Bridging ancient substances and modern psychiatry: the role of classic psychedelics in depression treatment.
Guilherme Lodetti, Gislaine Zilli Réus, Eduardo Pacheco Rico
Neuroscience January 22, 2026 DOI: 10.1016/j.neuroscience.2026.01.022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Population | Major depressive disorder patients |
| Intervention | Classic psychedelics |
| Topics | Depression Neuroplasticity |
| Keywords | Classic psychedelics Treatment |
| Key findings | Classic psychedelics produce antidepressant effects comparable to traditional treatments, likely through 5-HT2A receptor binding and promotion of neuroplasticity. |
Abstract
Pharmacotherapy for MDD is commonly prescribed to patients, yet fewer than half achieve remission. Moreover, many patients exhibit intolerant responses to pharmacological treatment, highlighting the need to explore new forms of therapy. The present work provides a narrative review of classic psychedelics as an alternative to MDD treatment. In addition, mechanisms by which psychedelics exert antidepressant effects are discussed. A literature review of recent studies regarding psychedelics used for the treatment of depressive disorders. The main search platform for relevant indexed articles used was PubMed, using keywords such as psychedelics, MDD, depression, and treatment. Studies have shown that classic psychedelics mainly bind to 5-HT2A receptors, increasing interaction between sensory and somatomotor brain networks. These substances play a significant role in treating psychiatric disorders. Also, classic psychedelics generate long-term behavioural responses comparable to traditional treatments. Therefore, they are strongly associated with the management of these conditions. Recent studies have shown that classic psychedelics yield favourable outcomes in alleviating symptoms of depression. This has been observed in clinical and experimental investigations. The improvement in mood is thought to arise from their influence on molecular targets associated with neuroplasticity, including the promotion of neurogenesis and the behavioural responses linked to downstream and upstream signalling pathways.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cites 83
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
and 78 more in the library