538 If the subjective effects of the study drug enhance placebo responses, these responses should be larger in the active arm compared to the placebo arm of a randomised clinical trial, and the drug response would be overestimated. Reviews of antidepressant drug trials have found larger effects of the study drug when it has been compared to an inert placebo than when the study drug has been compared to an active placebo (Greenberg and Fisher 1994; Kirsch and Sapirstein 1998; Moncrieff 2003; Thomson 1982). This suggests that part of the difference between the study drug and the inert placebo are not due to the pharmacological effects of the drug but to an enhanced placebo effect in the drug group. However, the hypothesis that side effects can enhance the placebo effect has not been subjected to an experimental test. The present experiment tested whether expectations of pain relief, and the resultant placebo analgesic effect, were enhanced by the subjective effects of caffeine. It was hypothesised that the subjective effects of caffeine would confirm the verbal information that a painkiller had been administrated, and make subjects more certain of pain relief. A within-subjects balanced placebo design (Ross et al. 1962) was used. Information that a painkiller had been or had not been administered was crossed with administra- tion of 0 or 4 mg/kg body weight caffeine. Caffeine increased subjective and physiological arousal at doses below 100 mg (Silverman and Griffiths 1992), and was hypothesised to act as an active placebo with little or no effect on pain. Pain was recorded by numerical rating scales (NRS) and by laser-evoked potentials (LEPs) that provide evidence of pain that is not influenced by response bias (Aslaksen et al. 2007). Laser stimuli activate Aδ- and C-fibers which are responsible for nociceptive processing. The typical response to a noxious laser stimulus consists of two components, the N2 and P2. The P2 component has been found to correlate with pain report and is reduced during placebo analgesia (Aslaksen et al. 2010; Colloca et al. 2008; Granovsky et al. 2008; Wager et al. 2006; Watson et al. 2007). Placebo-induced reductions in LEPs could mean attenuation of nociceptive input to the brain, attentional reorientation, or reduced saliency of the stimulus (Iannetti et al. 2008; Mouraux and Iannetti 2009; Wager et al. 2006). It was predicted that (1) caffeine should increase subjective arousal. (2) Subjects should report being more certain that they had received a painkiller after adminis- tration of 4 mg/kg bw caffeine compared to 0 mg/kg bw caffeine. (3) Information that a painkiller had been administered should decrease pain and LEPs. (4) Infor- mation that a painkiller had been administrated should reduce pain and LEPs more when it was paired with administration of caffeine, compared to the same infor- mation without caffeine. Psychopharmacology (2011) 215:537–548 Method Subjects Twenty-three subjects (seven females, age range 17–25 years, mean age 21 years, mean weight 74.5 ±15.9 kg (SD)) participated in the study. All subjects were recruited via advertisements at the campus of the University of Tromsø, Norway. Three subjects were excluded because they did not experience the stimulus as painful. Hence, twenty subjects were included in the final analysis. All subjects gave informed consent and fulfilled the inclusion criteria of no history of serious injuries, no use of medication with the exception of contraceptive pills, normal blood pressure, non-smokers, non-pregnant and between menstrual phases. Only regular coffee drinkers were included (mean coffee consumption per day 1.71 ± SD 1.22). Participants were told to abstain from nicotine and caffeine for 5 h prior to testing. They were paid 600 NOK for participating in the experiment (about 105 $). The experimental protocol was in agreement with the Declaration of Helsinki and was approved by the Regional Committee for Medical Research Ethics North Norway (project no. 30/2008). Drug and double-blind procedure The study was designed by the first author who never had any contact with the subjects. Two experimenters (one female) ran the study. The experimenters knew the purpose of the study and that caffeine could be administered. To double-blind the study, the experimenters were informed that some of the subjects would receive a painkiller instead of caffeine. In fact, all subjects received caffeine. The drink was mixed by the first author in a separate room out of view of the experimenter. Subjects were weighed and the experimenter reported the weight to the first author via telephone. Caffeine powder (Coffeinum 0.15 mm; Apotekproduksjon AS, Oslo, Norway) was administered in 1.5 dl grapefruit juice in a 4-mg/kg body weight dose. The appropriate amount of caffeine powder was weighed on a medical scale (Mettler P162, Mettler Toledo, Columbus, USA) and mixed with 1.5 dl grapefruit juice with pulp. Grapefruit juice with pulp was used because the bitter taste effectively masks the taste of caffeine and the pulp reduces the risk of detecting the added caffeine powder. In order to further avoid the risk of subjects detecting white caffeine powder in the juice the powder was crushed thoroughly, and stirred with a small amount of juice before adding the rest of the juice. Finally, the first author did a visual inspection of the drink to check whether the powder had been dissolved properly. To secure the double-blind procedure, the first author placed the drink in a refrigerator in the lab while the experimenter was performing the pretest in the shielded chamber. Hence, there was never any visual contact between