Electrophysiological effects of psilocybin co-administered with midazolam

Sutherland, M. H.; Nicholas, C. R.; Lennertz, R.; WENTHUR, C. J.; Krause, B. M.; Sauder, C. J.; Riedner, B. A.; Smith, R. F.; Hutson, P. R.; Raison, C. L.; Banks, M. I.

doi:10.1101/2025.07.25.666887

bioRxiv · 10.1101/2025.07.25.666887

Electrophysiological effects of psilocybin co-administered with midazolam

Sutherland, M. H.·Nicholas, C. R.·Lennertz, R.·WENTHUR, C. J.·Krause, B. M.·Sauder, C. J.·Riedner, B. A.·Smith, R. F.·Hutson, P. R.·Raison, C. L.·Banks, M. I.

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Abstract

The serotonergic psychedelic psilocybin induces neural plasticity and profoundly alters consciousness. The benzodiazepine midazolam blunts neural plasticity and induces conscious sedation and amnesia at low doses. In our recent open label pilot study, we administered oral psilocybin (25 mg) along with intravenous midazolam at doses allowing a full psychedelic experience while blunting memory for the experience. We previously reported preliminary results from high density scalp electroencephalography (EEG) recorded during the dosing session. Here, we examined changes in EEG band power, normalized Lempel Ziv complexity (LZCn), and spectral exponent. We used linear mixed effects models that incorporated time and the subjective effects of midazolam and psilocybin, measured with the Observers Assessment of Arousal and Sedation (OAA/S) and selected items from the Altered States of Consciousness (ASC) questionnaire, respectively. At 15-30 mins, when midazolam (but likely not psilocybin) was at its targeted effect site concentration, we observed increased beta power and decreased spectral exponent. As the subjective effects of psilocybin commenced and over the next six hours, we observed increased LZCn and spectral exponent and decreased broadband power. OAA/S improved model fits for alpha power while ASC improved model fits for LZCn and spectral exponent. These data are further evidence that the effects of psilocybin are maintained in the presence of midazolam, supporting its utility in mechanistic studies of psilocybins therapeutic activity.

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Sutherland, M. H., Nicholas, C. R., Lennertz, R., WENTHUR, C. J., Krause, B. M., Sauder, C. J., Riedner, B. A., Smith, R. F., Hutson, P. R., Raison, C. L., Banks, M. I.. 2025-07-29. Electrophysiological effects of psilocybin co-administered with midazolam. https://doi.org/10.1101/2025.07.25.666887

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