with this broader group of people. Rondouma was at Yale, George Agachanian at Yale, Eric Nessler, Dennis Charny, obviously, my collaborator and mentor, and many other people. So, one of the things that was really striking was when we had made this finding with ketamine and shared the results with Ron, I had the feeling that Ron thought that it was more important than we did. So, you know, he would say, this is like the most important finding in 50 years? And we would say, what?

• 1:05:38Speaker 01

  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 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 there's been some work to show that that might happen in human brain as well. And he was one of the pioneers of studying the role of neurotrophic signaling in depression and its treatment. So his laboratory had all the pieces of the story about how nerve growth might be involved in antidepressant treatment.

• 1:06:23Speaker 01

  And so he was, in some ways, uniquely situated to discover this profound structural change. And what was really important about the work is not only that they described the profound structural change, but they mapped the molecular signaling mechanisms that you alluded to about nerve growth factors engaging a fundamental mechanism for resilience in the brain, these growth factors, as a consequence of chemical communication in the brain. So although ketamine is a glutamate receptor blocker, one of the things that it does is block the excitation of inhibition inhibitory cells. That's a really complicated...

• 1:07:06Speaker 01

  It's like 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. So ketamine allows more glutamate release to happen in certain circuits of the brain. You get a pulse, if you will, of glutamate, which is good for the brain, as opposed to sustained high levels of glutamate, which is toxic for the brain. The brain is really sensitive to temporal dynamics. 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.

• 1:07:52Speaker 01

  And activates signaling. And then a key way station, and I'm going to get a little technical because I know we're probably going to come back to this point later. A key way station in the signaling of the nerve growth factor is a protein in nerve cells that's got the name mTOR or mtorc. And mTOR is the mechanist is called 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

• 1:08:32Speaker 01

  that lead to the regrowth of these and stabilization of these new synaptic connections. This might be a good time to come back and think about a little bit about the complexity of the neurobiology of glutamate abnormalities in depression. Is this a good time? Do you think this would be a good time to do it?

• 1:08:51Tim Ferriss?

  Or do I think we should do that? But I want to just follow up on what you said to ask, how was the hypothesis formed at all that ketamine, instead of a million other interventions or 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

• 1:09:36Tim Ferriss?

  and that led to hypothesis generation 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 going to mess around with ketamine?

• 1:09:53Speaker 01

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

• 1:10:10Tim Ferriss?

  To be clear, this isn't specific to you. It's just, I'm so fascinated by the genesis stories of these things. I think they're important. So I'd love to hear the real story as opposed to the Santa Claus version.

• 1:10:22Speaker 01

  So the real story is not related to depression at all. It's related to schizophrenia. So it so happens in the great cosmic universe of coincidence that a friend of my dad's in Detroit and his family was a friend of our family and we went on vacation together. I remember intertubing down a river in northern Michigan, I grew up in Michigan, intertubing down a river with his daughter. We were maybe 10 or nine or 10 at the time. His daughter is now is named Joan Luby. She's now an endowed professor and expert in child psychiatry

• 1:11:04Speaker 01

  at Washington University in St. Louis. Anyway, this fellow's name was Elliot Luby. And in 1959, he published a paper that was the first time fencycloidine or Cernul was given to a human being. This happened at the Lafayette Clinic in Detroit, an entity, a building which no longer exists, unfortunately, an extremely, extremely generative place in its era. And he said, if you gave Cernul, which was the company name for fencycloidine, PCP, Angel Dust, if you gave it to people, it produced something like schizophrenia

• 1:11:46Speaker 01

  in them. 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 83, 84. So it was this fascinating observation, which couldn't go anywhere scientifically. But they did research, and this is going to bring us to other topics that we'll probably talk about, in which they compared the effects of fencycloidine to the effects of LSD in people.

• 1:12:26Tim Ferriss?

  Good old psychomimetic.

• 1:12:28Speaker 01

  Yeah.

• 1:12:30Speaker 01

  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.

• 1:12:53Tim Ferriss?

  Great name, too.

• 1:12:56Speaker 01

  Yeah, my cousin, Tom, I apologize for mentioning his name, who was a medical student at the University of Michigan, brought me to sit in one of his classes when I was applying to medical schools, and it just happened to be Ed Domino. And my friends, my cousin and his friends, when Ed Domino came up to talk, sang a bit of the Van Morrison song Domino, which you may be familiar with. Anyway, unforgettable to me because Ed became a very dear friend and colleague over the years, but Ed was the first to give ketamine to animals and humans, because it was a shorter

• 1:13:38Speaker 01

  acting, safer version of a small structural modification in the phenylcholine chemical structure that made it possible to be shorter acting, more manageable, easier to control.

• 1:13:53Tim Ferriss?

  And for what reason was he administering the ketamine in those particular studies?

• 1:13:58Speaker 01

  For anesthesia.

• 1:14:00Tim Ferriss?

  For anesthesia, got it.

• 1:14:01Speaker 01

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

• 1:14:36Speaker 01

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

• 1:15:20Speaker 01

  of pioneers had an incredible tool, but no conceptual framework to use it to generate real, deep scientific insight. And that's because they were 30 years ahead of the field. And, you know, it wasn't even known that there was a binding site for phenylchylate. So, first studies published in 1959, it wasn't even known that there was a binding site for phenylchylate.

• 1:15:48Tim Ferriss?

  Now, by binding site, you mean a receptor that it could...

• 1:15:51Speaker 01

  Some kind of something that where the drug act in a... They didn't know that it acted in a specific way at a specific target in the brain. What that target was, they didn't yet know until the early 1980s, that it was a glutamate receptor. But they just didn't even know that there was a binding site for phenylchylate until a landmark paper in 1979 from Steve and Suzanne Zuccan. So, it was darkness, right? It was like the Middle Ages of neuroscience. And so, they had a brilliant insight, but they couldn't take it anywhere because there was no framework for it. So, around 88, 89, joined the faculty

• 1:16:34Speaker 01

  in 88 Yale. And I wasn't sure what I was going to do. And my boss said to me, Dr. Chiney said, "Well, you can be the chief of the schizophrenia program or the deputy chief of the PTSD program." And I said, "Well, I like the idea of being the chief."

• 1:16:59Speaker 01

  That's how I went into the field of schizophrenia researcher. And so I found myself as a new, completely inexperienced schizophrenia researcher, setting up a research program related to the neurobiology and treatment of schizophrenia. And it happened to be just at that time that clozapine, which is an antipsychotic medication that's a little bit more effective than other antipsychotics, was introduced. And I'd been raised studying monoamine pharmacology. That's what I knew. That's really what I had anticipated studying. I treated patients with clozapine and I thought it was a pretty good medication.

• 1:17:43Speaker 01

  But I didn't want my legacy after 40 years of schizophrenia research to be that you figured out why clozapine was a little bit more effective than other antipsychotic medications. So I felt like I just had to go out of the box. And this is where my father's legacy really had had a big impact. It's like, well, if you could do anything, what would you do? And it was like, well, I don't want to study these few cells contributing to dopamine or norepinephrine. I want to study the main information highway of the brain. And just a few years before, they figured out that drugs like ketamine, PCP, blocked

• 1:18:28Speaker 01

  this receptor for glutamate. And so what brought me to ketamine was really the effort to probe glutamate synaptic function in higher cortical circuits as a way of understanding the cognitive impairments, negative symptoms, and other aspects of schizophrenia. So our path in our institution, my path, was the development of a research program on glutamate psychopharmacology, developing circuit and mechanistic hypotheses. And one of my collaborators in those days was a pharmacologist named Bedamokadam.

• 1:19:08Speaker 01

  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. And, you know, that line of research has its own story because we began using the ketamine administration as a platform for trying to identify novel alternatives to antipsychotic medication for the treatment of schizophrenia. And, and that has had its own life and story, and maybe someday we'll, we'll talk about that.

• 1:19:53Speaker 01

  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 those doses. And if you give it at even a little bit lower level, it doesn't stimulate the glutamate release. There's this tiny, narrow window 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.

• 1:20:36Speaker 01

  We just stumbled on that. Because it was optimal, you know, the thing was, we couldn't give higher doses to people because we needed them to perform cognitive tests and be able to answer our questions. When we gave people much higher doses of ketamine, they would have pretty interesting experiences, but they couldn't answer any of our questions. So it wasn't any good for me as a research tool. I mean, I remember one person that we gave this higher dose of ketamine to, who couldn't answer a lot of our questions, but he was holding on to the bed really tightly. And, um, and I said, Well, that's interesting. Why were you holding on to the bed? He said, well,

• 1:21:19Speaker 01

  basically, the dress, the blue in the dress of the interviewer had become outer space. The white polka dots in her dress had become planets and solar systems. And his bed was flying among the planets and the, and the, you know, 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 not make it back. Well, that was really fascinating.

• 1:21:48Tim Ferriss?

  Seems reasonable.

• 1:21:50Speaker 01

  Yeah, it was really, really interesting, but useless. I couldn't get him, he couldn't do any tests. He couldn't perform anything. So what that essentially did was create the upper bound of the dosing that we were using with ketamine. And then the lower doses just turned out to be completely ineffective and have repeatedly been shown to be so in single doses in antidepressant trials. So that's how we got to ketamine. And that's how we got to the dose of ketamine and the route of ketamine that we 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?

• 1:22:32Speaker 01

  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 risemic ketamine administration for the treatment of depression.

• 1:23:02Tim Ferriss?

  So John, may I, may I interject for a second? So I want to talk about I think 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 or a bug, whether that is important for the clinical

• 1:23:44Tim Ferriss?

  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 effects that we see, the antidepressant effects?

• 1:24:18Speaker 01

  You know, sometimes I have started papers on dissociation and stopped because I would get hung up on what the definition of dissociation is. But our consciousness, our experience of the world, our sense of ourself in the world, our sense of our bodies, our sense of ourselves embedded in time, all of these things which people take for granted are constructions of our brain, active constructions. And when these fundamental aspects of the organization of consciousness are perturbed, we experience ourselves as disconnected from ourselves, whether it's depersonalized

• 1:25:03Speaker 01

  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.

• 1:25:48Speaker 01

  I got interested in dissociation because of working with Vietnam veterans with post-traumatic stress disorder, for whom dissociation is a complication or a part of the syndrome of post-traumatic stress disorder for many people. And it's a whole nuanced range of things, from these states of feeling disconnected and that things are not real, to sensory distortions, to what people know as a very dramatic aspect of PTSD, which are these flashbacks, where people are completely absorbed in another state and lose touch with what's happening around them.

