Psilocybin was shown to acutely activate the brain’s stress system while simultaneously reducing how strongly it reacts to future stressors, revealing a paradox that may explain its therapeutic effects. In mice given a single 3 mg/kg dose, psilocybin rapidly activated corticotropin-releasing hormone neurons in the hypothalamus and raised stress hormone levels for about 1 hour, returning to baseline within 24 hours. Female mice showed significantly stronger responses, with higher stress hormone release and greater neural activation than males. Crucially, when exposed to handling or a new environment after dosing, psilocybin blunted the usual stress response, even reducing stress-neuron activity below baseline. This context-specific dampening suggests psilocybin may help “retrain” the stress axis, promoting greater flexibility rather than chronic overreaction.