Psychedelics and ketamine/esketamine in depressive disorders: biological mechanisms and associated neuroimaging and clinical changes.
Giacomo D’andrea, Stefania Chiappini, Laura Ciavoni, Rolando Tucci, Fabrizio Martino, Francesco Maria Semeraro, Daniele Di Battista, Alessio Mosca, Andrea Miuli, Francesco di Carlo, Mirella Russo, Gilberto Di Petta, Michele Fornaro, Mauro Pettorruso, Stefano L. Sensi, Giovanni Martinotti
Transl Psychiatry October 31, 2025 DOI: 10.1038/s41398-025-03654-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Double-blind Open-label Peer reviewed |
|---|---|
| Interventions | LSD psilocybin ayahuasca DMT ketamine esketamine |
| Measures | Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), functional Magnetic Resonance Imaging (fMRI), MRI |
| Topics | Depression Ketamine Neuroplasticity Psychedelic-assisted therapy Esketamine |
| Keywords | Psychedelics Compounds Innovative therapies Effective therapies Psychedelic medicine Psychopharmacology Depressive symptoms Struggling with depression Mood disorders Mental health Brain changes Biological impacts Observable brain alterations Neural connectivity Neurobiology Brain science |
| Citations | 3 |
| Key findings | Across 49 imaging studies, the authors conclude that psilocybin appears to reset default mode network activity, yielding long-lasting antidepressant effects, whereas ketamine acts more specifically on prefrontal networks that indirectly affect the default mode network, which the authors propose may explain ketamine's anti-anhedonic activity and its role in increasing cognitive control over emotional stimuli. |
Abstract
Background: Over the past ten years, several psychedelic compounds, including tryptamines like lysergic acid diethylamide/LSD, psilocybin, ayahuasca, and dimethyltryptamine/DMT, have been tested in clinical trials for a range of psychiatric conditions, such as anxiety and depression. While these compounds are relatively available for treatment, ketamine and its S(+) enantiomer, esketamine, are increasingly used to manage treatment-resistant depression. The biological mechanisms set in motion by these compounds are still largely unexplored. Preliminary data indicate modulatory activity of distinct brain networks and selected neurotransmitter pathways (i.e., glutamate, serotonin).
Objective: This systematic review investigates functional changes in neural activity generated by these compounds (i.e., LSD, psilocybin, ayahuasca, and DMT or ketamine/esketamine) in depressive disorders. Studies involving different techniques (i.e. Positron Emission Tomography/PET, Single Photon Emission Computed Tomography/SPECT, functional Magnetic Resonance Imaging/fMRI and MRI) were included.
Method: A literature search was conducted following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines of 2015. The search was performed using PubMed Web of Science and Scopus databases, taking into consideration publications up to March 2022, without any time restrictions.
Results: The search produced a final set of 49 articles. Most were related to ketamine/esketamine (n = 44). A smaller number (n = 5) pertained to psychedelic tryptamines (one on ayahuasca and four on psilocybin). From the total of 49 studies, 9 were randomized-controlled trials, 25 were open-label studies, 4 were double-blind trials, 8 were observational studies, and 3 cross-over studies.
Conclusions: Psylocibin seems to reset Default Mode Network (DMN) activity, thereby reducing depressive symptoms with long-term and sustainable antidepressant efficacy. Compared to psychedelics, ketamine exhibits a more specific action on networks involving prefrontal areas that act indirectly on the DMN. This effect may help explain ketamine's anti-anhedonic activity and its critical role in increasing cognitive control over emotional stimuli, thus reducing negative mood stages.
Comparable studies
Other systematic reviews and meta-analyses on ketamine and psychedelic-assisted therapy, most cited first.