Psilocybin (1.0–5.0 mg/kg) rapidly reversed depression-like behavior in stressed mice while restoring astrocyte function in the prefrontal cortex. It reduced neurotoxic A1 astrocytes (C3 marker) and boosted energy signaling by increasing ATP, lactate, and glutamate release along with mitochondrial activity. This directly repairs brain support systems that regulate mood and neural communication, driving fast antidepressant effects.