Psychedelics distinctly alter brain entropy and complexity compared to psychostimulants
Kristian Larsen, Patrick M Fisher, Drummond E. Mcculloch, Anders S. Olsen, Felix Mueller, Matthias Liechti, Stefan Borgwardt, Friederike Holze, Patrick Vizeli, Laura Ley, Aaron Klaiber, Anna Becker, Brice Ozenne, Mihai Avram
medRxiv January 16, 2026 DOI: 10.64898/2026.01.15.26344193 via OpenAlex
Summary
AI-generated from the abstractClassical psychedelics such as LSD, psilocybin, and mescaline produce distinct changes in brain complexity and entropy that are not seen with stimulants like MDMA or d-Amphetamine. Using resting-state fMRI data from three placebo-controlled crossover trials with 79 participants across 255 sessions, the study found that psychedelics specifically increased meta-state complexity, short-timescale multiscale entropy, and dynamic conditional correlation entropy. Both drug classes increased Lempel-Ziv and spatial complexity and decreased absolute modularity, but only psychedelics showed these unique complexity and entropy increases. These findings suggest that psychedelic-specific brain signal changes may help distinguish the acute psychedelic state from other psychoactive drug effects and could be relevant to understanding their therapeutic potential.
Study at a glance
| Characteristics | Meta-analysis of three placebo-controlled crossover trials Peer reviewed |
|---|---|
| Sample size | 79 |
| Population | Human participants from three placebo-controlled crossover trials |
| Interventions | LSD psilocybin mescaline MDMA d-Amphetamine |
| Citations | 1 |
| Key finding | Psychedelics produce significant increases in meta-state complexity, short-timescale multiscale entropy, and dynamic conditional correlation entropy compared to stimulants. |
Abstract
Classical psychedelics have regained interest for their potential to treat psychiatric and neurological disorders, and explore neural mechanisms supporting perception, cognition, and mood. Acute psychedelic effects have been linked to increases in brain complexity and entropy, but it is unclear if these changes are specific to psychedelics or reflect more general psychoactive effects. Here, we examined whether brain complexity and entropy metrics can identify features specific to the psychedelic state. Using resting-state fMRI from three placebo-controlled crossover trials (N=79; 255 sessions), we compared LSD, psilocybin, and mescaline with psychostimulants MDMA and d-Amphetamine. Compared to stimulants, psychedelics produced significant increases in meta-state complexity, short-timescale multiscale entropy, and dynamic conditional correlation entropy. Both drug classes increased Lempel-Ziv and spatial complexity, and decreased absolute modularity. Our findings highlight psychedelic-specific effects on brain signals that distinguish the acute psychedelic state from other psychoactive drug effects and may be relevant for understanding their therapeutic potential.