Exploring the Therapeutic Potential of Psilocybin and Ketamine in Major Depressive Disorder including Treatment-Resistant Depression: A Narrative Review
Biuletyn Głównej Biblioteki Lekarskiej – June 01, 2025
Source: OpenAlex
Summary
Novel medicine offers hope for Major depressive disorder (MDD) and Treatment-resistant depression. Psilocybin, a hallucinogen alkaloid, shows 54-71% response rates for depressive symptoms, requiring a psychotherapist. Ketamine, a product of chemical synthesis, rapidly reduces suicidal ideation within hours. Both agents, influencing neurotransmitter receptors, represent a paradigm shift in psychiatry and clinical psychology. Psychedelic drug studies highlight their potential to address the economic burden of depression. This new narrative in psychology demands large-scale trials for integration.
Abstract
Abstract Major depressive disorder (MDD), including treatment-resistant depression (TRD), represents significant global health challenges with conventional therapies often yielding suboptimal outcomes. This narrative review examines the therapeutic potential of psilocybin and ketamine, two novel agents offering distinct mechanisms of action compared to traditional monoamine-based or monoamine reuptake inhibitor antidepressants. Psilocybin, a 5-HT2A receptor agonist, induces rapid and sustained antidepressant effects with some clinical trials demonstrating response rates of 54-71% in MDD. Ketamine, an NMDA receptor antagonist, exerts rapid antidepressant effects via glutamatergic signalling pathways, showing particular efficacy in reducing suicidal ideation within hours. While psilocybin requires structured psychotherapeutic support during its acute psychedelic effects, ketamine offers flexible administration routes (intranasal, intravenous, subcutaneous), some of which can be applied immediately in an emergency setting. Safety profiles for both compounds are favourable in controlled settings with transient adverse effects such as dissociation or nausea. However, current research faces limitations including small sample sizes, blinding challenges, and heterogeneity in trial design and therapeutic protocols. Despite these constraints, psilocybin and ketamine represent a paradigm shift in depression treatment. Future directions require large-scale trials, standardized protocols and long-term safety assessments to optimize their integration into clinical practice. These agents hold promise for reshaping therapeutic approaches to MDD, particularly for patients unresponsive to conventional therapies (TRD).