Psychedelics, entactogens and psychoplastogens for depression and related disorders
British Journal of Pharmacology June 15, 2025 DOI: 10.1111/bph.70088 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Psilocybin LSD N ayahuasca MDMA ibogaine ketamine esketamine dextromorphan/bupropion esmethadone |
| Topics | Anxiety Depression MDMA Psilocybin |
| Keywords | Hallucinogen Monoamine neurotransmitter Antidepressant |
| Citations | 9 |
| Key findings | Psychedelics, entactogens, and psychoplastogens target common pathways involving neuroplasticity and synaptogenesis, correcting neural network impairments in depression, anxiety, and PTSD. |
Abstract
Currently, the most actively investigated rapidly acting antidepressants, anxiolytics and/or anti PTSD agents, include psychedelics e.g. psilocybin, LSD, N , N ‐dimethyltryptamine, ayahuasca; non‐hallucinogenic entactogens, e.g. MDMA; psychoplastogens which rapidly promote neuroplasticity, e.g. ibogaine, ketamine and esketamine; and other atypicals e.g. dextromorphan/bupropion, esmethadone. Late‐stage clinical trials support psychedelics and/or MDMA‐assisted psychotherapy as rapidly acting treatments for major depressive disorder (MDD), treatment‐resistant depression (TRD), PTSD or generalised anxiety disorders (GAD). Psilocybin, MDMA and LSD were granted FDA breakthrough status for TRD/MDD, PTSD and GAD, respectively, although FDA recently rejected the new drug application of MDMA in PTSD. Most of these drugs target the 5‐HT and monoamine systems. Classical psychedelics act as 5‐HT 2A receptor agonists, although LSD, DMT and psilocybin target other 5‐HT and/or dopamine receptors. Psychedelic‐dependent 5‐HT 2A receptor agonism also has profound anti‐(neuro)inflammatory effects. Advanced imaging studies suggest that brain 5‐HT levels are reduced in depression. Functional magnetic resonance studies show that neural networks (cortico thalamic, salience, default mode) are profoundly impaired in depression. Such network defects are corrected upon psychedelic/entactogen treatment, offering a unique opportunity to serve as biomarkers for depression, anxiety and PTSD precision medicine trials. Psychedelics and entactogens target common end pathways, namely neuroplasticity/synaptogenesis, either directly via monoamine or glutamate receptors and/or indirectly, via BDNF and mTORC1 pathways. Together, these findings strongly support a biological basis for MDD, GAD, PTSD and related conditions, which can be considered as mixed biochemical, neurological and neuroimmune disorders, and are profoundly modified by psychedelics, entactogens and the newly developed psychoplastogens.
Comparable studies
Other narrative reviews on MDMA for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |
| Top Ten Tips Palliative Care Clinicians Should Know About Psychedelic-Assisted Therapy in the Context of Serious Illness. Palliative care clinicians and patients | 2022 | Review | |
| MDMA and MDMA-Assisted Therapy. | 2025 | Review | |
| Role of Psychedelics in Treatment-Resistant Depression. | 2023 | Review | |
| Is it now time to prepare psychiatry for a psychedelic future? | 2024 | Review |
Citations in the library
Cited by 9
- LSD: Mechanisms and relevance to the treatment of depression Neuroscience & Biobehavioral Reviews October 10, 2025
- The Emergence of Isotryptamine Analogs as Novel Serotonergic Agents with Psychotherapeutic Potential ACS Pharmacology & Translational Science August 18, 2026
- Investigational drugs in PTSD. Neuropsychopharmacology June 1, 2026
- A trip through the psychiatric use of psychedelics in Brazil: A scoping review Psychedelics May 30, 2026
- A Systematic Review of the efficacy, safety, and Tolerability of Psychedelics in the Treatment of post-traumatic Stress Disorder Current Treatment Options in Psychiatry December 26, 2025
and 4 more in the library
Cites 123
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 118 more in the library