ArticleProceedings of the National Academy of Sciences of the United States of America2021
Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 208 papers, 4 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
208 citing papers in PubMed, 4 syntheses or guidelines pooled it, 367 citations in OpenAlex.
- Multilevel Mechanisms and Clinical Efficacy of Psilocybin in Depression Treatment: A Systematic Review.International journal of molecular sciences · 2026Pooled it
- Psilocybin in the treatment of eating disorders: a systematic review of the literature and registered clinical trials.Eating and weight disorders : EWD · 2025Pooled it
- Effects of psychedelics on neurogenesis and broader neuroplasticity: a systematic review.Molecular medicine (Cambridge, Mass.) · 2024Pooled it
- The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder.Canadian journal of psychiatry. Revue canadienne de psychiatrie · 2023Pooled it
- Psilocybin therapy for mood dysfunction in Parkinson's disease: an open-label pilot trial.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Trial
- Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Trial
- Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants.The international journal of neuropsychopharmacology · 2023Trial
- αMolecular psychiatry · 2026Article
- Serotonin 1B receptors expressed on forebrain excitatory neurons mediate the post-acute anxiolytic response to psilocybin in mice.Psychopharmacology · 2026Article
- Acute anxiogenic effects of psilocybin and the related tryptamine, norbaeocystin, in male and female rats.Psychopharmacology · 2026Article
- Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study to Identify a Subperceptual Dose of Psilocybin in Healthy Adults.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Resetting the hippocampal buffer: a neurocognitive account of psychedelic therapy for anxiety-related psychopathology.Psychopharmacology · 2026Review
- Psilocybin enhances sociability only in altered behavioural state and does not need an awake experience to be effective.Nature communications · 2026Article
- Psilocybin-Assisted Therapy in Psychiatry: A Narrative Clinical Review of Mechanisms, Therapeutic Applications, and Emerging Evidence (2025-2026).Journal of clinical medicine · 2026Review
- Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics.Molecular psychiatry · 2026Article
- Dorsolateral Prefrontal Cortex Circuitry at the Intersection of Cognition and Disease.Biological psychiatry · 2026Review
- Psilocybin restores behavior and 5-HTCell reports. Medicine · 2026Article
- Psychedelic drug action at dendrites is gated by behavioral state and serotonin receptors.bioRxiv : the preprint server for biology · 2026Article
148 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin's efficacy. We conclude that psilocybin's mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.