In the nocebo effect - the opposite of the placebo effect - expectations of symptom worsening play a crucial role. Most of our knowledge about the analgesic placebo effect comes from the field of pain. It has been associated with decreased activity in the anterior cingulate and is diminished by antagonists of opiodergic peptide systems. The worsening of pain by exppectation has not been studied as thoroughly. Benedetti et al have now used a neuropharmacological approach to show that the hyperalgesic nocebo effect is associated with the activation of the CCKergic brain peptide system, as well as activation of the hypothalamic–pituitary–adrenal axis activated by stress. Thus the the analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.