Rethinking Depression: The Role of Serotonin and Ketamine

Dr. John Krystal — All Things Ketamine, The Most Comprehensive Podcast Episode Ever | Brought to you by Athletic Greens all-in-one nutritional supplement, Helix Sleep premium mattresses, and Allform premium, modular furniture. 

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!

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[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.

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