#625: Dr. John Krystal – All Things Ketamine, The Most Comprehensive Podcast Episode Ever (Premium) | Tim Ferriss Show

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Key Takeaways

  • Depression is a state that affects your entire body medical factors related to obesity, cardiac disease, arthritis, asthma – things that cause inflammation in the body increase your risk for depression, and vice versa
  • Untreated depression shortens your life by five years (because of medical outcomes, not by suicide)
  • A single dose of ketamine administered to stressed animals produces a rapid and profound biochemical, electrophysiological, and structural change in the brain within 24 hours
  • Ketamine overcomes intrinsic resistance to the recovery of the brain and restores the innate capacity to develop and maintain structural connectivity
  • Ketamine allows for glutamate release to happen in pulses in certain circuits instead of sustaining high levels of glutamate which is toxic to the brain
  • For people without synaptic deficit, the therapeutic effects of ketamine may be tied to instead increasing the efficiency of synaptic connections instead of restoration of synapses
  • There’s a thin therapeutic margin for effectively dosing ketamine – generally, 0.5mg/kg administered via intravenous infusion is the standard
  • “People have undersold the risk of ketamine addiction in the United States. In some parts of the world, ketamine is known as a very significant, commonly abused substance, often as an alternative to alcohol or sometimes as an alternative to cannabis.” – Dr. John Krystal
  • Best practice for ketamine dosing to avoid abuse: when ketamine doses are properly spaced, there is no tolerance build up and no increase in dose given (conversely, when ketamine is used every day or regularly, you are tolerant to the effects)
  • Ketamine may treat or reset chronic pain: (1) NMDA receptors (ketamine target) are in the pain pathway; (2) can help prevent the development of tolerance to anti-pain effects of opiates; (3) prevent sensitization of the pain pathway
  • Unexpectedly, rapamycin extends the antidepressant effects of ketamine – surprising because rapamycin blocks mTOR in the brain but mTor activation is critical to the antidepressant effects of ketamine
  • Psychedelics vary in mechanism and structure but overlap on certain points: increase of excitability, increase of glutamate output, triggering downstream neurotropic effects, triggering regrowth of lost synapses (in animal models)
  • Key understanding coming in psychedelic research over the next 5-10 years: psychedelics can signal the same receptor via different downstream mechanisms

Introduction

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. He 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.

The definitive discussion on Ketamine with legendary Yale researcher, John Krystal PhD – who discovered and first published on Ketamine for use in Depression. 

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. He 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.

Dr. John Krystal 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.

In this episode, Tim Ferriss and Dr. John Krystal take a deep dive into all things ketamine – the complexity of depression and its treatment, Western medicine approaches, emergence of ketamine as therapy, effects of ketamine on body systems, and future predictions. This is full Premium notes of their discussion.

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