Psilocybin has a narrow therapeutic window as an antidepressant treatment.
Lenka Seillier, Barbora Čechová, Alexandre Seillier, Romana Šlamberová
Progress in Neuro-Psychopharmacology and Biological Psychiatry April 2, 2025 DOI: 10.1016/j.pnpbp.2025.111368 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Wistar rats |
| Intervention | Psilocybin |
| Dose | 0.1, 0.32, 1.0, and 3.2 mg/kg |
| Topics | Psilocybin |
| Keywords | Antidepressant-like behavior Head-twitch response Locomotor activity Rectal temperature Weight gain Hallucinogens Psychedelics Antidepressants mood enhancers Depression treatment Dosage optimization dose- |
| Citations | 3 |
| Key findings | Psilocybin at 0.32 mg/kg, but not lower or higher doses, produced antidepressant-like effects in rats without the adverse effects observed at higher doses. |
Abstract
Psilocybin, a naturally occurring psychedelic compound in magic mushrooms, shows promise as a novel intervention with a single administration inducing rapid and long-lasting antidepressant effects. However, there are limited studies on the optimal dosing required for the beneficial effects of psilocybin given its side effects. To address this gap, we investigated in Wistar rats whether a single psilocybin administration (0.1, 0.32, 1.0, and 3.2 mg/kg) had antidepressant-like effects in the forced swim test (FST), a pro-social effect in the social interaction test (SIT), and the ability to alter pleasure using the sucrose preference test (SPT). We also examined the dose-response relationships of psilocybin on the head-twitch response (HTR), locomotor activity, body temperature, and weight gain. Furthermore, we explored whether the brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex (PFC) paralleled the behavioral changes observed after psilocybin. In the FST, psilocybin induced dose-dependent inverted-U-shaped responses with only the intermediate dose of 0.32 mg/kg producing short and long-term antidepressant-like effects. A similar pattern was observed for the SIT, the SPT, and the HTR. In contrast, the high doses of psilocybin (1.0 and 3.2 mg/kg), while deprived of anti-depressant-like activity, significantly reduced body temperature, locomotor activity, and body weight gain. BDNF levels in the hippocampus and PFC increased dose-dependently after psilocybin, but linearly suggesting a dissociation between high BDNF levels and the observed antidepressant-like behaviors. Our results indicated that there is a narrow window for the therapeutic potential of psilocybin, with 0.32 mg/kg effectively producing antidepressant-like effects without the accompanying adverse effects observed only at higher doses.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 5
- Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms Pharmacological Research December 29, 2025
- Blocking 5-HT2B receptors abolishes psilocybin’s efficacy in the rat forced swim test Journal of Psychopharmacology June 23, 2026
- Psilocybin selectively suppresses novelty-induced grooming via 5-HT2B receptors: A microstructure analysis in Wistar rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry September 9, 2026
- Psilocybin-associated microRNA changes in the pig brain: Establishing an nCounter pipeline for cross-species microRNA quantification. European Journal of Pharmacology August 1, 2026
- Classic psychedelics and autism spectrum disorder: preclinical evidence, mechanistic insights and unresolved challenges. Neuroscience & Biobehavioral Reviews August 1, 2026
Cites 47
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- 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
and 42 more in the library