Altered States

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

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“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 Musicor on your favorite podcast platform. You can watch the interview on YouTube here.

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

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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.




  • [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.


“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


The Tim Ferriss Show is one of the most popular podcasts in the world with more than 800 million downloads. It has been selected for “Best of Apple Podcasts” three times, it is often the #1 interview podcast across all of Apple Podcasts, and it’s been ranked #1 out of 400,000+ podcasts on many occasions. To listen to any of the past episodes for free, check out this page.

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