AI-powered
podcast player
Listen to all your favourite podcasts with AI-powered features
The Tim Ferriss Show
#625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever
Sep 29, 2022
03:54:07
Episode guests
AI Summary
Highlights
AI Chapters
Episode notes
Podcast summary created with Snipd AI
Quick takeaways
- The shift from the serotonin hypothesis to exploring the role of glutamate opened up new avenues for understanding and treating depression.
- Ketamine's ability to rapidly restore synaptic connections and promote behavioral resilience challenges traditional views of depression.
- Research on ketamine's impact on stressed animals provided deeper insights into depression as a circuit-based disorder.
- Ketamine's mechanism of action involves blocking the NMDA glutamate receptor, leading to increased neuroplasticity and regrowth of synaptic connections.
- Dissociation experienced during ketamine treatment weakens the impact of maladaptive memories associated with trauma and addiction.
- Ketamine shows potential in treating chronic pain by reducing sensitization of pain pathways and modulating emotional responses to pain.
Deep dives
The Serotonin Hypothesis and the Shift Towards Glutamate Signaling
The serotonin hypothesis, which suggested that low serotonin levels cause depression, was a dominant theory in psychiatry. However, research on the efficacy of serotonin-based treatments like Prozac led to some skepticism. In the 1980s, researchers began exploring the role of glutamate, the main excitatory neurotransmitter in the brain, in depression. This shift in focus challenged the idea that depression was solely caused by serotonin abnormalities. It prompted investigations into the cortical and limbic circuits involved in emotion and reward processing, which are predominantly driven by glutamate. This change in perspective opened up new avenues for understanding and treating depression.
The Discovery of Ketamine's Antidepressant Effects
In the late 1990s, researchers, including Dr. John Crystal and Dennis Charney, conducted studies on ketamine to investigate its role in synaptic signaling and its potential therapeutic effects on depression. Initial findings showed that ketamine produced rapid and profound changes in the brain, restoring synaptic connections and promoting behavioral resilience within 24 hours. These results challenged the traditional view of depression and inspired further research. Replication studies confirmed ketamine's antidepressant effects, leading to growing acceptance of its potential as a treatment for depression.
The Significance of Ron Duman's Work and FDA Approval
In 2010, Ron Duman conducted a study that demonstrated the impact of ketamine on stressed animals, revealing its ability to induce biochemical, electrophysiological, and structural changes in the brain. This study shed light on the mechanisms underlying ketamine's antidepressant effects and provided a deeper understanding of depression as a circuit-based disorder. Subsequent research supported these findings, and ketamine gained recognition as a powerful and rapidly acting treatment for depression. In 2019, the FDA approved S-ketamine, a nasal spray formulation of ketamine, for treatment-resistant depression. This marked a significant milestone in the recognition and acceptance of ketamine as a therapeutic option for depression.
Key Point 1: Discovery of Ketamine's Mechanism and Research Motivation
The discovery of ketamine's mechanism and its potential in treating depression was motivated by research on its use as an anesthetic and its effects on the NMDA glutamate receptor. Scientists noticed that ketamine produced dissociative anesthesia and wanted to understand its impact on the brain. Ron Duman, a Yale researcher, played a significant role in investigating ketamine's antidepressant effects due to his prior work on neurogenesis and neurotrophic signaling in depression.
Key Point 2: Ketamine's Mechanism and Neuroplasticity
Ketamine works by blocking the NMDA glutamate receptor, which leads to a temporary increase in glutamate release. This increased glutamate release triggers the elevation of BDNF levels and activates the mTOR protein, a key player in the regrowth and stabilization of synaptic connections. The antidepressant effects are believed to be a result of rapid changes in glutamate synaptic function and increased neuroplasticity in the brain.
Key Point 3: Dissociation, Trauma Memories, and Treatment Outcomes
Dissociation is a subjective experience characterized by feelings of depersonalization and derealization. It can be beneficial in ketamine treatment for PTSD and addiction as it weakens the impact of maladaptive memories associated with trauma and addictive behaviors. Reactivating trauma memories during ketamine infusion has been shown to reduce their potency and potentially alleviate symptoms. However, the relationship between dissociation and therapeutic outcomes in both depression and PTSD is complex, and more research is needed to fully understand the role of dissociation in ketamine treatment.
Ketamine's effects on pain and resilience
Ketamine has shown potential in treating chronic pain by blocking NMDA glutamate receptors and reducing sensitization of pain pathways. It can also improve resilience to pain by reducing depression and anxiety associated with pain. The durability of pain relief experienced by some individuals may be due to the rewiring of neural circuits and the modulation of emotional responses to pain.
