Psilocybin induces sex- and context-specific recruitment of the stress axis
Current Biology December 9, 2025 Sarah G. Cook, Stephanie J. Lee, Emma Ference et al. 3 citations
Psilocybin activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). This activation is more pronounced in female mice and depends on serotonergic 5-HT2A and 5-HT2C receptors. The 5-HT2A receptor effects involve direct post-synaptic depolarization of CRHPVN neurons and increased presynaptic glutamate release. Psilocybin also alters how CRHPVN neurons respond to environmental changes, leading to a surprising decrease in activity that contrasts with typical stress responses. This context-specific modulation may be a key mechanism for recalibrating maladaptive stress reactivity, supporting the influence of setting on the psychedelic experience.