© 2017 International Anesthesia Research Society. BACKGROUND: Every day, millions of people undergo surgical procedures facilitated by anesthesia. Yet, there is no clinically accepted measure to predict the effects of sedation or anesthesia on the central nervous system. Auditory brain activation may provide an objective and quantifiable method to measure of the effects of sedation on neuronal processing. METHODS: This is a randomized clinical trial. Forty-eight healthy volunteers were randomly assigned to receive 1 of 3 sedative drugs (midazolam [n = 11], propofol [n = 12], or dexmedetomidine [n = 12]) at a concentration adjusted to achieve mild sedation by self-rating, or to a no-drug control group (n = 13). Participants underwent functional magnetic resonance imaging while listening to music in a 5-minute block design experiment. We tested the hypothesis that mild sedation changes the magnitude or extent of cortical activation of an auditory stimulus. RESULTS: We observed a significant reduction in auditory activation in both the dexmedetomidine (P = .001) and midazolam (P = .029) but not the propofol group (P = .619) when compared with saline control. CONCLUSIONS: Our findings indicate that, compared with saline control, there is a significant reduction of brain activation in the auditory cortex in response to midazolam and dexmedetomidine but not propofol when given at mildly sedative doses. This method serves as a novel approach to quantify the effects of sedative agents in an objective fashion.