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.


S6: Presentation for OLP and control group
To optimize the placebo manipulation, participants in study 1 and study 2 were asked to read articles on either placebos or pain. The OLP group read an article about placebos, e.g., explaining the participants that placebos are powerful, have been shown to work even without deception, can affect behavior and physiological processes. The control group received a similar article on pain. Both texts were comparable with respect to narrative structure, valanced words, and length. The articles were taken from Guevarra et al. (2020).
The reading manipulation was identical for study 1 and 2, but in study 2 we asked the participants to recall and write about what they remembered from the presentation at the end of the reading (identical to Guevarra et al., 2020).
After the reading manipulation step the nasal sprays were given and the image viewing task started (study 1). In study 2 participants completed the recall task and then also received the nasal spray before entering the fMRI room. The verbal instructions of the experimenter when giving the nasal spray were identical to Guevarra et al. (2020) (for both studies).

S7: Questions to examine belief in OLP
These 5 questions aimed to examine the belief in OLPs and were embedded in other more general belief items on pain. All questions are taken from Guevarra et al., 2020. Participants had to rate the statements on a 11-point scale from 0 (definitely not true) to 10 (definitely true).
"A placebo can still work on me even though I know that I am taking a placebo." "In order for placebos to work, the person needs to be deceived into believing they are taking an actual medicine." "A placebo can reduce my negative emotions even though I know I am taking a placebo." "A placebo only works if the person is deceived into thinking they are taking an actual medicine." "A placebo can reduce my pain even though I know that I am taking a placebo."

S8: Question to examine expectations with respect to nasal spray
For the control-group the nasal spray was introduced due to technical reasons. Thus, it may be surprising for those participants when asking about relief of emotional distress due to the spray. Therefore, for this group we added the following statement before asking about their expectations: "Sometimes the saline nasal spray has the incidental effect of reducing people's negative emotional response. " Then for both groups we asked to rate how strong they think the nasal spray had reduced their emotional response to the pictures. Subjects had to rate this statement on a visual analogue scale with the ends "not at all" and "very strong".

S9: Questions to examine general belief in placebos
These four items have been taken from Leibowitz et al. (2019) and had to be rated on a 11-point scale from 0 (definitely not true) to 10 (definitely true): "Placebo effects are a part of all active medications." "Placebo effects can occur in all illnesses and conditions." "Placebo effects happen because the mind has the power to heal." "Placebo effects work because placebos influence people's expectations about a particular treatment." S10: Instructions of the experimenter (study 2) Before administering the placebo nasal spray, the experimenter explained to the participants (taken from Guevarra et al., 2020):

Placebo condition:
"From what you have read, you know that placebos are inert substances or procedures that make people feel better mostly because they believe it will. You also know that placebos are powerful and can help reduce pain, depression, anxiety, and negative emotions. On top of that, you've read that placebos affect more than how you feel, they actually can change your behavior, physiology, and even brain activity. And new research has also shown that placebos can work even if you know you are taking one since the key ingredient is the positive belief that it can help and that it works." Then the administration provides the nasal spray and explains further: "I just want to remind you that I just administered a placebo nasal spray that contains no active ingredients, but if you believe it will reduce your negative emotional reactions to these images, then it will. The placebo really works because of your positive beliefs and expectations." Control condition: "Your sinuses consist of passageways that surround the nasal cavity. Two of these passageways are located above and under your eyes. One is located between the eyes. The last one is located behind them. The nasal cavity is a large space above and behind the nose in the middle of the face. These spaces are naturally filled with a thick membrane that gets recycled throughout the day. Unfortunately, this thick membrane often interferes with the metabolic signals produced by your brain. So, to help us get better signals, we administer a saline nasal spray to help clear some of this space. "