Optimizing Ketamine's Effectiveness
Researchers are exploring ways to extend the efficacy of ketamine in treating depression. One approach involves inhibiting the mTOR protein, which triggers the regrowth of synaptic connections. Preliminary studies combining ketamine with an mTOR blocker called rapamycin have shown promising results, with response rates at two weeks increasing from 13% to over 40%. The immunosuppressive effects of rapamycin may play a role in extending ketamine's antidepressant effects by modulating the immune cells in the brain, particularly microglia.
Alternative Ketamine Applications
Ketamine's potential uses extend beyond depression and pain management. For example, S-ketamine, an isomer of ketamine, is being explored as a treatment for depression. Additionally, other NMDA glutamate receptor antagonists like S-methadone show promise in treating depression and reducing anhedonia. These alternative treatments aim to provide additional options for individuals who may not respond to ketamine or experience adverse side effects.
Ketamine and Rapamycin's Effects on Microglia and Synaptic Density
Ketamine and the immunosuppressant rapamycin have been found to affect microglia, a type of brain cell involved in synaptic elimination. In conditions like depression, where microglia are activated, they contribute to deficits in synaptic density. The combination of ketamine and rapamycin may prevent microglia from engulfing newly created synapses, thereby extending the antidepressant effects of ketamine. However, further research is needed to determine the optimal dosage and long-term effects of this combination therapy.
Comparing Ketamine and Other Psychedelics
Ketamine and other psychedelics, while structurally and mechanistically different, converge in how they perturb microcircuits in the brain. Both ketamine and psychedelics increase the excitability and glutamate output of microcircuits, triggering downstream effects such as neurotrophic activity and the regrowth of synapses. These common effects point to a potential foundation for the therapeutic benefits of psychedelics. Ongoing research is exploring novel approaches, including targeting specific signaling pathways, to maximize the antidepressant effects while minimizing the psychedelic experiences.
4.
I've Always Felt That There Was No Challenge That Could Ever Match the Challenges That My Father's Father Faced in His Life
3min
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.
Follow Tim:
Twitter: twitter.com/tferriss
Instagram: instagram.com/timferriss
YouTube: youtube.com/timferriss
Facebook: facebook.com/timferriss
LinkedIn: linkedin.com/in/timferriss
Past guests on The Tim Ferriss Show include Jerry Seinfeld, Hugh Jackman, Dr. Jane Goodall, LeBron James, Kevin Hart, Doris Kearns Goodwin, Jamie Foxx, Matthew McConaughey, Esther Perel, Elizabeth Gilbert, Terry Crews, Sia, Yuval Noah Harari, Malcolm Gladwell, Madeleine Albright, Cheryl Strayed, Jim Collins, Mary Karr, Maria Popova, Sam Harris, Michael Phelps, Bob Iger, Edward Norton, Arnold Schwarzenegger, Neil Strauss, Ken Burns, Maria Sharapova, Marc Andreessen, Neil Gaiman, Neil de Grasse Tyson, Jocko Willink, Daniel Ek, Kelly Slater, Dr. Peter Attia, Seth Godin, Howard Marks, Dr. Brené Brown, Eric Schmidt, Michael Lewis, Joe Gebbia, Michael Pollan, Dr. Jordan Peterson, Vince Vaughn, Brian Koppelman, Ramit Sethi, Dax Shepard, Tony Robbins, Jim Dethmer, Dan Harris, Ray Dalio, Naval Ravikant, Vitalik Buterin, Elizabeth Lesser, Amanda Palmer, Katie Haun, Sir Richard Branson, Chuck Palahniuk, Arianna Huffington, Reid Hoffman, Bill Burr, Whitney Cummings, Rick Rubin, Dr. Vivek Murthy, Darren Aronofsky, Margaret Atwood, Mark Zuckerberg, Peter Thiel, Dr. Gabor Maté, Anne Lamott, Sarah Silverman, Dr. Andrew Huberman, and many more.
See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
Get the Snipd
podcast app
Unlock the knowledge in podcasts with the podcast player of the future.
AI-powered
Discover
highlights
Listen to the best highlights from the podcasts you love and dive into the full episode
Save any
moment
Hear something you like? Tap your headphones to save it with AI-generated key takeaways
Share
& Export
Send highlights to Twitter, WhatsApp or export them to Notion, Readwise & more
AI-powered
podcast player
Listen to all your favourite podcasts with AI-powered features
Discover
highlights
Listen to the best highlights from the podcasts you love and dive into the full episode