Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity
Hannah M. Kramer, Meghan Hibicke, Jason W. Middleton, Alaina M Jaster, Jesper L. Kristensen, Charles D. Nichols
Neuropsychopharmacology November 12, 2025 DOI: 10.1038/s41386-025-02272-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Psilocybin 25CN-NBOH |
| Duration | At least three months after a single administration |
| Topics | Neuroplasticity Psilocybin Serotonin |
| Keywords | Excitatory postsynaptic potential Prefrontal cortex Pyramidal cell Agonist Antidepressant Glutamate receptor Electrophysiology Dendritic spine Postsynaptic density Hallucinogen Inhibitory postsynaptic potential |
| Citations | 7 |
| Key points | A single administration of psilocybin or 25CN-NBOH produces long-lasting behavioral and functional cellular changes in the medial prefrontal cortex through enduring functional plasticity rather than structural plasticity. |
Abstract
Activation of serotonin 2A (5-HT2A) receptors is thought to underly the long-lasting antidepressant effects of psychedelics such as psilocybin, but beyond that, the molecular and cellular mechanisms involved are not well understood. Recent preclinical studies using mice have primarily examined relatively short time points after psychedelic administration, which does not address the long-lasting effects of psilocybin in humans (i.e., several months or more). We utilized a rat experimental system to demonstrate that both psilocybin and the selective 5-HT2A receptor agonist 25CN-NBOH reduce immobility in the forced swim test without a decrease in effect size for at least three months after a single administration of the psychedelic. There were no overt behavioral differences between psilocybin and 25CN-NBOH treated animals, suggesting 5-HT2A receptor activation is sufficient to produce long-lasting behavioral changes. Functional cellular plasticity in neurons from the medial prefrontal cortex (mPFC) of these animals was assessed using brain slice electrophysiology. Functional plasticity was evident for both psychedelics several months after treatment, and Layer 5 excitatory pyramidal neurons demonstrated significant changes in resting membrane potential, firing rates, and synaptic excitation. Recorded neurons were examined by microscopy for synaptic density and spine classification, which found no differences between control and psychedelic-treated. Gene expression studies for several presynaptic and postsynaptic markers in the mPFC indicated no differences in expression between groups. Together, our results indicate a single treatment with a psychedelic is sufficient to elicit very long-lasting behavioral and cellular changes through enduring function plasticity rather than structural plasticity.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 7
- The entropic brain today Brain December 12, 2025
- 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
- Psilocybin selectively rescues cognitive flexibility impairments caused by aberrant prefrontal error signaling bioRxiv July 9, 2026
- Psychedelics and longevity: implications for lifespan, healthspan and functional aging Longevity July 5, 2026
- Chronic psilocin microdosing produces limited behavioral effects and does not enhance neurogenesis in rats. Pharmacology, Biochemistry, and Behavior June 30, 2026
and 2 more in the library
Cites 19
- 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
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 14 more in the library