Placebo responses to painful stimuli are mediated by both opioid and non-opioid mechanisms, and the latter are poorly understood. Here, Benedetti and colleagues examined the role of the endocannabinoid system in such responses. The authors conditioned individuals, who were undergoing daily pain tolerance tests, to expect analgesia from either an opioid drug (morphine) or a non-opioid drug (ketorolac). They then administered rimonabant — an antagonist of cannabinoid receptor 1 — to a subset of these individuals, to assess the impact of this compound on the placebo analgesic effects. Interestingly, rimonabant blocked the placebo effect in people who had undergone non-opioid preconditioning but not those who had been subjected to opioid preconditioning. This finding suggests that the endocannabinoid system plays an important part in non-opioid-mediated placebo effects.