Opioid drugs influence multiple brain circuits in parallel to produce analgesia as well as side effects including respiratory depression. At present we do not have real-time clinical biomarkers of these brain effects. We describe here the results of an experiment to characterize the electroencephalographic signatures of fentanyl in humans. We find that increasing concentrations of fentanyl induce a frontal theta band (4-8 Hz) signature distinct from slow-delta oscillations related to sleep and sedation. We also report that respiratory depression, quantified by decline in an index of instantaneous minute ventilation, occurs at ≈ 1700-fold lower concentrations than those that produce sedation as measured by reaction time. The EEG biomarker we describe could facilitate real-time monitoring of opioid drug effects and enable more precise and personalized opioid administration.