• 1:26:27Speaker 01

  And so, one of the things that was exciting about the initial ketamine research was, it was not only providing us a way, a new way to think about the neurobiology of psychosis and cognitive impairments associated with schizophrenia, but it was also, at the same time, providing us with really the first pure neurobiological path to studying the neurobiology of dissociation and PTSD, and that's a whole other kind of discussion, which we can come back to. So what about dissociation in the antidepressant effects academy? This is really an interesting and complicated question because to really answer your question,

• 1:27:08Speaker 01

  you have to acknowledge, I have to acknowledge that I come from, I'm a translational neuroscientist and psychiatrist. I do work on trying to understand the most basic aspects of biochemistry, synaptic signaling, network function, computational modeling, whatever. 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 so a lot of people say that the dissociative experience is a very meaningful experience for them, particularly if there's some kind of guided experience to do that. And I have no argument with that whatsoever. I, why not?

• 1:27:52Speaker 01

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

• 1:28:28Tim Ferriss?

  That sounds unpleasant.

• 1:28:29Speaker 01

  Yeah, you know, stuff like that. And that is not a productive insight and it's not healing. It's not important for them to even remember that after the ketamine is worn off. So I would say the dissociation is clearly not a necessity in terms of producing attitude change and things like that. I would also say that some people, they get the ketamine and I once had a, treated a guy, or it wasn't, it was a research study, but I gave him a dose of ketamine. He had never, 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 he described ketamine as the most fun he ever had since he arrived at Yale. So it was like a roller coaster of doing all these things.

• 1:29:14Speaker 01

  And so, I mean, it clearly has that part to it. As well. So the question is, is dissociation telling us something important? And I think there are ways that it does on my side of the street, which is that, as I've mentioned, it just so happens that the dose of ketamine that is optimal for inducing the antidepressant effects is for many people, the dose at which they experience dissociative symptoms. I mean, the dose that produces the therapeutic effects, the dose that produce dissociation overlap. And so that if you're giving a dose of ketamine that is, is not producing any dissociative symptoms, for some people, it will mean you have

• 1:29:55Speaker 01

  underdosed the ketamine. And there are 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, as they do have a built in tolerance, some of them, to the effects of alcohol. And that's another story, which we can get to if you want sometime. But my colleagues, Arina Estaldis and Sophie Holmes, and the broader group of collaborators with Yale Pet Center, did a study, which I think is incredibly important and interesting, related to the neurobiology of ketamine, which sheds light a little bit on dissociation.

• 1:30:40Speaker 01

  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 molecular tag for synapses. And so, okay, so there are these depressed patients who have reductions in synaptic density. Great. So far, that could be relevant to translating the animal work to the human work. 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,

• 1:31:25Speaker 01

  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 an increase in synaptic density. And the more dissociative symptoms they get, the bigger the increase in synaptic density. And the bigger the increase in synaptic density, the greater their clinical improvement. Pilot data, really preliminary, but very interesting. So it suggests that in people who have synaptic density deficits, that dissociative symptoms produced by ketamine can be a marker that you've got enough ketamine into the brain and you're triggering the therapeutic antidepressant effects.

• 1:32:10Speaker 01

  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 dissociation in these two groups of patients during ketamine means two different things. In one, it's a signature of clinical improvement. And another, it's not.

• 1:32:50Speaker 01

  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? So I'm going to take a step back to point out that reduction in the density of synaptic connections in the brain isn't the only kind of glutamate abnormality that we have in depression. Another kind of abnormality that we've seen in people with PTSD and depression, and that

• 1:33:35Speaker 01

  was published this year also from, the first author is a colleague, Chadi Abdallah, who's now at Baylor College of Medicine. Using a really newfangled clever technical technique, where we can give a isotopically tagged infusion of acetate or glucose, and then track its incorporation into a variety of metabolic intermediates in the brain. This technique allows us to measure two things. One is how much glutamate's being released, and how much metabolic activity is triggered. So you can say, "Amount of metabolic activity per glutamate."

• 1:34:18Speaker 01

  It's a measure of the effectiveness of that synaptic connection. How much is glutamate able to activate the brain? Low 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.

• 1:34:38Tim Ferriss?

  Not necessarily a deficit in synaptic density, but just a decreased efficiency.

• 1:34:46Speaker 01

  Exactly. Another deficit. So, one of the ideas related to that is that probably that reduction in efficiency, efficacy, is present more broadly in depression. And only a subgroup of the more severe chronic, more treatment-resistant depression have the reduction in synaptic density. 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

• 1:35:27Speaker 01

  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 Zirati. 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 sensory evoke potentials, the ability of a sensory input to activate the brain. And you can measure that electrical or magnetic signature, if you will, using this technique. That's a little bit blunted in depressed patients.

• 1:36:11Speaker 01

  And if you give a single dose of ketamine to patients with depression, you'll discover that there are two groups. Those people who don't respond don't show any change in the magnitude of this evoked response in the brain. But the people who do respond show an increase in the evoked response. In other words, the synaptic connections get potentiated functionally and not structurally. And so what we take from these kinds of studies and others like FMRI studies and other things from ketamine is that ketamine has the ability both to increase the functionality of synapses, something that probably happens very rapidly within hours of ketamine administration.

• 1:36:51Speaker 01

  And for some people will be the bulk of their antidepressant response and restore synaptic connections. And that happens in a more delayed way and is involved in sustaining for many people the antidepressant response. And we know a lot about the mechanisms because it directly emerges out of Ron Duman's work and B. Tomogatane's work. We know a lot about the biology of the restoration of structural connectivity. And we know much less at this point about how ketamine restores the efficiency of the network. But it's kind of, my sense is that both are probably contributing to the clinical effect.

• 1:37:32Tim 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 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.

• 1:37:59Speaker 01

  I wouldn't use that word.

• 1:38:00Tim Ferriss?

  Well, well.

• 1:38:01Speaker 01

  Subtypes.

• 1:38:02Tim Ferriss?

  Subtypes, there we go. I feel like I'm kind of allowed to play it fast and loose since I fit into the broad category of someone who has treatment-resistant depression. So I feel like I can sling loosely, but you have different responses to 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 the, 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 I think about, for instance,

• 1:38:42Tim Ferriss?

  cardiology and dealing with lipid markers that are out of whack and how brute force and nonspecific certain approaches are. High cholesterol, statins, instead of automatically doing that, which can be a tool in the toolkit determining if one is a hyper absorber of cholesterol versus a hyper producer of cholesterol versus 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 can imagine that in a group of depressed, self-described depressed

• 1:39:27Tim Ferriss?

  patients, even if they take an assessment, like a, not sure what the proper assessment would be, like a Hamdi 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. And to just, again, I'm speculating here, but to, to then jump from that, I can imagine that for some people, perhaps those who also respond to

• 1:40:07Tim Ferriss?

  the dissociative effects, or let me be clear, have a high correlation of positive improvement 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 want to dive into this further with you, but.

• 1:40:43Tim Ferriss?

  Having gone through a five infusion, well, I 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 presented differently for them.

• 1:41:25Tim Ferriss?

  These are just thoughts that are occurring to me as we're talking and we're going to dig into all sorts of this. Let me ask, if I may, just because I think people are chomping at the bit for this and then we're going to go in a bunch of different directions. If you had, say, a 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, miggs per kigs or weight dependent or whatever? But what might it look like? Because before we start recording and also based on what you said perhaps 10, 15 minutes

• 1:42:08Tim Ferriss?

  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 narrow dosing window. But also, there are all these other questions. Intravenous versus intramuscular versus something else? Is there therapy during the session or only before and after? 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?

• 1:42:40Speaker 01

  The first thing is the choice of esketamine versus intravenous ketamine. And it's really not clear how they stack up against each other in terms of efficacy and tolerability. There's a clear difference in ease of use, which is if you're the sort of person who doesn't like needles, getting the medication intranasal is a huge benefit. And if you're the sort of person who doesn't like sticking things in your nose, then getting ketamine intravenously would be a benefit. And that sounds like a trivial thing, but there are a lot of people who don't get a lot of treatment because they're afraid of needles.

• 1:43:23Speaker 01

  And that can be a problem for, for some people. And esketamine can be given intranasally and that's really, can be given in more settings that might be more congenial and all has all kinds of other implications.

• 1:43:35Tim Ferriss?

  And for the sake of our hypothetical, let's say this person is not averse to needles. So IV or intramuscular is okay.

• 1:43:42Speaker 01

  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 esketamine. And because of the fixed milligram dose of esketamine, some people start, it's recommended that you start at 56 milligrams of esketamine and then work your way up, if you tolerate that, to 84 milligrams. And that means that for many people, they're going to start on a dose which is not the maximally therapeutic dose for them, or maybe even an ineffective dose for them before they get to a therapeutic dose.

• 1:44:26Speaker 01

  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 you're, 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 early to say because we don't, we don't only have good head to head data. It's mostly derived from secondary.

• 1:44:59Speaker 01

  Comparison of secondary data, secondary analyses. But for some people, there may be an advantage of the intravenous dose.

• 1:45:05Tim Ferriss?

  I'd love for you to also just speak to the cost differences, potentially.

• 1:45:09Speaker 01

  The cost differences, eskadamine is a little bit expensive medication. It's about 600 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, at least 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. But sometimes it's the individuals paying out of pocket and ketamine is obviously generic and much less expensive.

• 1:45:38Tim 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? 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.

• 1:46:14Speaker 01

  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, you know, another hour or two and then head out. And they'll do that for the initial four weeks, at least four weeks. They'll do it twice a week. Most people after four weeks of twice a week will go to once a week. And if they tolerate that, eventually they'll go to once every other week. And after a longer term treatment, several months, some people will go to every three weeks, sometimes as infrequently

• 1:46:59Speaker 01

  as once a month and be able to be maintained on ketamine after that. People will come in, do a short term course, six treatments, 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 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 then they'll be done.

• 1:47:42Speaker 01

  But others will need ongoing, some kind of ongoing maintenance treatment to sustain the benefit.

• 1:47:47Tim Ferriss?

  So let's just say 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, we said this in the introduction, and I will have recorded this by the time this comes out. 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 tapering, so to speak, not tapering, but the greater distribution after that?

• 1:48:28Tim Ferriss?

  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?

• 1:48:44Speaker 01

  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 multiple days in a row, might produce more lasting benefit. I don't think we can conclude that yet from the from the evidence that we have. So we tend to do twice a week. In my view, For treatment-resistant depression, this is a pretty good strategy.

• 1:49:29Speaker 01

  The question about how to wrap psychotherapy around this is really an interesting one. And there are some important points to make about ketamine generally before going into the wraparound treatment, because in my view, ketamine is an intervention and it's part of an overall treatment. In other words, that it's really important that somebody is thinking about the overall well-being of the patient, providing support, providing oftentimes psychotherapy, and thinking about how the other medications that patients are taking are interacting with ketamine, and looking out in a big-picture way for the overall well-being of patients. Ketamine's an intervention embedded in overall treatment.

