Electrophysiological effects of psilocybin co-administered with midazolam

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 Observer's Assessment of Arousal and Sedation (OAA/S) and selected items from the Altered States of Consciousness (ASC) questionnaire, respectively. At 15-30 min, when midazolam but 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, with the most prominent power reductions in the delta, theta, and alpha frequency bands. OAA/S improved model fits for alpha power while ASC improved model fits for LZCn and spectral exponent. While recognizing limitations inherent to the small sample size and variability in dosages of midazolam, these data are further evidence that the effects of psilocybin are maintained in the presence of midazolam, supporting its utility in mechanistic studies of psilocybin's therapeutic activity.