Article
Open access
Published: 17 July 2024

Psilocybin desynchronizes the human brain

Joshua S. Siegel, Subha Subramanian, Demetrius Perry, Benjamin P. Kay, Evan M. Gordon, Timothy O. Laumann, T. Rick Reneau, Nicholas V. Metcalf, Ravi V. Chacko, Caterina Gratton, Christine Horan, Samuel R. Krimmel, Joshua S. Shimony, Julie A. Schweiger, Dean F. Wong, David A. Bender, Kristen M. Scheidter, Forrest I. Whiting, Jonah A. Padawer-Curry, Russell T. Shinohara, Yong Chen, Julia Moser, Essa Yacoub, Steven M. Nelson, …Nico U. F. Dosenbach

Nature (2024)

Abstract
A single dose of psilocybin, a psychedelic that acutely causes distortions of space–time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1,2,3,4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5,6,7,8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6–12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Main
Psychedelic drugs can reliably induce powerful acute changes in the perception of self, time and space by agonism of the serotonin 2A (5-HT2A) receptor9,10. In clinical trials, a single high dose of psilocybin (25 mg) has demonstrated rapid and sustained symptom relief in depression1,2,3,11,12,13,14, addiction4,15 and end-of-life anxiety13,14. Together, these observations indicate that psychedelics should induce potent acute (lasting roughly 6 hours) and persistent (24 hours to 21 days) neurobiological changes.