Neural underpinnings of open-label placebo effects in emotional distress

While placebo effects are well-known, research in the last decade revealed intriguing effects that placebos may have beneficial effects even when given without deception. At first glance, this seems paradoxical, but several studies have reported improvements in pain, depression, or anxiety. However, it still remains unclear whether these results represent objective biological effects or simply a bias in response and what neural underpinnings are associated with the open-label placebo effects. In two studies, we address this gap by demonstrating that open-label placebos reduce self-reported emotional distress when viewing highly arousing negative pictures. This reduced emotional distress was associated with an activation of brain areas known to modulate affective states such as the periaqueductal gray, the bilateral anterior hippocampi, and the anterior cingulate cortex. We did not find any prefrontal brain activation. Furthermore, brain activation was not associated with expectation of effects. In contrast, we found that brain responses were linked to general belief in placebos. The results demonstrate that the neural mechanisms of open-label placebo effects are partly identical to the neurobiological underpinnings of conventional placebos, but our study also highlights important differences with respect to a missing engagement of prefrontal brain regions, suggesting that expectation of effects may play a less prominent role in open-label placebos.