Clayton R. Coleman

Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that induces a profoundly altered conscious state. In conjunction with psychological support, it is currently being explored as a treatment for generalized anxiety disorder and depression. The dorsolateral prefrontal cortex (DLPFC) is a brain region that is known to be involved in mood regulation and disorders; hypofunction in the left DLPFC is associated with depression. This study investigated the role of the DLPFC in the psycho‐emotional effects of LSD with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) data of healthy human participants during the acute LSD experience. In the fMRI data, we measured the correlation between changes in resting‐state functional connectivity (RSFC) of the DLPFC and post‐scan subjective ratings of positive mood, emotional arousal, and ego dissolution. We found significant, positive correlations between ego dissolution and functional connectivity between the left & right DLPFC, thalamus, and a higher‐order visual area, the fusiform face area (FFA). Additionally, emotional arousal was significantly associated with increased connectivity between the right DLPFC, intraparietal sulcus (IPS), and the salience network (SN). A confirmational “reverse” analysis, in which the outputs of the original RSFC analysis were used as input seeds, substantiated the role of the right DLPFC and the aforementioned regions in both ego dissolution and emotional arousal. Subsequently, we measured the effects of LSD on directed functional connectivity in MEG data that was source‐localized to the input and output regions of both the original and reverse analyses. The Granger causality (GC) analysis revealed that LSD increased information flow between two nodes of the ‘ego dissolution network’, the thalamus and the DLPFC, in the theta band, substantiating the hypothesis that disruptions in thalamic gating underlie the experience of ego dissolution. Overall, this multimodal study elucidates a role for the DLPFC in LSD‐induced states of consciousness and sheds more light on the brain basis of ego dissolution.

Lysergic acid diethylamide (LSD) and other psychedelic substances profoundly alter human consciousness. While several studies have demonstrated changes in brain function and connectivity associated with psychedelics, we still have a limited understanding of how LSD reshapes brain networks operating across different frequency bands. In this study, we applied the recently developed FREQ-NESS method to MEG data from 14 healthy participants who received LSD under four conditions: eyes-closed with or without music and eyes-open with or without a video stimulus. LSD significantly restructures canonical networks in the alpha and beta bands. Relative to broadband brain activity, it enhances the prominence of high alpha (12.1, 13.3 Hz) across all experimental conditions and high beta (25.3 Hz) in three conditions. Conversely, LSD decreases the prominence of low beta (18.1, 19.3 Hz) in both Open and Closed conditions and low alpha (8.5 Hz) in the latter. In addition, LSD substantially alters the spatial distributions or topographies of the networks. Under LSD, the low alpha (8.5 Hz) network shifts anteriorly toward the motor cortex, while high alpha (12.1, 13.3 Hz) becomes more localized to the visual cortex. Low beta (18.1, 19.3 Hz) expands over the temporal and occipital cortices, whereas high beta (25.3, 26.5 Hz) topographies remain unchanged. Our findings provide critical insights into the specific frequencies and spatial networks in which LSD modulates brain connectivity, adding nuance to prevailing theories about network disintegration under psychedelics. Significance statement: Psychedelic substances such as lysergic acid diethylamide (LSD) profoundly alter perception and cognition, yet their effect on brain activity across different frequency bands remains unclear. Using FREQ-NESS applied to MEG data, we show that LSD reorganizes brain networks by enhancing high-frequency alpha and beta rhythms while suppressing lower-frequency counterparts. These changes occur across various experimental conditions and shift the spatial distribution of brain activity, particularly in motor and visual regions. Our findings suggest that LSD modulates brain connectivity in a frequency- and region-specific manner, offering new insights into how psychedelics alter consciousness. This work advances our understanding of LSD’s neural effects, which may be relevant for therapeutic applications and models of brain function.