LSD is a potent serotonergic psychedelic compound. Findings indicate that psychotherapeutic applications of LSD and related psychedelic compounds have value in the treatment of mental health disorders. Deepening our understanding of LSD brain action may shed light on the mechanisms underlying the effectiveness of psychedelic therapy. A recent model hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. Here, we applied an unsupervised manifold learning technique that is sensitive to cortical hierarchy to pharmacological resting-state fMRI data to assess cortical organization in the LSD state. Results directly supported our primary hypothesis: The Principal Gradient, describing a hierarchical transition from unimodal to transmodal cortex, was significantly contracted under LSD relative to placebo. Between-condition contrasts revealed that this was primarily driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor cortex at the lower. In addition, results pertaining to the visual-somatomotor Second Gradient revealed that LSD reduced the differentiation of visual from auditory/somatomotor and association regions. Significantly, gradient changes tracked state-specific changes in specific dimensions of self-reported LSD experience. These findings support a recent mechanistic model of the psychedelic state that has relevance to therapeutic applications of psychedelics. More fundamentally, these findings provide the first evidence that cortical hierarchical organization can be modulated in a state-dependent manner, highlighting an important relationship between the features of neural topography and ongoing conscious experience.

LSD flattens the functional hierarchy of the human brain