• 1:50:13Speaker 01

  And for many people, there is some kind of ongoing psychotherapy. And there's evidence that because ketamine increases the neuroplasticity of the brain, that there may be synergy between ketamine and other treatments that are given outside of the ketamine session. In other words, oftentimes sessions 24 hours after. And that these sessions can both potentially extend and augment the effectiveness of ketamine. A paper by Sam Wilkinson here at Yale suggests that. 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.

• 1:50:58Speaker 01

  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 Harpaiz-Rotham is that if you activate trauma memories during the ketamine infusion...

• 1:51:22Speaker 01

  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 impede their overall ability to be advocates for the groups that they're often committed to. In other words, say combat veterans to their fellow combat veterans, or rape survivors to other rape survivors. And oftentimes, they believe that the trauma memories are a burden, but in some ways valuable to them. And I would want to reassure anybody who is in that kind of state, that we're not talking about removing or deleting memories in any way.

• 1:52:07Speaker 01

  That all we're trying to do is to reduce the intensity of these memories, so that they don't interfere with the ability to achieve things in life, and they don't 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. And what we don't yet know is how it fits in the overall treatment of these folks, in the sense that there are some signs that you can reduce the potency of a particular trauma memory, so that you can talk about the worst event that ever happened, and now

• 1:52:48Speaker 01

  it doesn't trigger a whole exacerbation of their PTSD symptoms, but it doesn't necessarily resolve the broader issues. And this is partly a bit about what I'm talking about, about the broader psychotherapeutic context 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 you can, there is a sign that not only craving for alcohol, but actually alcohol consumption may be reduced, from a preliminary study conducted by a group in London, Ravi Das's the lead author on that paper, it was in Nature of Communications a few years ago. And people are trying to develop that into a treatment for alcohol use disorder.

• 1:53:29Tim Ferriss?

  Quick question on that. Is that independent of the content of the session? In other words, is that a pharmacological factor? Is that in combination with, say, bringing up maybe early trauma that they attribute their alcohol use disorder, alcoholism to?

• 1:53:52Speaker 01

  This is one of the kind of really interesting byproducts of ketamine in relation to other drugs like 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 that memory into a somewhat labile state. In other words, you can strengthen the impact of that memory by rehearsing it in a negative way. And in fact, we think that's part of how PTSD develops. You have a negative trauma memory. You bring it up, you rehearse it. It gets more powerful, 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.

• 1:54:37Speaker 01

  And your reaction and expectation of trauma becomes triggered every time that memory gets activated. The same thing is like an addiction. Use the alcohol, you like it. Use it again, you like 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. 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 may be relevant to some addictions. It may be relevant to PTSD. And particularly relevant to PTSD because in a large, for its kind of large study that we published this year with about 50 patients in the group

• 1:55:21Speaker 01

  where we compared standard dose ketamine to a lower dose ketamine to placebo in people with military-related PTSD, that we found that there was a robust antidepressant effect, but a really weak and didn't quite meet statistical significance effect on the core PTSD 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 of the ketamine infusion 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

• 1:56:06Speaker 01

  will have a major clinical response just to the pharmacologic effect of the drug, even if no reactivating of memories happens during the infusion.

• 1:56:16Tim Ferriss?

  All right, 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?

• 1:56:40Speaker 01

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

• 1:57:25Speaker 01

  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 still get some efficacy. So it's a really narrow range. I mean, if you think about almost any medication that you take, 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 that with a 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

• 1:58:07Speaker 01

  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. And we don't know if those treatments are effective for various conditions or not really at this point. But whatever they're doing, they're not doing what the traditional antidepressant dose of ketamine is doing.

• 1:58:34Tim Ferriss?

  So let me ask a few follow-up questions. Well, actually, let me just maybe explain for folks. If 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?

• 1:59:15Tim Ferriss?

  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?

• 1:59:35Speaker 01

  It depends really whether it's a clinical or research procedure. So when we do research with ketamine, we give a bolus and then a slow infusion to maintain that peak level of ketamine throughout the test period, because this gives us a longer period of time where the brain has a steady exposure for ketamine, where we can really do brain imaging studies or 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 when he got a big bolus right up, because you get the full effects within about 30 seconds or a minute of the infusion.

• 2:00:19Speaker 01

  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.

• 2:00:33Tim Ferriss?

  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 0.5 milligrams per kilogram. So that would be 20, if I'm not screwing this up, 20 milligrams total. One option would be the 0.5 milligrams every minute for 40 minutes. And if it were a bolus, certainly there are some clinics I've observed

• 2:01:12Tim Ferriss?

  who might administer 20 or 30% of that total in the first handful of minutes. So my question is, for you, if you think there are, 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 is acceptable. If you're looking at clinical outcomes with depressed patients, do you think there is a difference between the continuous administration, the waiting into the pool versus the bolus in the beginning? And if you do use a bolus for a clinically depressed patient,

• 2:01:57Tim Ferriss?

  what does that potentially look like, just as a percentage of the total, over what period of time in the beginning?

• 2:02:02Speaker 01

  We don't have data to really inform us. But in theory, what we want to do is to get up to a certain occupancy of the NMDA glutamate receptor. And as far as I can tell, that's the critical thing. So if we get there quickly, or if we get there a little more slowly, so far, it seems like both.

• 2:02:25Speaker 01

  Have the potential to produce an antidepressant response. What is different is that if you took the infusion rate and doubled it. And so you said, we're going to give you the same. And I think my math, if my math is correct, 80 kilograms, half a milligram, kilogram would be 40 milligrams. I'm going to stick to my math. This should be right. This should be right. If you took those 40 milligrams and you infused them over 80 minutes, then you would get the same total dose, but the peak blood level would be half. That would be, as far as we can tell, that would be more like giving a lower dose. I don't think that would be as effective.

• 2:03:08Speaker 01

  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.

• 2:03:23Tim Ferriss?

  Is the choice for IV over, say, intramuscular injection, which is another, let's just call it common means of administration, 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 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?

• 2:03:58Speaker 01

  So as far as I can tell, the main pro of IM 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 IM 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.

• 2:04:40Speaker 01

  But once you've given the dose intramuscularly, you can't take it back.

• 2:04:45Tim Ferriss?

  Yeah, once you've hit the golf ball, you can't unhit the golf ball.

• 2:04:48Speaker 01

  Exactly. So then you're counting on the person being able to ride out whatever side effect they get from the medication.

• 2:04:56Tim Ferriss?

  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. 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?

• 2:05:38Speaker 01

  The one that's probably most disturbing to people is nausea. Nobody likes to get nauseous. Nobody likes to vomit that I know of. So this 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. 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

• 2:06:21Speaker 01

  can boost your blood pressure up in a range where you wouldn't want it. So when that is a risk, we pre-treat people with a drug that blocks the beta adrenergic receptor drug like perpanolol, and that works pretty well. Those are the main side effects that we have to manage. People often think that the main concern is the side effect of dissociation, or transient psychosis, or cognitive impairment. And the main way we manage that when we're administering the drug intravenously is by stopping the infusion. And so, we can stop an infusion, within 30 minutes, a person is pretty much back to themselves.

• 2:07:03Speaker 01

  And even if they get the full dose, the side effects usually don't last that long. And in my experience of administering ketamine a very large number of times, the main thing that's helpful is getting right up to people and talking to them so that they have a kind of visceral sense of your presence there, and assuring them that they're going to be okay, and that this isn't going to last. Because one of the things that can happen during 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.

• 2:07:44Speaker 01

  So what we do before we give anybody ketamine is spend a fair amount of time telling them what ketamine effects could be like, preparing them so they're not surprised when it happens. And then, when it does happen, say if they happen to have a prominent feeling of unreality, or changes in environmental perception, or perception of their body, we tell them, "You remember before the session, we talked about how you might have these kinds of effects? Well, it's happening, and it's going to go away." And most people find that very comforting, because they kind of knew it was going to happen all along. And you tell them, "This is what we're talking about." It does change their frame of reference, but they usually tolerate it pretty well.

• 2:08:29Tim Ferriss?

  That makes me remember a sign that at one point was inside a...

• 2:08:38Tim Ferriss?

  Yert 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 yert where there will be sober sitters and volunteers and managers and so on to look after them. And 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."

• 2:09:17Speaker 01

  Exactly.

• 2:09:18Tim Ferriss?

  This is a big reminder. Now, let me share a few things from my experience, which I am sure, just to be clear, format wise diverged quite a bit from what you're 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. We'll come back to that. 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.

• 2:10:03Tim Ferriss?

  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 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."

• 2:10:47Tim Ferriss?

  That was the name of the technician or medic who a former medic who was administering 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.

• 2:11:30Tim Ferriss?

  And I standardized on one Redwood video. 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 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

• 2:12:12Tim Ferriss?

  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 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?

• 2:12:45Tim Ferriss?

  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?

• 2:12:55Speaker 01

  You know, I've seen all of the above in terms of settings. And we've always used blank rooms, partly because what we're trying to do is to make ketamine available to as many people as possible and have the most efficient settings. So in our clinic, which is led, co-led by Dr. Robert Ostroff and Gerard Santacora, both experts in this work, it would look like a surgical recovery room with a number of bays. And everybody has their own space. They're shielded from seeing other people by curtains and things like that. So they do have some privacy, but the doctors are moving and the nursing staff are moving from patient to patient to patient in the session.

• 2:13:40Speaker 01

  So it's more of a strange, in some way, almost a communal experience. Not that people are wanting the communal experience per se, but it is a very efficient way to deliver the treatment. One of the things about ketamine is that it distorts perception in exactly the way that you described. So some groups try to keep the level of stimulation limited because the more intense the sensory input on ketamine, the more you get distortions of the experience. And it is said by mentors of mine who worked the emergency rooms when you would get PCP

• 2:14:21Speaker 01

  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 so you tend to have a little bit more stimulation in the emergency room setting

• 2:15:06Speaker 01

  with psychedelics than you do with PCP.

• 2:15:10Tim Ferriss?

  Is there, well, actually, I think you answered the question I was going to ask you. 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, 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.

• 2:15:53Tim Ferriss?

  But do you have any other thoughts on what that might look like?

• 2:15:57Speaker 01

  My general feeling about ketamine, like most clinical experiences, is that when the patient is comfortable and feels well cared for and supported, that outcomes tend to be better. So the whole setting that you described, 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 for, you know, that's describing a treatment where not much is happening during the infusion. If you're going to reactivate a trauma memories, or if you're going to reactivate alcohol memories,

• 2:16:41Speaker 01

  that itself is going to be a pretty engrossing intervention and probably will occupy a lot of the kind of sensory space of the infusion. And it sounds like you had some version of that.

