LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics

Twenty healthy participants received intravenous LSD (75 µg) or placebo in a double-blind crossover design, with whole-brain MEG data recorded using a CTF 275-gradiometer system. Neural source activity was reconstructed across 90 anatomical regions of interest using a linearly constrained minimum-variance (LCMV) beamformer applied to the AAL parcellation atlas. Temporal irreversibility was quantified for each region using the INSIDEOUT measure — computed as the squared difference between the forward and time-reversed cross-correlations of source-level signals — thereby capturing the directionality of information flow without requiring explicit connectivity modelling. Hierarchical coherence was assessed by correlating regional irreversibility values with an established cortical gradient of functional connectivity; a reduction in this correlation under LSD was interpreted as evidence of flattened hierarchical organisation. Recurrence rate — the proportion of time the system spent revisiting prior dynamic states — was computed as a complementary measure of dynamic repertoire. A random forest classifier was trained on irreversibility and undirected functional connectivity features to discriminate LSD from placebo conditions, allowing direct comparison of their discriminative power.

LSD produced a significant and widespread reduction in temporal irreversibility across all four experimental conditions (p < 0.0001 in each), indicating a marked decrease in directed, entropy-producing information flow at the whole-brain level. The correlation between regional irreversibility and the cortical hierarchy gradient — which was strong and positive under placebo — was significantly diminished under LSD, demonstrating a flattening of the hierarchical organisation of directed information flow across the cortex. Recurrence rate was significantly increased under LSD, indicating that the system spent more time revisiting prior dynamic states, consistent with a reduction in the diversity and exploratory range of neural trajectories. The random forest classifier discriminated LSD from placebo significantly better when trained on irreversibility features than on undirected functional connectivity features, confirming that directionality — rather than connection strength per se — captures the most distinctive neural signature of the drug state. These findings were consistent across participants and robust to alternative signal processing approaches.

The reduction in temporal irreversibility under LSD is interpreted as direct empirical support for the REBUS hypothesis: LSD appears to relax the top-down hierarchical constraints that ordinarily enforce directed, predictive information flow across the cortex, producing a more symmetric and less entropy-intensive neural dynamic. The increase in recurrence rate is framed as consistent with a reduction in the global diversity of neural trajectories — a finding that sits alongside, rather than contradicting, reports of increased entropy from Lempel-Ziv complexity measures, which capture a different facet of signal structure. The study underscores the value of directed, irreversibility-based measures over conventional undirected functional connectivity analyses for characterising psychedelic brain states, and the INSIDEOUT framework is proposed as a principled tool for detecting the asymmetric, hierarchically organised dynamics that underlie ordinary consciousness. The authors acknowledge that MEG source reconstruction introduces spatial uncertainty and that the relationship between irreversibility changes and the subjective qualities of the LSD experience was not directly assessed in this dataset.

By demonstrating that LSD significantly reduces temporal irreversibility and flattens the hierarchy of directed information flow in whole-brain MEG dynamics, this study provides strong empirical support for the REBUS model of psychedelic action. The findings establish irreversibility as a sensitive and informative neural marker of the psychedelic brain state and highlight the importance of directional frameworks for understanding how consciousness is organised and how psychedelic drugs alter it.