Sex-dependent developmental changes in behavior, brain structure, functional connectivity, and sensory perception following exposure to psilocybin during adolescence
Itishree Sahoo, Sairam Masadi, Ashwath Maheswari, Rachel Utama, Muhammad Abeer, Sima Soltanpour, Md Taufiq Nasseef, Tochi Chukwuemeka, Nandini Sinhal, Jyot Pandit, Richard J. Ortiz, Noah Cavallaro, Eric Brengel, Praveen P Kulkarni, Michael A. Gitcho, Craig F. Ferris
Neuropsychopharmacology February 18, 2026 DOI: 10.1038/s41386-026-02356-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Female and male mice |
| Intervention | Psilocybin |
| Dose | 3.0 mg/kg |
| Duration | Every other day from postnatal days 40-50 for five exposures, with evaluation between postnatal days 90-120 |
| Topics | Neuroplasticity Psilocybin |
| Keywords | Prefrontal cortex Hallucinogen Thalamus Brain mapping Affect linguistics Sensory system Insular cortex |
| Citations | 3 |
| Key findings | Adolescent psilocybin exposure in mice leads to long-term changes in brain volume, water diffusivity, functional connectivity, perception of rewarding and aversive stimuli, and neuroplasticity markers, with males more affected than females. |
Abstract
Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. Underlying these effects are changes in brain neuroplasticity. We hypothesized psilocybin given during adolescence, a time of heightened neuroplasticity, particularly in the forebrain, would affect emotional behavior and the associated underlying neuroanatomy, neurocircuitry, and epigenetics. Female and male mice were given vehicle or 3.0 mg/kg psilocybin every other day by oral gavage from postnatal days 40-50 for a total of five exposures. Between postnatal days 90-120 mice were imaged and evaluated for affective behavior and perception of rewarding and aversive stimuli. MRI data from voxel-based morphometry, diffusion weighted imaging, and BOLD resting state functional connectivity were registered to a mouse 3D MRI atlas with 139 brain regions providing site-specific differences in global brain structure and functional connectivity between experimental groups. The prefrontal cortex was measured for changes in proteins associated with epigenetics. Mice showed no significant differences in the light/dark box test, but female mice exposed to psilocybin showed reduced mobility in the open field as compared to controls. Mice with early psilocybin exposure showed reduced brain sensitivity to both rewarding and aversive odors during scanning sessions. There were regional reductions in brain volume and alteration in water diffusivity affecting males more than females. Global and regional functional connectivity were increased in both sexes with the prefrontal cortex showing enhanced connections to the hypothalamus, thalamus and midbrain. Males showed reduced levels of epigenetic and neuroplasticity protein markers in the prefrontal cortex. The pronounced changes in brain volume, water diffusivity - a surrogate marker of gray matter microarchitecture, increase in functional connectivity, altered perception of rewarding and aversive stimuli and altered levels of protein markers of neuroplasticity provide compelling evidence that exposure to psilocybin during adolescence has long term developmental consequences, particularly in males.
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
- The serotonin 1B receptor as a target for the treatment of depression and anxiety Expert Opinion on Therapeutic Targets September 21, 2026
- Current status and future prospects of research on psilocybin's regulation of neurotransmitters and their receptors related to the pathogenesis of tinnitus. Hearing research August 1, 2026
- Psychedelics and the thalamocortical system: A scoping review Pharmacology, Biochemistry, and Behavior July 9, 2026
- Study Protocol for "Exploring the safety and therapeutic potential of psilocybin in the treatment of anorexia nervosa in adolescents and young adults". PLoS One June 30, 2026
- Sex-sensitive serotonergic signaling in psychedelic pharmacology. TIPS - Trends in Pharmacological Sciences August 1, 2026
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
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 27 more in the library