• 2:16:56Tim Ferriss?

  The problem with video, well, one of the many potential complications with video is that not all content may provoke the warm and cozy feeling that you may be seeking. So I remember watching for the first time this video. And it's like beautiful redwoods and rivers, kind of 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 kind of strapped to the seat and on the ride. 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 I remember at one point on a higher dose, there's this one scene that popped up out

• 2:17:41Tim Ferriss?

  of nowhere and it was just this fox, this little fox. 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. That was not conducive to an optimal clinical experience. And let's talk not about necessarily the side effects in session, but some of the risks of ketamine. And I'm going to lead into that in a few ways. So one of the apparent

• 2:18:19Tim Ferriss?

  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 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 I began with cardiac risk. People die from these things. In contrast to some of these very powerful psychedelics, and there are certain psychedelics

• 2:18:58Tim Ferriss?

  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.

• 2:19:24Tim Ferriss?

  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 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 and 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. 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

• 2:20:08Tim Ferriss?

  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 were 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,

• 2:20:51Tim Ferriss?

  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 it again. 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 would also be fascinated to know.

• 2:21:24Tim Ferriss?

  Is the behavior that I've seen in humans, the addictive behavior, also found in animal experiments, or is it not?

• 2:21:32Speaker 01

  First, I think your point's really well taken, which is to think about a drug like ketamine. Most people gravitate to the risks that are the most flamboyant part of it. In other words, what's the risk of dissociation? What's the risk of a transient psychosis from single doses? And to tell the truth, I have found that those risks are really quite limited. People have undersold the addiction risk of ketamine 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,

• 2:22:15Speaker 01

  or sometimes as an alternative to cannabis. So 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 risks that have to be taken very seriously, all the way from drunk driving to really high dose ketamine use. We said earlier that the typical therapeutic dose for an 80 kilogram man was about 40 milligrams.

• 2:22:55Speaker 01

  And in China and in Taiwan, I've met with people who were using eight grams a day intranasally and orally. 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 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.

• 2:23:38Speaker 01

  We get potentiation of synaptic function. And in animal studies, there is some evidence that the inhibitory cells, which are sometimes atrophied in depressed patients, will come back to life. And all kinds of beneficial effects happen. And while the effects of a single dose don't seem to be permanent, those are all kinds of effects that we hope to see. And hopefully, over time with treatment, will become stabilized. And when we space the doses apart, we don't get tolerance to the effects 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

• 2:24:23Speaker 01

  has in some way adapted in a positive way. When you use ketamine regularly, when you use it every day, it produces the opposite pattern of adaptations. Instead of becoming sensitized to the effects of ketamine and having the ability to give doses that are spaced farther and farther apart, you become tolerant to the effects 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 spoken to people who started using ketamine to self-treat their depression. They would take it once a month, and that would initially hold them just fine. And then they'd take it, maybe if they were heading into a stressful time and a stressful weekend,

• 2:25:08Speaker 01

  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 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 had the ability to take it whenever they, whenever they needed. 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

• 2:25:50Speaker 01

  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 if you look at the brains of people who use ketamine very regularly, they have, rather than enrichment of synaptic connections, they tend to have loss reductions in white matter, you know, the marker of neural connections in the brain on MRI in parts of the brain. They tend to have impaired function of the brain with functional magnetic resonance imaging. They tend to have cognitive impairments. And those cognitive impairments tend not to

• 2:26:34Speaker 01

  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 high dose, long lasting ketamine use, they don't respond very well to antipsychotic medications. Those psychotic symptoms don't necessarily go away quickly when ketamine use is stopped. So ketamine is a drug that has to be given a lot of respect

• 2:27:19Speaker 01

  and treated with a way that recognizes that careful thought needs to go into protecting people from developing problems related to ketamine use. 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 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

• 2:28:01Speaker 01

  of depression will exclude people who have these substance use disorders. And that turns out to be a lot of people who are depressed in the first place. So you're cutting out a large group of people and there's, I believe, and I think others believe, that there's a need to really think about what the optimized way to treat these patients who have depression and comorbid substance use disorders. So one strategy is the strategy that was developed by the group in England that I mentioned earlier, at the University College London, and that is extended to, I think it's Manchester, but I may be wrong, where they're trying to activate the drug memories

• 2:28:41Speaker 01

  during the ketamine infusion to try to counteract whatever aggravating effect ketamine might have on addiction and in fact have produced beneficial effects on drug craving. The biggest step is to limit the availability of ketamine to the clinic setting and that protects people not only from taking more and more ketamine on their own, but it also helps to limit the possibility that the ketamine that they're given would be diverted to others who wanted to use it for recreational purposes. And that's really something that needs to be thought about really carefully because let's say a person got a bottle of ketamine that had a thousand milligrams of it, or

• 2:29:25Speaker 01

  let's say they got pills of ketamine that had a thousand milligrams, because a thousand milligrams might not be that many oral doses because your body metabolizes ketamine so rapidly that if you give it orally, you have to give a lot. And so giving a thousand milligrams might not be that much for someone who was just going to use it orally. But what if they gave that a thousand milligrams to someone who was going to dissolve it and administer it intravenously? Person can get high on maybe 10 milligrams.

• 2:29:54Tim Ferriss?

  Yeah, or snort it.

• 2:29:55Speaker 01

  Or snort it, exactly. So you're just giving the person who maybe just got a few doses of oral ketamine, all of a sudden maybe just got like 100 doses of intravenous ketamine. So the risks of diversion when you give ketamine to people for home use, you have to really be, you know, thoughtful and careful about thinking about that. And there are a variety of interesting. Strategies to deal with this. So for example, there's a company out there that's developing an intranasal delivery system to deliver controlled substances in a manner that has less risk.

• 2:30:33Tim Ferriss?

  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?

• 2:30:42Speaker 01

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

• 2:31:25Speaker 01

  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.

• 2:31:34Tim Ferriss?

  On that last point, and we don't have to get into any specifics you don't want to get into, but 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?

• 2:31:49Speaker 01

  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 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 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. It may or may not have similar degrees of abuse liability with ketamine. There's the strategy that Freedom is trying, which is combining An anti addiction medication with ketamine to reduce

• 2:32:34Tim Ferriss?

  Interesting.

• 2:32:34Speaker 01

  It's abuse risk. And so there are a variety of strategies that people are taking to try to reduce this risk because in many ways, abuse is the greatest risk associated with ketamine. Ketamine has been around since the 60s. It's medically safe and well tolerated by most people. When given in the in the way in which it's given for treatment, we don't see much evidence of persisting medical risk. The only persisting medical risk is when people are exposed to ketamine in the context of, you know, the persisting medical risk that we can't prevent is the one when people are developing addiction. So we want to think about ways to broaden the pool of people who would

• 2:33:17Speaker 01

  be considered for ketamine and and maybe to take advantage of the fact that treating depression is good for addiction, just like treating addiction is good for depression. So providing an avenue for the safe treatment of these patients is, we think is really important.

• 2:33:35Tim Ferriss?

  I wonder if there is a drug, and there may be, I just don't know my my biochemistry and my pharmacopeia, but 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 allowing my mind to go wild with all the different options. I mean, there are a lot of different options here. Let me come back to 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.

• 2:34:17Tim Ferriss?

  But 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 sort of attendant weaknesses of, let's just call it higher functioning neuroses and so on? Is the abuse witnessed in animals?

• 2:34:44Speaker 01

  What's interesting is that there are some drugs of abuse, like cocaine, that animals, you know, love.

• 2:34:53Tim Ferriss?

  Love.

• 2:34:57Speaker 01

  And humans seem to like as well, but ketamine is more like alcohol. So there are some strains of rodents that naturally consume alcohol or naturally consume ketamine. But generally speaking, you have to kind of gradually introduce them to alcohol or to ketamine. And then they can become compulsive alcohol consumers or ketamine consumers, just like humans. And it's bad. And, 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. And the rodent, the mice and rats are more active in the dark.

• 2:35:41Speaker 01

  And you give it a little bit and you take it away. And then the animals will, when you give them access again, they'll drink a little more, take a little more. And so they go through bouts of exposure to the drug and then they tend to develop heavier versions of alcohol or ketamine self-administration. They'll self-administr- ketamine, they'll self-administer PCP and, and other substances from that class.

• 2:36:07Tim Ferriss?

  I was speaking with an acquaintance who is commenting on a few subcultures. 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 to get really agitated and insist on getting it back like Schmiggle from Lord of the Rings.

• 2:36:45Tim Ferriss?

  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 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 any drugs outside of, in this case, ketamine.

• 2:37:29Tim Ferriss?

  So let's talk about, you mentioned the R ketamine versus S ketamine. There are a lot of urban myths around 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, but good at storytelling. And that's their new way of showing off is talking about how deep their expertise in ketamine consumption goes as connoisseurs. But this is just a question that I'm sure I will embarrass myself in asking. But 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 correctly.

• 2:38:11Speaker 01

  You've got it. You've got the lingo.

• 2:38:13Tim Ferriss?

  Just for people who are looking at video or 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. Another way to think of it would be like the state of Michigan, the glove, flip it the other way. Okay. So we have these two mirror images, but then I'm thinking to myself, 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 just very confused by this right and left handed shorthand that is sometimes used to describe the differences in these two, because it seems like, well, if I flipped one 180 degrees, you would have effectively the same molecule, the same series of hydrogens and carbons or configuration.

• 2:38:58Tim Ferriss?

  Would they not bind in exactly the same way? Could you just shed some light on that?

• 2:39:03Speaker 01

  Well, first, I think you do a great job of portraying the R and S enantiomers. That was very impressive. Thanks. But secondly, you said something which is extremely important, which is that what really counts for these molecules binding into the nooks and crannies is the three-dimensional space. So what you couldn't portray is that when you overlaid the two hand, your two hands in a way that made the sequence of the molecules in the two, in the two isomers, was that in one case, the first carbon might be sticking into the plane, but in the other case, the carbon was sticking out of the plane. Right.

• 2:39:45Speaker 01

  And, and so that when you saw the actual structure in three-dimensional space, they actually occupied them in, in ways that were not, couldn't be one where you couldn't superimpose one on the other. They're actually turning in opposite directions. And that turns out to make a big difference because our ketamine is somewhere between three and five times less potent in its ability to block what we perceive to be the, what we think is the primary target of ketamine in the brain, which is the NMDA glutamate receptor. And it's a really complicated story, too complicated for us to go into in detail. But the reality

• 2:40:27Speaker 01

  is that there are at least four subtypes of NMDA glutamate receptors and ketamine binds with a little bit different affinity to each of the four types of the NMDA receptors. The fact that there's that differential affinity for ketamine has been taken up by the pharmaceuticals industry where you have different companies developing alternatives to ketamine that target us just a subtype of the NMDA glutamate receptor to block. And that's a whole other area that's being developed by the pharmaceutical industry. But we go back to R versus S.

