Beyond Monoamines: Ketamine, Esketamine, and Classic Psychedelics in the Treatment of Depression
Zenodo (CERN European Organization for Nuclear Research) July 17, 2026 DOI: 10.5281/zenodo.21406175 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine Esketamine Psilocybin LSD DMT Mescaline |
| Topics | Depression Ketamine Neuroplasticity Serotonin Esketamine |
| Keywords | Monoaminergic Antidepressant Depression economics Psychotherapist Vortioxetine Dopamine Electroconvulsive therapy |
| Key findings | Ketamine and esketamine have the strongest evidence among rapid-acting antidepressant interventions for treatment-resistant depression, while psilocybin-assisted therapy shows promise but remains investigational. |
Abstract
Major depressive disorder is a highly burdensome psychiatric condition worldwide, and many patients do not achieve full remission after standard monoaminergic antidepressant treatment. This has contributed to growing interest in rapid-acting antidepressant interventionstargeting neurobiological pathways beyond traditional serotonin, norepinephrine, and dopamine mechanisms. This review summarizes currentevidence on ketamine, esketamine and classic psychedelics in depression, with particular emphasis on treatment-resistant depression,mechanisms of action, clinical efficacy and safety considerations. Ketamine and esketamine currently possess the strongest evidence base amongrapid-acting antidepressant interventions. Ketamine has demonstrated rapid antidepressant and anti-suicidal effects, while intranasal esketaminerepresents the first NMDA receptor antagonist approved specifically for treatment-resistant depression. Psilocybin-assisted therapy has shownpromising results in major depressive disorder and treatment-resistant depression, although it remains investigational and requires administrationwithin a structured psychotherapeutic framework. Evidence for LSD, DMT, mescaline and other emerging psychedelic compounds remainspreliminary and is derived mainly from small clinical trials, experimental studies or naturalistic observations. Overall, these treatments highlightthe relevance of glutamatergic modulation, serotonergic mechanisms, and neuroplasticity in depression. The main unresolved issues are whetherthese effects can be maintained over time, which patients are most likely to benefit, and how such treatments could be delivered safely outside highly specialized settings.