Psilocybin modulation of time-varying functional connectivity is associated with plasma psilocin and subjective effects

This open-label study (n=15) assessed the association between resting-state time-varying functional connectivity (tvFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after psilocybin intake (21mg/70kg). Findings suggest that the effects induced by psilocybin may stem from drug-level-associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs.

Abstract

“Background: Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has the potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state time-varying functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioural and clinical effects.

Aim: Evaluate the association between resting-state time-varying functional connectivity (tvFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans.

Methods: Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis.

Results: Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state partly associated with motion was positively associated with PPL and SDI.

Conclusion: Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs. We apply and argue for a modified approach to modelling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics.

Authors: Anders S. Olsen, Anders Lykkebo-Valloe, Brice Ozenne, Martin K. Madsen, Dea S. Stenbaek, Sophia Armand, Morten Morup, Melanie Ganz, Gitten M. Knudsen & Patrick M. Fisher

Summary of Psilocybin modulation of time-varying functional connectivity is associated with plasma psilocin and subjective effects

Psilocin, a neuroactive metabolite of psilocybin, induces an acute altered state of consciousness and lasting changes in mood and personality in healthy individuals. The authors evaluated the association between resting-state time-varying functional connectivity characteristics and plasma psilocin level and subjective drug intensity in healthy humans before and right after intake of a psychedelic dose of psilocybin. They found that the acute perceptual psychedelic effects may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs.

Psilocybin, a psychedelic compound, induces an altered state of consciousness and positive effects on mood, well-being, and personality. These effects may inform future drug development programs and identify patient subgroups that may benefit from psychedelic therapy or predict potential adverse drug effects.