#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 all-in-one nutritional supplement, Helix Sleep premium mattresses, and Allform premium, modular furniture.  Dr. 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, 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! Helix was selected as the #1 overall mattress of 2020 by GQ magazine, Wired, Apartment Therapy, and many others. With Helix, there’s a specific mattress to meet each and every body’s unique comfort needs. Just take their quiz—only two minutes to complete—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. * This episode is also brought to you by Athletic Greens. I get asked all the time, “If you could use only one supplement, what would it be?” My answer is usually AG1 by Athletic Greens, 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 further covers my bases with vitamins, minerals, and whole-food-sourced micronutrients that support gut health and the immune system.  Right now, Athletic Greens 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 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! 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 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 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. * [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, please visit tim.blog/podcast. For deals from sponsors of The Tim Ferriss Show, please visit tim.blog/podcast-sponsors Sign up for Tim’s email newsletter (5-Bullet Friday) at tim.blog/friday. For transcripts of episodes, go to tim.blog/transcripts. Discover Tim’s books: tim.blog/books. 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