Peer review of: Placebos without deception reduce self-report and neural measures of emotional distress (2020)

Reviewers' Comments: 
 
Reviewer #1: 
Remarks to the Author: 
This is an elegant study that addresses an important topic in affective neuroscience: are 
non-deceptive placebo effects on negative emotional responses "true" effects or do the 
simply reflect the demand characteristics of the task (i.e., if subjects say they feel less pain 
or distress from a non-deceptive placebo manipulation, do they simply say what they 
believe the experimenter wants to hear)? The key to answering this question is to provide 
evidence that the non-deceptive placebo condition affects objective behavioral or biological 
correlates of the to-be-modulated emotional response. 
 
The authors have conducted a thorough and well-designed investigation of the topic that 
involves two studies where a non-deceptive placebo group is compared to a control group 
not receiving any explicit expectation manipulation in their responses to negative and 
neutral affective pictures. Study 1 provides only self-report ratings of negative affect, study 
2 provides only EEG measures (Late Positive Potential, LPP). The paper is well written, the 
argumentation is clear and convincing, the statistical analyses are suitable and rigorous. 
The results demonstrate an effect of the placebo manipulation on the EEG. 
 
I nevertheless have two major concerns that I feel the authors need to address before I can 
make an informed recommendation. 
 
1. Specificity 
 
a) Subjects in the control condition are made to read an article about pain before the 
experiment. I was wondering if this might induce a general negative emotional state or even 
negative expectations about the effects of negative or unpleasant emotional material on 
well-being, distress, or health. In other words: could the control condition effectively be a 
distress or even nocebo condition? (In which case the differences in ratings and EEG 
measures between the two groups could be driven by amplifying effects on affective 
responses in the control group rather than by dampening effects in the placebo condition.) 
b) In relation to this: I would be more confident that the group differences in rating and 
EEG are really due to the positive expectations raised by the placebo manipulation if the 
authors could demonstrate a correlation of rating/EEG effects with individual or group 
differences in the ratings of subjects' beliefs in the effects of non-deceptive placebos as well 
as in the effects of the nasal spray that the subjects provided at the end of the instruction 
phase (see Supplement p. 13 ff.). Supplementary Tables 2 and 3 show that these mostly 
differ between groups and also exhibit substantial variability within groups, and the 
numbers of subjects included in the two studies (62 and 100, resp.) are clearly sufficient for 
performing individual-differences analyses. Hence, these analyses are feasible. Showing a 
relationship between expectations and placebo effects is also more or less standard in 
placebo studies. 
c) Another related point: Supplementary Table 3 also shows that subjects in the control 
group of study 2 perceived experimenters as warmer and more competent. This is a surely 
unexpected effect of the manipulation that again may have had an impact on EEG in this 

case. The authors themselves think that this finding suggests "that there may be something 
about our non-deceptive placebo manipulation (i.e., verbal suggestion instructions during 
the nasal spray instructions) that decreases perception of warmth and competence. This 
may have influenced the effectiveness of our manipulation …". Hence, there is a clear need 
to disambiguate better the potential sources of the described differential EEG effect, which 
could be done by some kind of multiple regression including all the different ratings. [Note 
that the authors believe the reduced perceptions of experimenters' warmth and competence 
in the placebo group may have "reduced the effects we observed" (Suppl. Table 3). They 
thereby seem to suggest that this could only have made their EEG-based assay of the 
placebo effect less sensitive, but not have produced false positive findings. However, their 
EEG effects go both ways – relatively reduced responding in the placebo group in the 
sustained LPP (Fig. 2) and relatively enhanced responding in the early LPP (Fig. 3); hence, 
the argument does not count.] 
d) To sum up: The authors need to do more to convince me that the group differences they 
see are really placebo-specific effects. 
 
2. Robustness 
 
This study is done on a background of consistently negative findings in all five prior studies 
trying to show non-deceptive placebo effects on objective behavioral or biological measures, 
as the authors point out in their introduction. The authors argue that these tests were all 
not sensitive enough to find non-deceptive placebo effect since they are not even sensitive 
enough to demonstrate deceptive placebo effects (p. 4: "Put simply, if a deceptive placebo 
induced through verbal suggestion does not reliably impact objective outcomes in these 
contexts, there is no reason to expect a non-deceptive placebo should either.") I agree. And 
I applaud the authors for selecting a task (affective picture viewing, combined with EEG) 
that is likely to have sufficient sensitivity, based on prior successes with the task in 
detecting deceptive placebo effects (p. 4). Nevertheless, the EEG effects that the authors 
describe are not internally consistent (relative response dampening by placebo in sustained 
LPP, response amplification in early LPP, see 1.d), the directionality of placebo effects on 
EEG markers in the existing deceptive placebo literature is also very inconsistent (p. 10), 
the direction of the EEG effects in the current study was not predicted, and there is an 
absence of a to-be-expected three-way interaction (i.e., a picture valence effect) in the 
sustained EEG data. I also note that the authors have some difficulty in reconciling their 
divergent findings (p. 8, bottom: "general dampening effect", when referring to the 
sustained EEG effect, vs. p. 11: increased "willingness to engage with incoming unpleasant 
Stimuli", when referring to the early EEG effect). To me this suggests that EEG is quite 
sensitive in picking up something, but as long as there is no consistency within and across 
studies, this something may as well be a spurious, random effect, i.e., a false positive. This 
suspicion is, of course, strengthened given the consistent failure in prior work to show non-
deceptive placebo effects on objective measures (see above). At the same time, 
convincingly demonstrating an objective non-deceptive placebo effects would be a big 
advance for the field and a very important contribution to the literature. Therefore, I think 
that this paper would massively benefit from a replication study. As a single EEG study, I 
fear the experiment will never convince enough readers outside a "circle of believers". It will 
just be another EEG study. 

