#625: Dr. John Krystal – All Things Ketamine, The Most Comprehensive Podcast Episode Ever (Free Preview) | 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


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, the emergence of ketamine as therapy, the effects of ketamine on body systems, and future predictions.

Host: Tim Ferriss (@tferriss)

Understanding Depression

  • The parent-child interaction and the nurturing experience are fundamental to optimism and the feeling that things will work out
  • Despair instead of hope is a default setting for some, maybe provoked by an event or trauma
  • Depression is not just a fleeting feeling, it’s a pervasive mode of being that invades every aspect of one’s life and experience of the world; it affects the pattern of your thinking – you see the negative in everything
  • “What people don’t understand about depression is it goes beyond sadness; it can be a complete blunting of emotional experience and the loss of feeling.” – Dr. John Krystal
  • Symptoms of melancholy depression: loss of feeling, tossing and turning/difficulty sleeping, loss of energy, loss of concentration, waking up early, difficulty relaxing and feeling comfortable, being overcome with pervasive and intrusive negative thoughts, loss of appetite, decreased interest
  • Reactive depression: people with this depression have the capacity to see good and bad but cannot control their reaction
  • 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
  • Depression is extremely disabling

Complexity In Psychiatry

  • There is a history of blaming the patient when depression treatment fails (e.g., saying the patient wasn’t engaged enough in care) – the field of psychiatry is taking more ownership in recent times
  • Psychiatry doesn’t have tangible ways to test and assess progress – there is no x-ray, MRI, scan, etc. that can inform the process
  • When patients start to show improvements in reported symptoms, there’s often a failure on the system to push a little harder and see if additional progress can be made with other types of treatments
  • The USA has restricted some gold-standard treatments of depression such as electroconvulsive therapy (controversial but shows great benefit when balanced against the risk of depression)

MAO Inhibitors

  • The first antidepressant (MAO inhibitor) was discovered in 1957 serendipitously when it was being used to treat tuberculosis
  • MAO inhibitor mechanism: inhibit MAO which is involved in the breakdown/metabolism of norepinephrine and serotonin – this raises the level of serotonin and norepinephrine in the synapse and increases stimulation of receptors
  • MAO inhibitor risks & side effects: (1) can increase blood pressure to life-threatening levels; (2) serotonin syndrome can raise body temperature and stress the system; (3) many interactions, for example, can’t be combined with aged cheese and wines which can induce stroke

The Serotonin Hypothesis & The Early Days Of Ketamine

  • Tryptophan depletion: tryptophan is an essential amino acid – if depleted in the body, you can’t make serotonin
  • The antidepressant effect of drugs (like Prozac) depends on the ability of the brain to have a big supply of serotonin – but when serotonin is depleted in healthy people, it does not induce depression
  • Serotonin has acute effects on the brain and can be impacted with even one dose of Prozac, but the effects won’t be long lasting
  • Profound shift in how depression is studied and treated: since it wasn’t just a matter of serotonin levels, the model of thinking shifted to exploring higher cognitive centers (like the cerebral cortex) and higher emotional centers (in the limbic system)
  • Higher brain centers use glutamate (about 90% of synapses of the brain; main excitatory driver for brain activity) and GABA (main inhibitory neurotransmitter)
  • Ketamine probes glutamate synaptic signaling so started being studied for the treatment of depression
  • Skepticism was so high, ketamine results were first published in 1997 and not replicated until 2006
  • Psychedelic drugs change the activity rate of serotonin neurons
  • If you administer a dose of ketamine to stressed animals, it produces a rapid and profound biochemical, electrophysiological, and structural change in the brain within 24 hours

History Of Ketamine

  • Why ketamine? An effort to probe glutamate synaptic function in higher cortical circuits to understand schizophrenia
  • Ketamine is a dissociative anesthetic, widely used and very inexpensive
  • Ketamine is a World Health Organization essential medication
  • Ketamine is not a horse tranquilizer (despite rumors)
  • Ketamine is a glutamate receptor blocker but also blocks the excitation of inhibition inhibitory cells – it’s like “if you have a break but then have another break to release the break instead of stepping on the gas pedal” – Dr. John Kyrstal
  • Ketamine allows more glutamate release to happen in certain circuits of the brain so it happens in pulses instead of
  • Importance of dosing correctly: at a sub-anesthetic dose, it releases glutamate; if you give it at anesthetic doses, it depresses glutamate and is not an antidepressant – there’s a narrow dose window for the treatment of depression

Dissociation & Antidepressant Effects Of Ketamine

  • Dissociation: when aspects of consciousness are perturbed, and you enter distortions in perceptions of self and the world
  • Ketamine is not a meaningful experience for everyone
  • Dissociation is not a necessity for producing change, but it does seem that the optimal dose for depression does come with dissociative effects (this can be helpful for dosing)
  • People with a history of alcoholism in the family seem to have a built-in tolerance to the effects of ketamine
  • Dissociation can mean different things depending on the patient: (1) early research in people with synaptic deficits are more treatment-resistant show that the bigger the dose of ketamine, the greater their clinical improvement; (2) dissociation is unrelated to clinical response in patients without synaptic deficit – and there’s some evidence that the more dissociation, the fewer ketamine works for depression
  • Ketamine improves the functionality of synapses quickly and restores synaptic connections later

End of Free Preview—How to Get More!

We’ve only got started with this incredible deep dive on Ketamine with John Krystal. Become a Podcast Notes premium member today to get the rest, here’s what’s included:

  • What Does Ketamine Therapy Look Like?
  • Ketamine Side Effects
  • Ketamine Abuse
  • Lessons From Animal Studies
  • Ketamine Enantiomers & Similar Drugs
  • Ketamine Use For Chronic Pain
  • Understanding Other Substances
  • Rapamycin & Ketamine
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