by

Tim Ferriss

Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever (#625)

Leave a comment

Topics:
Artist's rendering of Dr. John Krystal.
Illustration via 99designs

“Depression is a disorder of the spirit, if you will—the brain but also the whole body. And that’s one of the reasons why it’s one of the most disabling conditions that we have in the world.”

— Dr. John Krystal

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!

Listen to the episode on Apple Podcasts, Spotify, Overcast, Podcast Addict, Pocket Casts, Castbox, Google Podcasts, Stitcher, Amazon Music, or on your favorite podcast platform. You can watch the interview on YouTube here. The transcript of this episode can be found here. Transcripts of all episodes can be found here.

Brought to you by AG1 all-in-one nutritional supplement and Helix Sleep premium mattresses.

Listen onApple Podcasts
Listen onSpotify
Listen onOvercast
#625: Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever

This episode is brought to you by Helix Sleep! Helix was named best overall mattress of 2026 by Forbes, Wired, and Sleepopolis; best mattress for couples by Oprah Daily; and one of the most trusted brands of 2026 by USA Today. 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 listeners 27% off sitewide for a limited time at HelixSleep.com/Tim.

This episode is brought to you by AG1. I’ve taken AG1 for more than a decade. Longtime listeners have heard me call it my nutritional insurance. Here’s the news: they’ve just launched AG1 Pro, designed for people focused on performance and longevity. I’ll be traveling soon, and I’m throwing this in my bag to cover my bases while I travel. Past a certain age, maintaining lean muscle becomes priority number one, and AG1 Pro is formulated to support exactly that. It includes HMB, a clinically studied compound that supports protein synthesis and helps reduce protein breakdown, plus zinc carnosine to support the gut lining. Remember: training is only half the equation. Recovery is where the work compounds, and AG1 Pro is built to support it. It’s NSF Certified for Sport, so what’s on the label is what’s in the pouch. Get your free AG1 Pro Yeti Shaker in the Welcome Kit at Drinkag1.com/Tim.

Want to hear another podcast episode with someone who’s exploring the beneficial properties of mind-altering compounds? Listen to my conversation with Dr. Suresh Muthukumaraswamy, in which we discuss how ketamine differs from other psychedelics, the durability of antidepressant effects, obstacles to getting ketamine labeled as an antidepressant, avoiding another 50 years of psychedelic research darkness, where aspiring psychedelic researchers should focus their education, and much more.

#619: Dr. Suresh Muthukumaraswamy — LSD Microdosing, Classical Psychedelics vs. Ketamine, Science and Speed in New Zealand, Placebo Options, and The Infinite Possibilities of Studying Mind-Altering Compounds

What was your favorite quote or lesson from this episode? Please let me know in the comments.

SCROLL BELOW FOR LINKS AND SHOW NOTES…

SELECTED LINKS FROM THE EPISODE

SHOW NOTES

  • [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.

MORE GUEST QUOTES FROM THE INTERVIEW

“Depression is a disorder of the spirit, if you will—the brain, but also the whole body. And that’s one of the reasons why it’s one of the most disabling conditions that we have in the world.”
— Dr. John Krystal

“The ideal antidepressant would be a drug that acted rapidly and lasted forever. We would call that, basically, cure. And we never use the word ‘cure’ in psychiatry. We don’t even think of the idea of cure. And that’s partly because we don’t really understand the brain well enough to really know how to completely undo the changes that we see there.”
— Dr. John Krystal

PEOPLE MENTIONED

Subscribe
Notify of
guest

Comment Rules: Remember what Fonzie was like? Cool. That's how we're gonna be — cool. Critical is fine, but if you're rude, we'll delete your stuff. Please do not put your URL in the comment text and please use your PERSONAL name or initials and not your business name, as the latter comes off like spam. Have fun and thanks for adding to the conversation! (Thanks to Brian Oberkirch for the inspiration.)

9 Comments
Oldest
Newest Most Voted

Keep exploring.