In methadone maintenance therapy methadone plasma concentrations of 400 ng/ml are necessary to suppress any further opiate action and to provide stabilized maintenance. In a controlled study we have searched for a differentiation in autonomous activation between patients having low and high methadone plasma levels, using static and dynamic pupillometry and habituation of skin conductance response. Results show that there is no difference in psychophysiological response between patients with high (greater than 400 ng/ml) or low (less than 400 ng/ml) plasma levels of methadone. This indicates that there is no reduction in behavioral arousal in patients with high plasma methadone levels. On the basis of these findings, there is no rationale to maintain patients on plasma levels below 400 ng/ml.