• 2:41:02Tim Ferriss?

  And John may interrupt for one second. So when people just say ketamine, is that

• 2:41:09Tim Ferriss?

  A third molecular configuration versus R and S? Or is it just a lazy shorthand that is omitting one of those?

• 2:41:19Speaker 01

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

• 2:41:26Tim Ferriss?

  I see.

• 2:41:26Speaker 01

  So the standard ketamine that we studied was a mixture of R and S. And when people say S ketamine, which is the version of ketamine that was developed by 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 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.

• 2:42:05Speaker 01

  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 targets is different than S ketamine. So if we bring R ketamine up to the same dose as S ketamine, the same comparable occupancy of NMDA receptors,

• 2:42:48Speaker 01

  maybe it'll be a little bit more tolerable. The alternative idea is, what if R ketamine works through some other target? Maybe it doesn't work through the NMDA receptor. In which case, you might be able to get some kind of effectiveness at a low dose that doesn't produce dissociative effects. You know, that would be, if it really is just as effective as S ketamine and doesn't produce addiction liability and doesn't produce dissociative effects and doesn't have other medical effects, that would be super. But the problem is, if R ketamine is working by some other mechanism, what is it? How does it work?

• 2:43:30Speaker 01

  Does it have any of the properties that we ascribe to resemic RS ketamine at lower NMDA receptor occupancy? And the answer there is, we have no idea. So as R ketamine gets developed, it has shown effectiveness in animal models in studies in Japan by Kenji Hashimoto and some other groups. So there's interest in R ketamine and how it should be dosed and what it would be like. It's still kind of getting sorted out. But it's really important to understand that there's a way to use R ketamine that's not that different than the way we currently use S ketamine. And then there's a way to use R ketamine that's some kind of lower dose

• 2:44:13Speaker 01

  treatment that if it works, would be working through some other pathway that we don't yet understand.

• 2:44:19Tim Ferriss?

  So I have 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. So but first, I just want to talk about 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 postulated that the origin of human tendency to alcohol abuse originates

• 2:45:02Tim Ferriss?

  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 don't know if there's any scientific consensus or acceptance of this, but relatively recently came on my radar, which I thought was at least interesting as a thought exercise. The application, potential application, I'd like to get your two cents on the scientific support for this, that I experienced firsthand was going in

• 2:45:47Tim Ferriss?

  for my series of ketamine infusions, which, just as a comedic side note, in these intake. Questionnaires, they would always ask, anxiety on a scale of one to 10. And I mean, starting from nothing. What I always do with these one to 10 questionnaires, because how the hell do you know? On some level. I mean, 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 fives that I can go above or below on subsequent intake forms. And I was doing, I think it was three a week.

• 2:46:29Tim Ferriss?

  I was coming in without any depression at the time. 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 because my short term memory was vanishing. And 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 infusions, or I should say my two weeks of infusions.

• 2:47:06Tim Ferriss?

  Chronic pain that I'd had on 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 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 is related to NMDA receptors to reboot or otherwise treat chronic pain?

• 2:47:50Speaker 01

  Yeah. And the answer is yes. And this is actually, there are two kind of interesting parts of this. One is the NMDA receptors are in the pain pathways. It's in the spinal cord. The NMDA receptors are in the spinal cord and involved in transmitting the, 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, and so it both can reduce the experience of pain and it can reduce how much pain is upsetting to you. So in both ways, ketamine can be helpful via its action and blocking the NMDA glutamate receptors. And it's now being already used commonly in pain centers for the treatment of pathological

• 2:48:35Speaker 01

  pain. There's another part of ketamine that from the pharmacology point of view is extremely interesting. And this goes back to the work of Keith Trujillo and Huda Akil, maybe in the nineties, I think in the late nineties. 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.

• 2:49:18Speaker 01

  But if you have like, you know, neuropathic pain, an 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. And the third thing that they, ketamine can do that's really interesting. Is prevent the sensitization of pain pathways.

• 2:50:00Speaker 01

  So let's say you're going to have a knee replacement. And you know that when you have a knee replacement, you know, you're going to do some things to the nurse to make it possible to replace the knee and that there's a risk for some chronic pain related to that knee replacement. As you know, because you've just said it, that ketamine interferes with neuroplasticity and while the ketamine is in your system can interfere with the encoding and the neuroadaptations associated with memory and so produce some temporary memory impairment. Well, it does the same thing for learning in the pain pathway. If you pre-treat people with ketamine and have ketamine in their system when they undergo

• 2:50:42Speaker 01

  the knee replacement, the chances that they're going to develop this nagging, long-lasting pain in neuropathic pain goes down. So it's very common to have a drug like ketamine given during an operation like that to reduce the development of neuropathic pain. So it can be used to treat pain and to prevent it.

• 2:51:01Tim Ferriss?

  What I found most incredible about the experience was the durability of the pain relief. And this is not a scientific explanation because I haven't done my 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, in the case of my mid-back, 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

• 2:51:41Tim Ferriss?

  pattern is dangerous and so your body delivers a learned pain signal in some capacity. It seems like, at least to me, that there was, as you mentioned, a learned Aspect to this that was oversensitizing and that that was rebooted or disabled with the use of ketamine, maybe to use a different analogy or metaphor for folks like imagine if you got severely sunburned, after the sunburn had passed, you would retain a certain sensitivity to the sun and oversensitivity as a like prophylactic learned precaution

• 2:52:23Tim Ferriss?

  so you would not get sunburned again. It is something like that. It's not the best comparison, but you get the idea. 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 I found just staggering. How do you explain that?

• 2:52:49Speaker 01

  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 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. And the second thing I would say is, is that there's a close tie between depression and anxiety and pain. And a lot of what we're managing when we're managing pain is our emotional response to

• 2:53:32Speaker 01

  the pain. And if you tone down the depression and anxiety, then you discover that the pain is actually much more manageable. Because anxiety and depression focuses our attention on pain and makes us vulnerable to blowing the pain out of proportion. It's not that we don't feel the pain more intensely, but we feel the pain more intensely because our attention tends to get drawn in such a focused way to it. So I think that there are many levels where, in many potential ways, the neuroplasticity part of it, the depression and anxiety cognitive part of it, the ability to engage a variety of strategies to suppress

• 2:54:17Speaker 01

  the pain signals through relaxation and other kinds of techniques. So I think chronic pain is like depression or PTSD in that it's often useful to think about being resilient to the pain as opposed to making, whether or not you have it or not. So I think one of the things that you're describing is that ketamine helped you to be resilient in the face of a potential source of pain. 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.

• 2:54:50Tim Ferriss?

  Yeah, I like, I like the comparison to PTSD. I mean, you can imagine, and this is getting into an entire different class of the, 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. 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

• 2:55:35Tim Ferriss?

  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 mid back, 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. We talked about R ketamine. Now here's one

• 2:56:15Tim Ferriss?

  that I don't know anything about, but it's in some notes. So I would love to hear you describe in any capacity, S methadone. What is S methadone?

• 2:56:27Speaker 01

  S methadone is yet another drug that blocks NMDA glutamate receptors and is a drug that has some potential to treat depression. So the other isomer of methadone is the methadone that we associate with opiate main. So this is the inactive isomer of methadone, which block, works by blocking NMDA glutamate receptors. And, and there's some preliminary data that's encouraging for the treatment of depression. You know, 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.

• 2:57:12Speaker 01

  And it'll probably be the case with NMDA glutamate receptor antagonists that ketamine works for some people and some people that don't like the side effects, they, they go to another NMDA receptor antagonist and, and maybe that one will work. So that's a drug that has some potential in that regard.

• 2:57:31Tim Ferriss?

  And 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, if I am getting my terminology straight, does that mean that S ketamine has 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?

• 2:58:02Speaker 01

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

• 2:58:28Tim Ferriss?

  But that's because of the mu opiate receptor effect or?

• 2:58:31Speaker 01

  I think it's both. I think it's, there's been a tendency to be more concerned about the mu opiate receptor activity than the NMDA receptor antagonist activity. But in my view, that's a bit of a distraction because ketamine, S ketamine is much more potent at NMDA receptors than at mu opiate receptors. At least it's more potent, several fold to maybe a tenfold, somewhere in between there. And so, 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.

• 2:59:14Speaker 01

  You know, the rate of ketamine abuse has been going up since, the rate of ketamine use disorders has been going up since the, about 2018 or so in the United States. So we do want to be careful about that.

• 2:59:26Tim 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 tumors appear to be exploding, but it doesn't mean their prevalence wasn't the same beforehand. In any case, what I was going to say is it seems like with the advent of social media

• 3:00:06Tim Ferriss?

  and the sort of social proof approval culture that is so heightened by those tools, it seems to me, and this is also just watching my audience, that the

• 3:00:21Tim Ferriss?

  Prevalence of just chronic anxiety, depression, certainly we saw during COVID, a sharp increase in suicide hotline volume. I wonder if ketamine and maybe alcohol abuse are also correlated because people are just looking away to numb themselves, to turn off certain feelings. I don't know the answer to that. But, you know, I wanted to mention one thing, 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

• 3:01:06Tim Ferriss?

  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?

• 3:01:25Speaker 01

  Let's backtrack and talk about these three or four compounds. First, alcohol. So alcohol is a ethanol, is a weak NMDA glutamate receptor antagonist. And that, we think, is a major contributor about why the subjective effects of a low enough dose of ketamine are often described like similar to a glass of wine. And if you get your alcohol dose high enough, let's say it's been reported that you can get numbing, distortions, impairments in cognitions, et cetera, et cetera, as we all know. And some of those effects are thought

• 3:02:08Speaker 01

  to be similar. In fact, we did a study where we gave ketamine to very experienced alcohol users who described the antidepressant dose of ketamine as similar, on average, to somewhere between six and 10 drinks of alcohol.

• 3:02:27Tim Ferriss?

  It's quite, yeah, quite a few.

• 3:02:28Speaker 01

  Okay.

• 3:02:29Tim Ferriss?

  Depending on the timeframe.

• 3:02:30Speaker 01

  Exactly. So as a result of our interest in this NMDA opiate interaction, we did a study where we gave people a high dose of naltrexone before we gave them a dose of ketamine.

• 3:02:44Tim Ferriss?

