A critical review of brain entropy as a biomarker of the psychedelic state

Serotonergic psychedelics induce profound alterations in consciousness, giving rise to an altered state commonly referred to as the psychedelic state. The entropic brain hypothesis proposes that brain entropy (i.e., the degree of uncertainty in the distribution of brain states) is elevated during the psychedelic state, as well as in other states characterized by an expanded breadth of phenomenal consciousness, whereas the opposite pattern is observed in states of diminished or absent consciousness. Given the numerous neuroimaging studies reporting heightened entropy under psychedelics, a substantial portion of the field has embraced entropy as a reliable biomarker of the psychedelic state. We argue that this view may be inherently oversimplified and offer a more nuanced and comprehensive perspective. We first review evidence supporting the use of entropy metrics and discuss their potential utility. We then identify key empirical, methodological, and conceptual challenges associated with using brain entropy as a psychedelic biomarker, organized into four themes: (1) entropy alterations are not specific to psychedelics or other states of heightened phenomenal richness; (2) current entropy-based approaches do not accommodate multidimensional operationalizations of conscious states; (3) multiple entropy metrics exist, each with distinct interpretations and varying levels of mutual consistency; and (4) limited evidence supports the neurophenomenological equivalence between brain entropy and phenomenal richness. Although substantial questions remain about the validity of entropy-based biomarkers of the psychedelic state, we conclude that the concept warrants further investigation and offer practical suggestions for future research to address these limitations.