Long- term administration of low doses of psilocybin causes epigenetic changes in the rat medial prefrontal cortex

Rationale: Psilocybin (PSI) microdosing, defined as a repeated administration of sub-perceptual doses, has gained increasing attention as a potential therapeutic strategy for affective and anxiety disorders. However, some molecular mechanisms, particularly regarding epigenetic regulation in the medial prefrontal cortex (mPFC), remain poorly understood.

Objectives: Therefore, the present study aimed to determine whether PSI microdosing induces adaptive epigenetic modifications in the rat mPFC in the absence of behavioural dysfunction, with a particular focus on chromatin accessibility, transcriptional regulators, and plasticity-related genes.

Methods: Rats were administered PSI or a vehicle every second day for 21 days. Behavioural impact was assessed using prepulse inhibition (PPI) of the acoustic startle response (ASR) and the novel object recognition test (NOR). Molecular dynamics in the mPFC were analysed via Western blot and quantitative reverse transcription PCR (qRT-PCR) in the early and late phases following the final dose.

Results: The microdosing regimen did not impair sensorimotor gating or cognitive performance, indicating absence of psychotomimetic-like effects. Molecular analyses in the early phase revealed epigenetic remodelling in the mPFC, including increased histone H3 acetylation, change in bromodomain-containing protein 4 (BRD4) levels and modulation of histone deacetylases. These early molecular effects were associated with a transcriptionally permissive chromatin state and increased expression of genes related to plasticity. In the later phase, enhanced expression of the serotonin receptor 2A (5-HT2A) was observed, while some epigenetic modifications partially persisted over time.

Conclusions: Repeated low-dose psilocybin promotes adaptive epigenetic remodelling in the mPFC, enhancing neuroplasticity without behavioural impairment and supporting its therapeutic potential.