Beyond Monoamines: Ketamine, Esketamine, and Classic Psychedelics in the Treatment of Depression
Zenodo (CERN European Organization for Nuclear Research) July 17, 2026 Bartosz Niciński, Magdalena Kloc, Ewa Wiench, Natasza Millan, Aleksandra Blicharz, Wojciech Kozdraś, Lidia Kozaczko, Gabriela Szewczyk, Elżbieta Bukowczan, Alicja Zając, Damian Broda, Alicja Benecka
Major depressive disorder is a common and burdensome condition, and many patients do not fully recover after standard antidepressant treatment, prompting interest in rapid-acting interventions that target brain pathways beyond serotonin, norepinephrine, and dopamine. This review examines ketamine, esketamine, and classic psychedelics for depression, especially treatment-resistant depression. Ketamine and esketamine have the strongest evidence, with ketamine showing rapid antidepressant and anti-suicidal effects, and intranasal esketamine being the first NMDA receptor antagonist approved for treatment-resistant depression. Psilocybin-assisted therapy has shown promising results but remains investigational and requires a structured therapeutic framework. Evidence for LSD, DMT, and mescaline is preliminary. These treatments highlight the roles of glutamatergic modulation, serotonergic mechanisms, and neuroplasticity. Key unresolved issues include maintaining effects over time, identifying which patients benefit most, and safe delivery outside specialized settings.