  Okay. Could you explain what naltrexone is? I mean, I know what it is.

• 3:02:47Speaker 01

  Yeah. An opiate receptor blocker. It blocks at low doses, it preferentially blocks the mu opiate receptor, the morphine receptor. At higher dose, if you give a high dose, it also blocks the delta opiate receptor, which is the main target or 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. So if we give a pretty high dose of naltrexone and give ketamine, we don't change the dissociative effects of ketamine at all.

• 3:03:21Tim Ferriss?

  You do not?

• 3:03:22Speaker 01

  Do not. Not at all.

• 3:03:24Tim Ferriss?

  Wow.

• 3:03:26Speaker 01

  What, what we do is we make, we tend to make a low dose of ketamine less pleasant for people. Then they get a little more anxious. They don't like it as much, but they don't, it doesn't block the dissociative effects. Now, salvinorin, if you give it, calvinorin is a very short acting drug in, in humans. My colleague Cyril D'Souza and Mohini Ranganathan dosed salvinorin. And you can get this very intense kind of psychedelic state in people that is relatively short lasting. And what's interesting about salvinorin is it's not such a positively euphoric experience as you get people uniformly rate, even if they don't like the experience,

• 3:04:12Speaker 01

  they still rate the ketamine experiences as euphorogenic and they still rate a lot of psychedelics.

• 3:04:17Tim Ferriss?

  Salvinorin tends to be highly dysphoric. Most people will say, I never ever in my life want to do that again.

• 3:04:24Speaker 01

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

• 3:04:52Tim Ferriss?

  Yeah, the inability to feel joy.

• 3:04:54Speaker 01

  Yeah, inability to feel joy. And my brother, who's a psychiatrist, you know, you know, you know, my family history. My father was a psychiatrist and psychoanalyst. My mother became a social worker. My brother is a psychiatrist. My cousin's a psychiatrist. I come from a genetically high vulnerability family for mental health professionals. My daughter's becoming a psychiatrist. My brother did a study as part of a consortium and gave a kappa opiate receptor blocker, in other words, the reverse of salvinorin, and looked at the effects on brain circuit activity and anhedonia in patients with depression

• 3:05:35Speaker 01

  and showed that you could affect the reward circuit activation and reduce anhedonia in depressed patients with this kind of mechanism, a kappa opiate antagonist. And so people are actually interested in the kappa opiate receptor blockers as potential treatments for some aspects of depression.

• 3:05:54Tim Ferriss?

  Super interesting. Yeah, I will say, just 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 Mazatex for hundreds, probably thousands of years. And

• 3:06:23Tim Ferriss?

  Before you ever touch this stuff, go on YouTube and search smoking salvia divinorum and you will see dozens of videos of people who thought it was a good idea to set up a camcorder or 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 of this experience. So just the more you know, Smokey the Bear, definitely think about it at least 37 times before you casually partake in any of these things. Okay, with that, thank you for providing all that context. So fascinating to me.

• 3:07:05Tim 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 want to take that? What are some of the potential ways or future ways to go about optimizing ketamine?

• 3:07:37Speaker 01

  Let's start with the end, if you will. What do we really want in treatment? What would be the ideal antidepressant? The ideal antidepressant would be a drug that acted rapidly and lasted forever. We would call that basically cure. And we never use the word cure in psychiatry. We don't even think of the idea of cure. And that's partly because we don't really understand the brain well enough to really know how to completely undo the changes that we see there. So let's start just with the shortest version of that, which is what if we could take ketamine,

• 3:08:19Speaker 01

  which is a very, has a short duration of antidepressant effectiveness at the beginning, somewhere between, say, three and seven days, and make it last two weeks or a little bit longer? And you might say, well, why would you think that 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.

• 3:08:57Speaker 01

  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 we did a study that really spurred our interest in this question. And it was led by, 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.

• 3:09:41Speaker 01

  It's one of the proteins that gets activated inside nerve cells that triggers the regrowth of those synaptic connections. And 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, you may recall, 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.

• 3:10:23Speaker 01

  mTOR is an immunosuppressing drug, and that was in our mind as well, for a reason that I'm going to come back to in a little bit. So we gave rapamycin with ketamine. So in the same group of 20 patients with treatment-resistant depression, they completed one ketamine day where they got just ketamine.

• 3:10:44Speaker 01

  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%.

• 3:11:07Tim Ferriss?

  I'm no scientist, but that seems, that seems non-trivial.

• 3:11:12Speaker 01

  It seemed to us to be non-trivial. And it was also a little bit perplexing in the sense that we knew we were giving a drug that had the potential to block mTOR in the brain. And if mTOR activation was critical, then why didn't rapamycin block the antidepressant effects of ketamine? And one of the ideas that we are wrestling with is maybe the immunosuppressive effects of rapamycin, which is a powerful immunosuppressant, are related to its ability to extend the antidepressant effects of ketamine. And in particular, you may recall that I said

• 3:11:57Speaker 01

  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.

• 3:12:29Tim Ferriss?

  I'm fascinated by microglia. I just like saying it, too. But yes, microglia. Please continue.

• 3:12:35Speaker 01

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

• 3:13:16Tim Ferriss?

  Sorry to interrupt. Are microglia correlated or is there a causal relationship between our subjective experience of stress and microglia activity?

• 3:13:26Speaker 01

  So, microglia tend to be activated under conditions of severe and persisting stress like you have in depression. The paradox, and I don't want to get us too distracted because frankly, I don't understand what we found. So I can't really explain it. But in patients with post-traumatic stress disorder, we find both in patients while they're alive with PET scanning and in analyzing post-mortem brain tissue, that the microglia are suppressed. And I've been talking to colleagues about this and they think, well, maybe at one point they were activated, but maybe there's kind of in a burned out state, you know, an exhausted state.

• 3:14:11Tim Ferriss?

  Microglia are tired. They're on the bench, out of the game.

• 3:14:14Speaker 01

  Exactly. Something like that. You know, I don't really know, and I don't think anybody does what's going on with the microglia. But it's really interesting to me that you have these two stress-related disorders. One like major depression, where you get a lot of cortisol in the body and the microglia tend to be activated in the brain. And you get the opposite pattern in PTSD where you don't tend to get so much cortisol chronically and you don't tend to get so much 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

• 3:14:56Speaker 01

  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 antidepressant effects of ketamine? We don't know the answer to that because.

• 3:15:16Speaker 01

  Since we didn't expect to see it, we only designed the study with a two-week window of follow-up. So we'll have to do, you know, longer studies to figure that out. But we're really interested in developing this idea, both from the point of view of academic research, and I have a colleague that I've collaborated with for many years, Tom Su in Taipei, who is doing a study looking at this combination. And then we're developing a version of this idea, one that we think may be optimized for use in the treatment environment within a company called Freedom Biosciences that I'm associated with.

• 3:15:55Tim 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 dosage range that you decided upon, or maybe the precise dosage or protocol for the rapamycin that you determined or hypothesized would be well tolerated?

• 3:16:28Speaker 01

  I think it's six milligrams.

• 3:16:29Tim Ferriss?

  Six milligrams, okay.

• 3:16:31Speaker 01

  Oral rapamycin. And we may have stumbled onto something by giving that dose. And what I mean by that is that we thought it should get into the brain at six milligrams, and we were pretty confident that it would get in the brain, it 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 sweet spot, high enough to interfere with gobbling up of the synapses, but not so high to interfere with the antidepressant effects.

• 3:17:18Speaker 01

  A little bit of serendipity.

• 3:17:20Tim Ferriss?

  I feel like a lot of science is 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, 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

• 3:18:04Tim Ferriss?

  a week 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 exactly, but how frequently would any one individual receive that rapamycin?

• 3:18:19Speaker 01

  So first, Tim, this is a experimental procedure. It's not really not ready for prime time. The finding hasn't even been replicated yet. You know, this is what you do when you're trying to develop a new treatment and it's very preliminary data in some ways, even though it's a very robust finding. But it was just a single dose of rapamycin given 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. So really the possibility that there's some synergy between the two treatments is really, you know, possibility from the preliminary findings.

• 3:19:01Tim Ferriss?

  It's very exciting. It's very exciting. And 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, I mean, I don't want to call it very speculative, but it's certainly not mainstream at this point, or for other purposes. My very cursory understanding is that you're trying to have an effect on mTOR such that

• 3:19:42Tim Ferriss?

  you trigger certain things like autophagy and sort of cellular cleaning and repair, but not so much that you bleed into, I think it's mTOR2 territory, where you start to really experience the immunosuppressant effects because you then run the risk of greater likelihood of infection. If you become infected, greater severity of infection, you have to be very careful with it. So in any case, 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.

• 3:20:27Tim Ferriss?

  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. So how do you think about ensuring that the sort of Zambones 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?

• 3:21:07Speaker 01

  This has been 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...

• 3:21:19Speaker 01

  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. We want the microglia to clean up the brain most of the time. What we want to try to do is to create an optimized environment so that in the time when these new synapses are particularly vulnerable to being engulfed, that we've protected them.

• 3:21:46Tim Ferriss?

  Sort of optimizing that window of plasticity that's produced by the treatment?

• 3:21:50Speaker 01

  Exactly, and enabling it to persist for a longer period of time. And one possible way this could play out, but it's certainly not, by no means the only possible way, would be that maybe the first time it lasts two weeks. And then maybe when you have repeated combinations of rapamycin and ketamine, maybe it can last longer and longer from there, which would be really great. And it would be great for a number of reasons. One is, as we say, and we keep coming back to, both of us have tried to make the point that no treatment, no medication is without risk. Every medication and treatment has risk. And so we want to provide a treatment that has as few exposures to the drug as possible

• 3:22:35Speaker 01

  because that's a way of limiting risk. And it's a way of ensuring at the same time, increasing the likelihood that people will stick out the treatment, and it will increase the likelihood that people will get the treatment because it will cost less. So, systems of care are more likely to adopt a less expensive treatment. People are likely to take a treatment that's less burdensome for them to take. And if we can space out, avoid that period of time when people are getting more frequent infusions, we reduce the cost, we increase the safety, improve the tolerability, and we provide a greater flow through the clinic so that more people can get access to the treatment. So, I think at every level, if we can,

• 3:23:20Speaker 01

  if there is truly a potential to realize here, and if we can realize that potential, then I think a lot of people could benefit by that.

• 3:23:29Tim Ferriss?

  Let's get to know ketamine a bit better by doing, I don't want to say a side by side comparison, but throwing it in the mix with a lineup, kind of usual suspect style. And the lineup consists of other psychedelics. And I should just take a second to say that in my subjective experience, particularly, I don't advise this, but at the doses that sort of push you through the looking glass, which I think no one really needs to do. But I consider ketamine much more of a psychedelic compound at higher doses than I do something like MDMA. If we take as characteristic of psychedelic experiences at higher doses, ego dissolution, et cetera.

