Psilocybin reduces depressive-like behavior and improves cognition in healthy aging mice via epigenetic regulation of plasticity- and immune-related genes
Sarah E. Mennenga, Toni J. Hanson, Moira G. Semple, Dylan J. Lifshitz, Beatriz Flores, Joseph Balducci, Samantha A. Harker, Alyssa Ford, Candace R. Lewis
Research Square November 5, 2025 preprint DOI: 10.21203/rs.3.rs-7890051/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Male and female C57BL/6 mice, 11 months old |
| Intervention | Psilocybin |
| Dose | 1 mg/kg |
| Duration | Two doses one week apart |
| Topics | Neuroplasticity Psilocybin |
| Keywords | Prefrontal cortex Epigenetics Hippocampus Dna methylation Cognition Cognitive decline Synapse Working memory Dendritic spine Ubiquitin ligase |
| Citations | 2 |
| Key findings | Psilocybin improves learning and memory in female mice and reduces depressive-like behavior across sexes, reversing age-associated DNA methylation changes in the prefrontal cortex and hippocampus, with effects mediated by Tbr1 promoter methylation in females. |
Abstract
Abstract For many, cognitive and affective health declines through typical aging. Although cognitive and affective symptoms are often studied in isolation, they share substantial overlap, and arise, in part, from common biological processes. Aging is accompanied by diminished neural plasticity, heightened neuroinflammation, and widespread alterations in the epigenome. These molecular changes mirror behavioral decline, linking the erosion of cellular adaptability to the decline of cognitive function and emotional well-being in aging. Here, we show that psilocybin reverses age-related behavioral and epigenetic alterations in aged mice. Male and female C57BL/6 mice (11 months old) received two intraperitoneal doses of psilocybin (1mg/kg) or saline one week apart and were evaluated for memory and affective behaviors. Psilocybin improved learning and memory in females and reduced depressive-like behavior across sexes. Genome-wide DNA methylation profiling in the prefrontal cortex and bilateral hippocampus revealed widespread, sex- and region-specific effects, with the right hippocampus of females showing the most extensive gene-level changes. Differentially methylated loci were enriched for pathways related to synaptic organization, axon guidance, and neuroimmune signaling. Notably, psilocybin reversed age-associated methylation at CpG sites linked to typical aging, including within the Tbr1 promoter, a transcription factor essential for excitatory neuron development and synapse formation. Moreover, methylation at Tbr1 mediated psilocybin’s pro-cognitive effects on Y-Maze performance in females. Together, these findings demonstrate that psilocybin induces coordinated behavioral and epigenetic remodeling in the aging brain, with lateralized and sex-dependent signatures implicating neuroimmune and neuroplasticity transcriptional networks. Psilocybin thus emerges as a candidate compound for promoting aging resilience.
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 2
Cites 32
- 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
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
and 27 more in the library