Twenty healthy subjects were included in this placebo-controlled, crossover study aimed at examining the effect of post-lysergic acid diethylamide (LSD) on the entropy of brain dynamics and how these changes may impact personality. Participants were administered 75 mg of LSD or placebo in two sessions with a washout period of two weeks between sessions. Personality was assessed using the standard 240-item revised five-factor personality inventory (NEO-PI-R), ego-dissolution was assessed using a visual analogue scale, and BOLD resting-state fMRI scans were used to evaluate brain entropy. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness, especially for music-listening scans and when “ego-dissolution” was reported during the acute experience.