• 3:24:12Tim Ferriss?

  Also, I wanted to hearken back to something you mentioned, which was Salvador in a being short lasting, short acting. And I just want to emphasize for anybody out there who's maybe psychedelic naive or not experienced, that short acting is the most relative term imaginable when applied to psychedelic experience. And I would say short lasting and earth time, yes, but let's just say if it's in the case of NNDMT or five MEODMT, only 15 to 20 minutes or 10 to 20 minutes, like put your hand on a hot stove and tell me only 20 minutes. Just not that you'd automatically have a hot stove experience, but it may not and very

• 3:24:56Tim Ferriss?

  frequently will not feel like 20 minutes. So to be aware of that. But if we look at other psychedelics, if we put ketamine in that class for the time being, or even just put ketamine by itself and then other psychedelics, there seem to be some, not all, not totally overlapping, but some similar effects, the release of glutamate, activating, say, mTOR affecting mTOR, BDNF, so brain derived neurotrophic factor. What are some of the closest comparables that you've seen and how are they most similar? And how are they most different?

• 3:25:32Speaker 01

  I think you captured the key point of convergence, which is these are

• 3:25:39Speaker 01

  Structurally, these drugs are not at all similar. Mechanism of action, these drugs are not at all similar. And where they converge, which is something you have to expect in the brain, which is this enormously complicated organ, that where they converge is how they perturb the effects of microcircuits. And microcircuit being a cluster of a small group of excitatory and inhibitory cells that are, you might say, the transistor, if you will, of the transistor radio. In other words, the lowest level that has the superordinate properties that you can study in relation to cognitive effects.

• 3:26:20Speaker 01

  So when you give a dose of ketamine, you do two things, mainly, three things. One is, you do activate inputs to the cortex from the thalamus. You're really disinhibiting them. And you're inhibiting the inhibitory nerve cells, the GABA nerve cells. So you're locally reducing the degree of inhibition and you're increasing a little bit the excitatory input.

• 3:26:47Tim Ferriss?

  Could you just repeat the effect on the thalamus? And I'll just say this, I don't know if it's the best metaphor again, but is it fair to say the thalamus is a bit like the traffic cop for sensory inputs going to the brain? It's like a relay station that, through which everything, or most things, must pass before going to the cortex for processing? Could you just repeat the effect that ketamine has on the thalamus?

• 3:27:13Speaker 01

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

• 3:27:52Speaker 01

  And similarly, in the cortex, ketamine is relieving inhibition and thereby increasing activation, and the psychedelics are driving autonomously excitation, again, creating a new message. And so that difference has been one of the reasons that people have thought that ketamine sensory experiences tend to be more distortions of sensory experience. In other words, the walls are breathing in and out, my arm is now a foot longer than it used to be, things like that. Whereas, oh, look, there's a shining glowing orb in the middle of the room that wasn't there previous, you know, from the psychedelic,

• 3:28:35Speaker 01

  right? A fully fledged hallucination. So, in that way, they're not exactly the same in terms of the microcircuit, but they both have as a common property this increase of excitability, increase in glutamate output, triggering the downstream neurotrophic effects, and triggering the regrowth of, in animal models, the triggering the regrowth of the synapses that have been lost. The key thing that we don't know yet, in terms of, and so we see evidence, hints of efficacy in the Imperial College study and in the studies done at Hopkins and some of the other trials, and a little bit of a stronger signal in

• 3:29:17Speaker 01

  the COMPASS data that's been released in the press releases. But we do not yet have data in the treatment-resistant depressed population, and there are a lot of reasons why we have different populations being studied for the different agents. But to make a long story short, even despite all the differences in the clinical data, at the basic science level, we do have this kind of common effect on, on microcircuits and regrowth of synapses. And, and that's encouraging as a potential foundation for the way people think about the potential therapeutic effects of, of psychedelics.

• 3:29:58Tim Ferriss?

  How important is the role of BDNF, again, brain-derived neurotrophic factor? I think I'm getting that right.

• 3:30:04Speaker 01

  You did.

• 3:30:04Tim Ferriss?

  To, you know, put a monkey in a suit and gets fancy. It's the equivalent of my vocab that I use. But how important is BDNF, as far as we know, to the increase in synaptic or dendritic growth or synaptic density or efficiency, if at all?

• 3:30:29Speaker 01

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

• 3:30:56Tim Ferriss?

  Rolls off the tongue.

• 3:30:57Speaker 01

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

• 3:31:43Speaker 01

  And it affects the synaptic efficacy because one of the things it does in the deep potentiated synapses, the less efficient synapses, when the BDNF levels goes up, it tends to drive more receptors for glutamate to the synaptic surface. In other words, it tends to make the neuron more receptive to glutamate. So that, in that way, compensating for the earlier deficits in synaptic efficiency. And it tends to be involved in the regrowth of the synapses via the mechanisms we just talked about, you know, that mTOR is a part of.

• 3:32:20Tim Ferriss?

  So I want to mention a few things. Number one is if you're listening to this podcast and you're thinking, I don't think I really want to use ketamine. I'm pretty sure I don't want to use rapamycin. But man, this BDNF stuff sounds pretty good. Sounds like it could be beneficial. I would suggest that you explore a few different types of exercise. There's actually a book that was published quite a long time ago called Spark that goes into some of the physiological underpinnings of psychological or mood improvement following exercise. And you can go to PubMed, where I spend a ridiculous amount of time. And I just pulled up one as an example. This

• 3:33:05Tim Ferriss?

  is the name of the paper, "Exercise promotes the expression of brain-derived neurotrophic factor, BDNF, through the action of the ketone body beta-hydroxybutyrate." Now, this is interesting on a number of levels. This was just the first one I pulled up. This is from 2016. Seems to be pretty decently cited. But the point being that you feel better often after certain types of exercise. Why is that? It's not magic. In fact, it is increasing one of the, let's call it agents or factors that we're talking about, BDNF. What's interesting about that particular paper to me also is that, and this ties into some other guests I've had

• 3:33:47Tim Ferriss?

  on the podcast, like Dr. Dominic D'Agostino, is it raises questions, and I'm sure Dom has an answer for this, because this is what he spends most of his time on. But could exogenous consumption of beta-hydroxybutyrate, BHB, which is available, there are synthetic versions, also provoke increases in BDNF? Actually, I have something to show you, John. So you might get a kick out of this. And this is before I even mention this, I just want to say this is a really good case of do as I say, not as I do. But I've always enjoyed drinking.

• 3:34:20Tim Ferriss?

  Alcohol with friends, having a few drinks here and there. I don't think I have any abusive behavior with it. I mean, maybe in my early twenties, I think like a lot of people in their early twenties probably didn't make the best decisions. But these days, maybe once every week or two, I'll have a few drinks with friends. But it vastly disrupts your sleep architecture. It causes all sorts of sleep issues in addition to other issues. And so I was looking for potential alternatives. I rolled out ketamine for all the reasons that we've spoken about. But I did find this, which is, so if you could see this, it says

• 3:34:58Tim Ferriss?

  R1,3 ginger mule hard ketones. So this is R13 butane dial, which is, it's an ethanol free alcohol. It's a ketone that produces some of the, I don't want to say delirium, but some of the effects that you would commonly associate with alcohol. I will say that it still seems to disrupt sleep if you consume it too close to bedtime, but not as much, at least based on our ring data and so on, not as much as ethanol itself. So, pretty interesting stuff. I want to use this as a very indirect meandering segue to a question about ketamine. Are you aware of any impact of ketamine on sleep architecture or sleep?

• 3:35:43Speaker 01

  Yeah, it does affect sleep. It's probably one of the ways that alcohol intoxication, particularly at high levels, affects sleep is by blocking NMDA glutamate receptors. And there's some EEG, sleepy EEG studies showing reduction in sleep quality after getting ketamine. And, and so when that data was reported, there were some people who thought, well, maybe the disruption in sleep is actually contributing to the antidepressant response. Because for so many people, the full antidepressant response doesn't really appear until at least one night of sleep after, after ketamine. But we don't really

• 3:36:22Speaker 01

  know the answer to that yet. Just to come back to exercise, exercise shows dose related antidepressant effects. And my colleague and I actually analyzed My colleague led this study, Adam Shakrude. And this remarkable data about how, in a pretty dose-related way, increasing exercise up to reasonably high levels, particularly in the context of team exercise, can be very helpful for depression. It is possible to engage in such extreme exercise that you lose the protective, or at least some of the protective effects of exercise. And we don't really know if that's a product of the exercise, or who is the people who are choosing to exercise at those very extreme levels. Yeah.

• 3:37:07Speaker 01

  You know, the stress that they're under. But the idea that you say about raising BDNF and other beneficial effects of exercise, and the possibility that that would synergize with antidepressant treatment, which also raises, you know, SSRIs also raise BDNF in the brain, and as does ketamine in psychedelics.

• 3:37:27Tim Ferriss?

  John, are there any other pictures you'd like to paint of possibilities, or teasers for things that you see being explored, or that you yourself would like to explore, just forward-looking, let's just say, within the next five years? It seems to me that ketamine, along with some of these other more classically labeled psychedelic compounds, so the tryptamine psychedelics, some phenethylamines, but to a lesser extent, you know, mescaline would be in that category, are not just being explored, but they're being taken apart, right? The car is being parked in the garage, every component is being removed.

• 3:38:06Tim Ferriss?

  And for therapeutic reasons, and also for economic reasons, things are being modified, repurposed, in every which way possible. What are some of the more interesting explorations that you are aware of, or that you anticipate seeing in the next, say, within the next five years?

• 3:38:26Speaker 01

  So I think within five to 10 years, the current generation of NMDA receptor antagonists, NMDA receptor. Subtype antagonists, at least the one type, subtype, a selective group called the NR2B antagonists, the R ketamine, and some of the combination therapies with ketamine. I think that will, that will settle out and we'll know whether there's meat on those bones. And I think in parallel, in the psychedelic space, there are certain key concepts that we're just getting into, that will play out over the next five, at most 10 years, before we have a good sense of how helpful they are.

• 3:39:09Speaker 01

  And probably the best known, and in some ways perhaps the scientifically strongest foundation, is the idea that psychedelics can signal at the same receptor via different downstream mechanisms. And the work of Brian Roth and David Olson, now each of them have been associated with different pharmaceutical companies and other people are pursuing this. And the idea is, imagine you're driving a car, and instead of the car that we're used to, it has two gas pedals. And if you step on one gas pedal, maybe you have, you drive the electric motor.