 
Minor points: 
3. p. 7 bottom/p. 8 top: "participants in the non-deceptive placebo group showed a gradual 
reduction in sustained LPP amplitude over Time". Please make clear right from the start that 
"time" is time within a trial, not across the experiment. 
4. Sometimes, the authors commit the fallacy of reverse inference when they equate a 
certain EEG phenomenon with a cognitive process, e.g., p. 10 bottom: "we observed a 
gradual increase in attention allocation to negative images relative to neutral Images" or p. 
14: "Participants in the non-deceptive placebo group showed a larger relative increase in 
attention allocation". 
5. p. 15 bottom: "non-deceptive placebos also offer an alternative emotion regulation 
strategy that is distinct from internally-generated reappraisal strategies, which often require 
intact cognitive control mechanisms and cognitive effort". How do the authors know that 
this is a distinct strategy? Can they show that the placebo effect does not require cognitive 
control and effort? Generally, it seems the authors read a bit too much into their EEG data. 
 
 
 
Reviewer #2: 
Remarks to the Author: 
In this manuscript, authors describe a solid study in a sample of undergraduate students, 
where non-deceptive placebo and a control condition are compared regarding their impact 
on cerebral (EEG/ERP) and self-reported emotional engagement. The rationale is clear and 
solid, stating that previous work on non-deceptive placebos has focused on dependent 
variables that are not modulated by deceptive placebos either. The present study measures 
variables that are more related to emotional reactivity or emotion regulation, with the 
expectation that these will be modulated. The authors find support for the expected result. 
The picture viewing task appears solid, even though the external validity is somewhat 
unclear - would a placebo not eventually be used in the context of pain or suffering rather 
than transient emotional state? The case for this facet of the study could be made more 
strongly. As-is, the clinical relevance of the findings is somewhat vague, especially as one 
would expect demand characteristics to prompt participants to produce the subjective report 
findings, which surprisingly is not discussed in the manuscript. This is an important point 
which may render one of two dependent variables hard to interpret. One additional major 
concern arises from the lack of a positive-picture control condition. The authors seem to 
claim that non-deceptive placebos trigger a process akin to or identical to emotion 
regulation (incidentally, what would then be the purpose of the placebo? One may just 
instruct people to feel less then?) of emotional distress. To demonstrate the negative-
emotion specificity however, a positive-picture control condition would be needed. In its 
absence, the data will be difficult to interpret. Further issues are related to the 
interpretation of the brain data. Is 400-1000 ms still considered an automatic response? 
Why is contrasted to subsequent conscious processing - is the first second supposed to be 
unconscious? The statistical analyses are standard and correctly executed. In summary, this 
is a solid study addressing a very specific problem of interest to researchers with a focus on 
emotion regulation via the placebo effect. Some concerns arise regarding the limitations of 
the experimental design, the potential presence of demand-prompted subjective report, and 

the interpretation of the brain data. 
 
 
 
Reviewer #3: 
Remarks to the Author: 
This study investigated the effects of a non-deceptive placebo on emotional distress and late 
electrocortical positivity (late positive potential; LPP). To the best of my knowledge, this is 
the first EEG experiment on this topic. Therefore, the results are novel and the manuscript 
is important to placebo researchers. Moreover, the findings have important translational 
implications (treatment of emotional distress in different health-related contexts). 
 
The authors conducted two experiments with an image viewing task. They administered 
negative pictures (mutilation, aggression) and neutral pictures (e.g., household items). The 
pictures were presented with/ without a non-deceptive placebo (nasal spray with a saline 
solution). 
In experiment 1, the group that received the non-deceptive placebo (n = 33 women) 
reported less emotional distress for the negative pictures than the control group (n = 29 
women). 
In experiment 2, the group that received the non-deceptive placebo (n = 50) showed a 
gradual reduction in the amplitude of the LPP for both neutral and negative images relative 
to the control group (n = 50). 
 
I have the following comments/ questions. 
The authors claim that the non-deceptive placebo reduced emotional distress as indexed by 
self-report and electrocortical responses. 
Previous EEG research has consistently shown that late positivity to affective pictures is 
modulated by the intrinsic motivational significance and the evaluative context of the picture 
presentation (e.g., Schupp et al., 2000). 
Therefore, different interpretations of the observed findings are possible: 
1) The authors created two different emotional/ evaluative contexts for the image viewing 
task. The control group read an article about the neurobiological processes of pain; the 
placebo group read an article about the placebo effect in different domains. Subsequently, 
pain-related images were shown (mutilation, aggression). This can be considered negative 
priming for the control group. 
2) The authors combined negative and neutral pictures in order to analyze the LPP. 
However, the neutral images do not elicit emotional distress and should not be responsive 
to the placebo intervention (as shown for the subjective ratings). The neutral condition is 
the control condition for the placebo effect on negative emotional picture processing. 
Please also note: Post-hoc t-tests (comparisons of LPP amplitudes between the placebo and 
control group for the five time windows of late positivity) are not statistically significant 
after correction for multiple comparisons. 
3) ‘Regular/deceptive’ placebos have produced heterogeneous electrocortical effects during 
the processing of negative affective pictures (e.g., decreased P2 amplitude and increased 
N2 amplitude, see Zhang et al., 2009, increased frontal LPP amplitude (Übel et al., 2015). 
Therefore, it would have been important to see a ‘regular placebo response’ to reference the 

response to the non-deceptive placebo (this could be easily introduced as additional 
condition of the present experiment). 
4) To test that the placebo and control group did not differ in key elements, the authors 
assessed the reading time of the articles, beliefs in the effectiveness of non-deceptive 
placebos, and personality traits. They did not assess uneasiness about blood and injury (the 
contents of the negative pictures).