When the psychedelic state’s over: limited evidence for persistent neurophysiological changes in naturalistic psychedelic users

Long-term naturalistic psychedelic users who had abstained for at least 30 days showed largely no significant differences in brain oscillatory power, signal complexity, or network connectivity compared to non-users, contrary to patterns seen in acute administration studies. Complexity was unexpectedly lower in users during eyes-open conditions. Effective connectivity within and between key brain networks (Default Mode, Salience, Central Executive) showed no group differences after correction. These null findings suggest that repeated psychedelic use may not produce lasting neurophysiological changes detectable in resting-state EEG during abstinence, possibly due to homeostatic adaptation or individual variability.

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Abstract

Abstract Background Contemporary research indicates that psychedelics induce notable neurophysiological changes, some lasting weeks to months after a single dose. However, most evidence derives from acute administration studies and limited post-acute follow-ups. Long-term naturalistic psychedelic users remain critically underexamined, yet may exhibit distinct neurobiological profiles informing our understanding of persistent alterations following repeated exposure. Methods We recorded resting-state EEG in 57 long-term psychedelic users (abstinent ≥30 days) and 49 matched non-users across two independent sites under eyes-open and eyes-closed conditions. We analyzed oscillatory power, signal complexity, and source-localized effective connectivity, focusing on five canonical frequency bands and regions of the Default Mode, Salience, and Central Executive Networks. Analyses included linear mixed-effects modeling for power spectra and complexity results and a rank-based approach combining ordinary least squares regression with randomization inference for effective connectivity. Results We observed predominantly null findings. No significant between-group differences emerged for oscillatory power. Complexity comparison yielded results contrary to our hypothesis: psychedelic users exhibited lower complexity values in the eyes-open condition. Effective connectivity revealed no within- or between-network differences that would survive statistical corrections. Additionally, we report a few small-magnitude effects uncovered by exploratory analyses. Conclusions Long-term naturalistic psychedelic users showed largely non-significant differences in oscillatory power, complexity, and network connectivity compared to non-users — across several measures commonly reported as altered in acute administration studies. These findings raise the question of whether psychedelics’ neurophysiological signatures persist during abstinence despite repeated prior use, or whether they reflect homeostatic receptor adaptation, individual variability, or contextual factors. Null, incongruous, or subtle effects contribute to the existing evidence base, yet underscore the need for replication in larger, more ecologically valid populations to advance the emerging field of psychedelic neuroscience.