• 3:39:50Speaker 01

  And if you step on the other gas pedal, you drive the internal combustion engine. And there are situations where you're driving where it's much better to drive the internal combustion engine, like there are no charging stations, but there are gas stations and you want to fill up. And we all know about that charge anxiety that comes with an electric vehicle. The other gas pedal gives you electric power, and that has all kinds of advantages as well. Well, a receptor is like that. Most receptors, including the serotonin 2A receptor, which is the target in the brain, can signal via two mechanisms.

• 3:40:29Speaker 01

  One pathway, sometimes called the traditional pathway or canonical pathway, involves internal substrates that have names like cyclic AMP or also lipacy, different kinds of signaling mechanisms, but particularly the cyclic AMP dependent pathway. And then the other gas pedal signals by a compound called beta- arrestin.

• 3:40:53Speaker 01

  And the idea is that different effects are mediated by these different signaling pathways. And if you could just selectively step on one gas pedal as opposed to the other, that maybe you can get the antidepressant effects of psychedelic drugs without getting the psychedelic effects. And so, some people, like my friend Roland Griffiths, would say that's the wrong idea in the first place, that the psychedelic effects in the context of embedded in psychotherapy adds to the intrinsic antidepressant effect that you would get just by triggering synaptic growth and doing things like that.

• 3:41:38Speaker 01

  And others would say, well, it certainly would be a lot easier to use these drugs, to take them and to prescribe them if they didn't produce these psychedelic effects.

• 3:41:48Tim Ferriss?

  They could both be true, right? Those could both be true. And for people who don't know, is it fair to say that you are to ketamine research what Roland Griffiths is to modern psilocybin research? I mean, is that fair to say?

• 3:42:03Speaker 01

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

• 3:42:40Tim Ferriss?

  Yeah, he's a wonderful human, and I feel also an impeccable scientist who's been such a gift to psychedelic research, in part because he did not begin with psychedelic research, if that makes sense. I mean, he was certainly at one point considered one of the foremost experts, if not the foremost expert, in caffeine metabolism, and has studied so many different compounds, and has been published so many times prior to engaging with this space, to be clear, when it was still considered career suicide by and large.

• 3:43:16Tim Ferriss?

  It's just been wonderful to get to know people like Roland and yourself. And I've so much enjoyed this conversation. Dr. John Krystal, thank you so much for making the time. And you are, as certainly I mentioned in the intro, the co-founder and chief scientific officer of Freedom Biosciences. Is there a best website or a best way people can learn more about Freedom Biosciences?

• 3:43:41Speaker 01

  I'm sure there is.

• 3:43:47Tim Ferriss?

  We will put that in the show notes. So this will be a teaser for people who would like the URL. We're going to put it in the show notes as per usual, in addition to links to everything that we've discussed. So all of the terms, all of the resources, all of the people, so ranging from BDNF to Sasha Shogan, there will be a link to everything in the show notes. If you go to tim.blog/podcast and just search, certainly John may be tough, but Krystal will not be tough. That is K-R-Y-S-T-A-L. And John, is there anything else that you would like to say? Any closing comments? Anything that you would like to request of my listening audience or share with them

• 3:44:31Tim Ferriss?

  before we bring this epic, very comprehensive conversation to a close?

• 3:44:38Speaker 01

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

• 3:45:23Speaker 01

  of making sure that if you're exposed to them, you're using them in the right way, in a way that doesn't put you at risk for harm. And a lot of the things we've talked about are very early-stage development ideas and really not ready to be built into recreational practice. And Let me just say it's been an extraordinary pleasure to hang out and chat. So I really appreciate the time.

• 3:45:48Tim Ferriss?

  Absolutely. I hope we have another chance like we did after South by Southwest some time ago to cheers and perhaps share a glass of my favorite neurotoxin, some type of wine, probably, or maybe gin tonic. Maybe I'll bring along some R13 butane dial for you to try. But for people who are listening, who are prone to depression or experiencing depression and want to learn more about ketamine assisted treatment options, are there any resources you can recommend or websites or organizations?

• 3:46:26Speaker 01

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

• 3:46:36Tim Ferriss?

  And this is bravado, is that the trade name?

• 3:46:38Speaker 01

  Right. But people are welcome to contact. We have the Interventional Psychiatry Service at Yale New Haven Hospital, Doctors Ostroff and Santa Cora, my office, or in most cities, most universities nowadays have a ketamine service in a place where you can get connected. So the availability of ketamine programs is growing and those are the places that I know of. But I'm sure there's some better centralized information source.

• 3:47:07Tim Ferriss?

  We'll try to pull a few things together, my team, and put them in the show notes as well. And I will just give yet another warning, cautionary note, which is there are also a lot of fly by night ketamine operations or ketamine clinics that really push people through the system like cattle going through a cattle shoot. And not all clinics or clinicians are created equal. And you may make certain assumptions about support and aftercare that will be misplaced with certain places. So I do think it's a great idea to first go to at least educate yourself with.

• 3:47:52Tim Ferriss?

  Credible university sources, if possible. And I will also speak to a few other folks and maybe follow up with you. And we'll put things in the show notes for everyone at tim.blog/podcast. Crystal, like I said, easy to find, K R Y S T A L. And we will add the link for Freedom Biosciences. And John, what a pleasure and what a gift to spend this time with you to learn so much. I have copious notes everywhere. And I think that this, and I hope that this will be of great use to people. And as you said in your closing comments, provide some hope, perhaps for those people who may feel hopeless and helpless. Certainly, I've been there before.

• 3:48:36Tim Ferriss?

  And to reiterate what you said, there are tools that can help. There are people who can help. So, thank you very much, John.

• 3:48:43Speaker 01

  Take care. Thanks so much.

• 3:48:46Tim Ferriss?

  Hey, guys. This is Tim again. Just one more thing before you take off, and that is Five Bullet Friday. Would you enjoy getting a short email from me every Friday that provides a little fun before the weekend? Between one and a half and two million people subscribe to my free newsletter, my super short newsletter called Five Bullet Friday. Easy to sign up, easy to cancel. It is basically a half-page that I send out every Friday to share the coolest things I've found or discovered, or have started exploring over that week. It's kind of like my diary of cool things. It often includes articles I'm reading, books I'm reading, albums, perhaps, gadgets, gizmos, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcast guests.

• 3:49:29Tim Ferriss?

  And these strange esoteric things end up in my field, and then I test them, and then I share them with you. So, if that sounds fun, again, it's very short, a little tiny bite of goodness before you head off for the weekend, something to think about. If you'd like to try it out, just go to tim.blog/friday. Type that into your browser, tim.blog/friday. Drop in your email, and you'll get the very next one. Thanks for listening. This episode is brought to you by Allform. If you've been listening to this podcast for a while, you've probably heard me talk about Helix Sleep. Their mattresses, which I've been using since 2017. I have two of them upstairs from where I'm sitting at this moment. Helix has gone beyond the bedroom and started making sofas. They've

• 3:50:11Tim Ferriss?

  launched a company called Allform, A-L-L-F-O-R-M, and they're making premium customizable sofas and chairs shipped right to your door at a fraction of the cost of traditional stores. So I'm sitting in my living room right now and it's entirely Allform furniture. I've got two chairs, I've got an ottoman, and I have an L-sectional couch. And I'll come back to that. You can pick your fabric. They're all spill, stain, and scratch resistant. The sofa color, the color of the legs, the sofa size, the shape to make sure it's perfect for you in your home. Also, Allform arrives in just three to seven days and you can assemble it all yourself in a few minutes. No tools needed. I was quite astonished by how modular and easy these things fit together, kind of like Lego pieces. They've got armchairs, love seats, all the way up to an eight-seat sectional, so there's something for everyone. You can

• 3:50:56Tim Ferriss?

  also start small and kind of build on top of it if you wanted to get a smaller couch and then build out on it, which is actually in a way what I did, because I can turn my L-sectional couch into a normal straight couch and then with a separate ottoman in a matter of about 60 seconds. It's pretty rad. So I mentioned I have all of these different things in this room. I use the natural leg finish, which is their lightest color, and I dig it. And I've been using these things hours and hours and hours every single day. So I am using what I am sharing with you guys. And if getting a sofa without trying it in-store sounds risky, you don't need to worry. Allform sofas are delivered directly to your home with fast, free shipping, and you get 100 days to decide if you want to keep it. That's more than three months, and if you don't love it, they'll pick it up

• 3:51:40Tim Ferriss?

  for free and give you a full refund. Your sofa frame also has a forever warranty. That's literally forever. So check it out. Take a look. They've got all sorts of cool stuff to choose from. I was skeptical, and it actually worked. It worked much better than I could have imagined, and I'm very, very happy. So to find your perfect sofa, check out allform.com/tim. That's A-L-L-F-O-R-M.com/tim. Allform is offering 20% off all orders to you, my dear listeners, at allform.com/tim. Make sure to use the code TIM at checkout. That's allform.com/tim and use code TIM at checkout. This episode is brought to you by Helix Sleep. Helix Sleep is a premium mattress brand that provides tailored mattresses based on your sleep preferences.

• 3:52:24Tim Ferriss?

  Their lineup includes 14 unique mattresses, including a collection of luxury models, a mattress for big and tall sleepers - that's not me - and even a mattress made specifically for kids. They have models with memory foam layers to provide optimal pressure relief if you sleep on your side, as I often do and did last night on one of their beds. Models with more responsive foam to cradle your body for essential support in stomach and back sleeping positions, and on and on. They have you covered. So how will you know which Helix mattress works best for you and your body? Take the Helix Sleep Quiz at helixsleep.com/tim and find your perfect mattress in less than two minutes. Personally, for the last few years, I have been sleeping on a Helix Midnight Luxe mattress. I also have one of those in the guest bedroom, and feedback from friends has always been fantastic.

• 3:53:09Tim Ferriss?

  They frequently say it's the best night of sleep they've had in ages. It's something they comment on without any prompting from me whatsoever. Helix mattresses are American-made and come with a 10- or 15-year warranty, depending on the model. Your mattress will be shipped straight to your door, free of charge. And there's no better way to test out a new mattress than by sleeping on it in your own home. That's why they offer a 100-night risk-free trial. If you decide it's not the best fit, you're welcome to return it for a full refund. Helix has been awarded "Number One Mattress" by both GQ and Wired magazines. For you, my dear listeners, Helix is offering up to $200 off of all mattress orders and two free pillows. Go to helixsleep.com/tim. That's helixsleep.com/tim.

• 3:53:52Tim Ferriss?

  Helix, H-E-L-I-X, sleep.com/tim. Or click the link in the episode's description. Helixsleep.com/tim. With Helix Sleep, better sleep starts now.