A new cross-species model shows how psilocybin from Psilocybe cubensis is absorbed, metabolized, and distributed in mice, rats, and humans. After ingestion, psilocybin is rapidly converted to psilocin, which enters the bloodstream and concentrates in the brain, about 2.5 times higher than plasma levels in humans. This simulation-based model helps predict psilocin effects and metabolism across different doses (3–30 mg), laying groundwork for safer, personalized therapies.