Dive into the incredible, 60-year saga of ketamine! Our deep dive explores the fascinating journey of this molecule, originally known as CI-581, from its origins as an 'older sibling' to PCP (phencyclidine). Discover how it became the subject of the first-in-human study for a novel anesthetic. Learn about its unique status as the only "dissociative anesthetic", noted for rapid onset, short duration, and minimal adverse cardiovascular or respiratory effects, yet also for its distinct psychic "syndrome" that led to the term "dissociative anesthesia".

Explore how ketamine faced controversy and fell out of favor due to psychotomimetic effects and patient nightmares, only to experience a "rebirth" through scientific understanding of its NMDA receptor antagonism and the use of benzodiazepines to mitigate side effects. Witness its dramatic resurgence in anesthesiology and pain management, driven by the opioid crisis, making opioid-sparing anesthesia ubiquitous.

Most recently, delve into its "explosive" life as a rapid-acting antidepressant, a discovery that has revolutionized psychiatry and led to the FDA approval of S(+)-ketamine nasal spray. Ketamine's story highlights its pharmacologic complexity and its role as a "pharmacologic agent provocateur", challenging classical drug development paradigms by showing effects that "outlast" plasma exposure. This powerful journey raises critical questions about modern drug discovery and whether such a complex molecule would even be approved today.

Learn more in the insightful commentary that guided this episode: The Nine Lives of Ketamine from CI-581 to Present Day Clinical Application—Commentary on Domino et al. by Evan D. Kharasch, published in Clinical Pharmacology and Therapeutics. Link to the study: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.3634