Discovery of the involvement of endogenous opiates in placebo analgesia represents an important step in understanding the mechanisms underlying placebo response. In the present study, we investigated the effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia in a human model of experimentally induced ischemic pain. First, we found that part of the placebo response was reversed by naloxone, confirming previous studies on the role of opioids in the placebo phenomenon. Second, since it was demonstrated that the action of exogenous and endogenous opiates is potentiated by proglumide, we analysed the effects of this cholecystokinin antagonist on placebo response and found that it enhanced placebo analgesia. The placebo effect can thus be modulated in two opposite directions: it can be partially abolished by naloxone and potentiated by proglumide. The fact that placebo potentiation by proglumide occurred only in placebo responders, but not in non-responders, suggests that activation of an endogenous opiate system is a necessary condition for the action of proglumide. These results suggest an inhibitory role for cholecystokinin in placebo response, although the low affinity of proglumide for cholecystokinin receptors does not rule out the possibility of other mechanisms.