Tim Ferriss

September 30, 2022

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

“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 selected as the best overall mattress of 2025 by Forbes and Wired magazines and best in category by Good Housekeeping, GQ, 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 20% off all mattress orders at HelixSleep.com/Tim.

This episode is brought to you by AG1! I get asked all the time, “If you could use only one supplement, what would it be?” My answer is usually AG1, my all-in-one nutritional insurance. I recommended it in The 4-Hour Body in 2010 and did not get paid to do so. And right now, when you first subscribe to AG1, you’ll get an AG1 Welcome Kit, a bottle of Vitamin D3+K2, a Morning Person hat, AND you’ll get to try each new flavor of AG1 and their new sleep supplement, AGZ. That’s $126 in free gifts for new subscribers! Visit DrinkAG1.com/Tim to claim this special offer today

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

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

Inline Feedbacks

View all comments

Michael Brooks | Website Developer/Blogger

3 years ago

Another great podcast episode. Thank you Tim!

Glynn Rees

3 years ago

Thank you Tim for making the transcripts available for the hearing impaired. I’m not sure if you get any acknowledgement of the transcripts, just wanted to Kota let you know I am very appreciative oa.
Thank you sincerely.

James Cox

3 years ago

Dr. Krystal made it sound like insurance will cover these treatments but my brief research indicates this isn’t so. Anyone know the scoop?

morganbarritola

3 years ago

Dear Tim, thank you for this conversation. Talk can be such a catalyst for change and your podcast with Dr. Krystal was fantastic. Everyone’s Thanksgiving dinner table offers a seating chart of disorder!
As a former professional athlete who has suffered from sever depression from a young age and who is now pursuing a career in clinical counseling, I really appreciate you and the work you do.

Dan

3 years ago

I’m wondering why, after talking about dosage/administration routes/abuse potential, they did not discuss sublingual administration (ie rapid dissolve tables). There are so many people taking it at home – it seems deliberate to skip over that method.

Clinical treatment is not-sustainable – both in cost and the difficulty with scheduling. The advantages of at-home options are immense and will surely save even more lives.

Maria Terris

3 years ago

I am currently doing oral ketamine. Was wondering if one day you can do a comprehensive on that?

Carlos Alberto Solano Ortiz

2 years ago

What should we give our dogs then? Any additional ideas would be helpful such as dose, frequency, side effects, etc. when giving it to dogs. Thanks so much!

Renelle LeBlanc-Scott

2 years ago

I just can’t thank you enough for this hugely informative and educational episode!!! Although I’m a closet-science-geek and just really enjoy learning about the world around me, I’m particularly interested in ketamine assisted psychotherapy because I’ve recently decided to explore this avenue of treatment for depression and problematic addictive eating. In Canada (and especially on the East Coast), access to such innovative therapies is not only difficult but also often cost prohibitive (private clinics are the only option). The clinic I’ll be attending offers a six week program for $4725 which includes once a week treatment (2 hours of ART followed by 1.5-2 hours of KAT). After much internet research and after listening to this particular podcast, I’m feeling even more hopeful for my future. Thank you Tim and Dr. Krystal!!

Renelle xx

Jhon

1 year ago

Thank you