This episode tackles the profound challenge of treatment-resistant depression (TRD), a severe mental illness affecting 280 million people globally. While low-dose subanesthetic intravenous ketamine treatment has shown rapid improvement for TRD, its effects are often transient, lasting only days to weeks, and IV administration can be impractical and expensive for long-term use.

We shift focus to a novel, more accessible approach: very low-dose subcutaneous ketamine. Drawing on a unique case report, we explore its potential as a maintenance option for severe TRD. This method is highlighted for being less invasive, more cost-effective, practical, and accessible, potentially offering a more gradual absorption that could decrease adverse effects. The case study featured a patient with severe TRD who, after 15 years of struggle, achieved a stable mental state and maintained occupational functioning for four years with subcutaneous ketamine.

Study discussed: https://onlinelibrary.wiley.com/doi/10.1002/ccr3.6675

Explore a groundbreaking single case study from 2025 on ketamine-assisted psychotherapy (KAP) for the notoriously challenging anorexia nervosa (AN). Discover how KAP, coupled with Acceptance and Commitment Therapy (ACT), potentially creates a "neuroplastic window" for change in rigid thought patterns. The case study reveals marked symptom reduction in AN pathology, depression, and anxiety, alongside improved quality of life for one patient. This unique case highlights the critical synergy between ketamine and therapy for sustained gains, while also navigating complexities like post-treatment weight loss and a subsequent psilocybin experience. It's a powerful glimpse of hope for treatment-resistant conditions, demanding further rigorous research.

Find the full report here: https://jeatdisord.biomedcentral.com/articles/10.1186/s40337-025-01313-y

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