A large body of evidence, including longitudinal analyses of personality change, suggests that core personality traits are predominantly stable after age 30. To our knowledge, no study has demonstrated changes in personality in healthy adults after an experimentally manipulated discrete event. Intriguingly, double-blind controlled studies have shown that the classic hallucinogen psilocybin occasions personally and spiritually significant mystical experiences that predict long-term changes in behaviors, attitudes and values. In the present report we assessed the effect of psilocybin on changes in the five broad domains of personality – Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness. Consistent with participant claims of hallucinogen-occasioned increases in aesthetic appreciation, imagination, and creativity, we found significant increases in Openness following a high-dose psilocybin session. In participants who had mystical experiences during their psilocybin session, Openness remained significantly higher than baseline more than 1 year after the session. The findings suggest a specific role for psilocybin and mystical-type experiences in adult personality change.