Katrin H Preller1, Patricia Duerler2, Joshua B Burt3, Jie Lisa Ji4, Brendan Adkinson4, Philipp Stämpfli5, Erich Seifritz5, Grega Repovš6, John H Krystal4, John D Murray7, Alan Anticevic4, Franz X Vollenweider2. 1. Neuropsychopharmacology and Brain Imaging Unit, University Hospital for Psychiatry Zurich, Zurich, Switzerland; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Electronic address: preller@bli.uzh.ch. 2. Neuropsychopharmacology and Brain Imaging Unit, University Hospital for Psychiatry Zurich, Zurich, Switzerland. 3. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Physics, Yale University, New Haven, Connecticut. 4. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 5. Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Zurich, Switzerland. 6. Mind and Brain Laboratory, Department of Psychology, University of Ljubljana, Ljubljana, Slovenia. 7. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut; Department of Physics, Yale University, New Haven, Connecticut.
Abstract
BACKGROUND: The use of psilocybin in scientific and experimental clinical contexts has triggered renewed interest in the mechanism of action of psychedelics. However, its time-dependent systems-level neurobiology remains sparsely investigated in humans. METHODS: We conducted a double-blind, randomized, counterbalanced, crossover study comprising 23 healthy human participants who receivedplacebo and 0.2 mg/kg of psilocybin orally on 2 different test days. Participants underwent magnetic resonance imaging at 3 time points between administration and peak effects: 20 minutes, 40 minutes, and 70 minutes after administration. Resting-state functional connectivity was quantified via a data-driven global brain connectivity method and compared with cortical gene expression maps. RESULTS:Psilocybin reduced associative, but concurrently increased sensory, brain-wide connectivity. This pattern emerged over time from administration to peak effects. Furthermore, we showed that baseline connectivity is associated with the extent of psilocybin-induced changes in functional connectivity. Lastly, psilocybin-induced changes correlated in a time-dependent manner with spatial gene expression patterns of the 5-HT2A (5-hydroxytryptamine 2A) and 5-HT1A (5-hydroxytryptamine 1A) receptors. CONCLUSIONS: These results suggest that the integration of functional connectivity in sensory regions and the disintegration in associative regions may underlie the psychedelic state and pinpoint the critical role of the serotonin 2A and 1A receptor systems. Furthermore, baseline connectivity may represent a predictive marker of the magnitude of changes induced by psilocybin and may therefore contribute to a personalized medicine approach within the potential framework of psychedelic treatment.
RCT Entities:
BACKGROUND: The use of psilocybin in scientific and experimental clinical contexts has triggered renewed interest in the mechanism of action of psychedelics. However, its time-dependent systems-level neurobiology remains sparsely investigated in humans. METHODS: We conducted a double-blind, randomized, counterbalanced, crossover study comprising 23 healthy humanparticipants who received placebo and 0.2 mg/kg of psilocybin orally on 2 different test days. Participants underwent magnetic resonance imaging at 3 time points between administration and peak effects: 20 minutes, 40 minutes, and 70 minutes after administration. Resting-state functional connectivity was quantified via a data-driven global brain connectivity method and compared with cortical gene expression maps. RESULTS: Psilocybin reduced associative, but concurrently increased sensory, brain-wide connectivity. This pattern emerged over time from administration to peak effects. Furthermore, we showed that baseline connectivity is associated with the extent of psilocybin-induced changes in functional connectivity. Lastly, psilocybin-induced changes correlated in a time-dependent manner with spatial gene expression patterns of the 5-HT2A (5-hydroxytryptamine 2A) and 5-HT1A (5-hydroxytryptamine 1A) receptors. CONCLUSIONS: These results suggest that the integration of functional connectivity in sensory regions and the disintegration in associative regions may underlie the psychedelic state and pinpoint the critical role of the serotonin 2A and 1A receptor systems. Furthermore, baseline connectivity may represent a predictive marker of the magnitude of changes induced by psilocybin and may therefore contribute to a personalized medicine approach within the potential framework of psychedelic treatment.
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