Placebo treatment entails resource-dependent downregulation of negative inputs

Clinical trials with antidepressants reveal significant improvements in placebo groups, with effects of up to 80% compared to real treatment. While it has been suggested that treatment expectations rely on cognitive control, direct evidence for affective placebo effects is sparse. Here, we investigated how cognitive resources at both the behavioral and neural levels influence the effects of positive expectations on emotional processing. Forty-nine healthy volunteers participated in a cross-over fMRI study where positive expectations were induced through an alleged oxytocin nasal spray and verbal instruction. Participants completed a spatial cueing task that manipulated attention to emotional face distractors while being scanned and were characterized regarding their general attention control ability. Placebo treatment improved mood and reduced distractibility from fearful compared to happy faces, particularly when more attentional resources were available for processing face distractors. This aligned with changes in activation and functional coupling within prefrontal-limbic networks, suggesting that expectations induce top-down regulation of aversive inputs. Additionally, neurobehavioral effects correlated with individual control ability. Our findings highlight the critical role of cognitive resources in verbally instructed placebo effects. This may be particularly relevant in patients with major depressive disorder, who often demonstrate enhanced negativity processing but have limited cognitive control capacity.