Using heart rate and GPS data from wild vulturine guineafowl, Brandl et al. show that initiating group movements is physiologically costly—especially when consensus is low. These findings reveal hidde...

Background Systemic inflammation triggers a wide range of sickness symptoms, including bodily discomfort and affective symptoms, which are relevant to numerous health conditions. While extensive research in the placebo field demonstrates that positive expectations can improve symptoms, it remains unclear if interventions designed to augment positive treatment expectations can alleviate sickness symptoms in the context of immunomodulatory drug therapies. Methods In this randomized, controlled, fully balanced 2 × 2 factorial placebo design, N = 124 healthy volunteers received either active ibuprofen treatment (600 mg per os) or placebo, combined with either a positive or neutral labeling of the treatment by the physician. All participants were intravenously injected with lipopolysaccharide (LPS, 0.8 ng per kg of body weight) as a translational model of inflammation-induced sickness symptoms. Primary outcomes were bodily and affective symptoms, assessed at baseline and up to 6 h after injection, along with a range of inflammatory markers. Results Ibuprofen substantially alleviated inflammation-induced symptoms. Positive labeling also improved bodily and affective symptoms of sickness, even in placebo-treated groups. Notably, positive labeling enhanced ibuprofen’s efficacy for alleviating affective symptoms, supporting that expectations can boost the efficacy of a highly effective anti-inflammatory treatment. However, labeling did not influence changes in physiological markers of inflammation, suggesting that the effects of expectations primarily act through mechanisms distinct from direct modulation of peripheral immune responses. Conclusions Placebo mechanisms engaged by physician communication can independently alleviate inflammation-induced symptom burden and enhance the efficacy of an anti-inflammatory medication. Results underscore the critical role of healthcare provider communication and pave the way for improved treatment strategies for conditions characterized by inflammation-driven symptoms. Trial registration DRKS00023088, registration website German Clinical Trials Register (date registered: 10/22/2020).