We have suggested previously that acute tolerance to the chronotropic effect of cocaine develops and that tolerance is incomplete, such that the heart-rate decline in the presence of stable plasma cocaine concentrations approaches a plateau that exceeds the baseline heart rate. One possible mechanism for heart-rate decline could be pressor-induced reflex slowing. We have investigated this phenomenon in intravenous (i.v.) cocaine users given prolonged steady-state i.v. cocaine infusions, as described previously. We have found that the contour of the pressor response, under conditions of the study, is identical to that of the chronotropic response. We also analyzed data presented in a report at variance with our conclusion (Drug and Alcohol Dep 22:169, 1988). In that study, heart-rate, pressor, and subjective effect data were collected after repeated intranasal doses of cocaine in a “naturalistic” setting. We found that the data are describable by our model and, in fact, provide further evidence to support our view. Application of our kinetic-dynamic model gave a tolerance factor of 19 min, suggesting that the adaptation process far exceeds the expected time course of cardiovascular reflexes or baroreceptor resetting. We conclude that tolerance does indeed develop to the pressor effects of cocaine, that the response is similar to the tolerance to heart-rate effect, and that our mathematical model of tolerance can also be used to describe the effects of cocaine taken intranasally in a naturalistic setting.