All Things Ketamine — The Most Comprehensive Podcast Episode Ever with Dr. John Krystal

Tim Ferriss interviews Dr. John Krystal in an in-depth conversation covering everything about ketamine. Krystal traces the history of depression treatment from the failed serotonin hypothesis to the discovery that ketamine acts on glutamate, the brain's main excitatory signal, to rapidly regrow lost synaptic connections. He details best practices for dosing, the role of dissociation, the serious and underappreciated addiction risk, and applications beyond depression including PTSD and chronic pain. The episode closes on cutting-edge research such as combining ketamine with rapamycin to extend its effects, R-ketamine, and the comparison between ketamine and classic psychedelics.

• Psychiatry spent 50 years studying serotonin and norepinephrine, which make up only about 2% of brain synapses, while ignoring glutamate, which accounts for roughly 90% of synapses and is the main information highway of the brain.
  00:52:30
• In the first ketamine study, the antidepressant effect was discovered almost by accident: patients went home and reported the next day that their depression was all better, an effect the researchers initially didn't know what to make of.
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• Ron Duman and George Aghajanian showed in 2010 that a single dose of ketamine produced rapid structural regrowth of brain synapses within 24 hours, reversing the synaptic losses caused by chronic stress.
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• In patients with synaptic deficits, more dissociation during ketamine correlated with greater synaptic regrowth and clinical improvement; in patients without deficits, dissociation was unrelated to response, meaning it means two different things in two groups.
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• The therapeutic window for IV ketamine is extremely narrow: 0.5 mg/kg works, but going down to 0.2 mg/kg is barely effective for anyone, while anesthetic doses lose the antidepressant effect entirely.
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• Krystal met heavy ketamine abusers in China and Taiwan using up to 8 grams (8,000 mg) a day intranasally, roughly 100 to 200 times a therapeutic dose, who became persistently psychotic even after stopping.
  02:27:15
• Pre-treating treatment-resistant depression patients with the immunosuppressant rapamycin raised the two-week ketamine response rate from about 13% to over 40%, possibly by stopping microglia from eating the newly created synapses.
  03:18:24
• Giving a high dose of naltrexone (an opiate blocker) before ketamine did not change ketamine's dissociative effects at all, undercutting the idea that dissociation depends on opioid receptor activity.
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• Untreated depression shortens lifespan by about five years on average, not through suicide, because depression worsens inflammation and the medical illnesses driven by it.
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• The first antidepressant, a monoamine oxidase inhibitor, was discovered in 1957 by accident when tuberculosis patients given it found both their TB and their depression improving.
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• MAO inhibitors require avoiding aged cheese and wine because the tyramine they contain can spike blood pressure dangerously, occasionally causing strokes.
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• PCP (angel dust) was first given to a human in 1959 in Detroit and produced something like schizophrenia, but its mechanism (blocking the NMDA glutamate receptor) wasn't identified until the mid-1980s.
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• Ed Domino's early ketamine paper coined the term dissociative anesthesia, noting sensory information reached sensory cortex but was blocked in transmission to association cortex.
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• People with a personal or family history of alcohol use disorder have a built-in tolerance to ketamine's dissociative effects yet still get the antidepressant benefit.
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• S-ketamine (Spravato) starts at a fixed 56 mg dose working up to 84 mg, while IV ketamine is dosed by weight at 0.5 mg/kg, giving IV a theoretical speed advantage.
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• The most effective way to manage a patient losing perspective during ketamine is simply preparing them beforehand for what may happen, then reminding them it is the drug and it will pass.
  02:11:37
• Ferriss reports that two weeks of ketamine infusions eliminated chronic thoracic back pain he'd had for years, with complete relief lasting five to six months.
  02:53:48
• Exercise raises BDNF (brain-derived neurotrophic factor) in a dose-related way, offering a natural route to some of the same neurotrophic benefits ketamine triggers.
  03:41:55