Jeremy Howick
Senior Researcher & Director, Oxford Empathetic Care Programme, Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom.

Review on adverse events in trial placebo groups


Trial participants in placebo groups experience adverse events (AEs). Existing systematic reviews have not been synthesized, leaving questions about why these events occur as well as their the prevalence of AEs across different conditions unanswered.


(1) To synthesize the evidence of prevalence of AEs in trial placebo groups across different conditions.

(2) To compare adverse events in trial placebo groups with adverse events reported in untreated groups within randomized trials.

Search methods

We searched PubMed for records with the word ‘nocebo’ in the title and ‘systematic’ in any field. We also contacted experts and hand-searched references of included studies.

Study eligibility

We included any systematic review of randomized trials where nocebo effects were reported. We excluded systematic reviews of non-randomised studies.

Participants and interventions

We included studies in any disease area.

Study appraisal and synthesis methods

We appraised the quality of the studies using a shortened version of the Assessment of Multiple Systematic Reviews tool (AMSTAR) tool. We reported medians and interquartile ranges of AEs. Among the trials within the review that included untreated groups, we compared the prevalence of adverse events in untreated groups with the prevalence of adverse events in placebo groups.


We identified 20 systematic reviews. These included 1271 randomized trials and 250,726 placebo-treated patients. The median prevalence of adverse events in trial placebo groups 49.1% (interquartile range 25.7%-64.4%). The median rate of dropouts due to adverse events was 5% (interquartile range 2.28%-8.4%). Within the 15 of trials that reported adverse events in untreated groups, we found that the adverse event rate in placebo groups (6.51%) was higher than that reported in untreated groups (4.25%).


This study was limited by the quality of included reviews, and the small number of trials that included untreated groups.

Conclusions and implications of key findings

Adverse events in trial placebo groups are common and cannot be attributed to natural history. Trial methodologies that reduce AEs in placebo groups while satisfying the requirement of informed consent should be developed and implemented.



I investigate medical questions that require input from philosophy and clinical epidemiology. These include: the ontology, effects, and ethics of placebo treatments in clinical trials and clinical practice, the benefits and harms of informed consent, the extent to which basic science and mechanism research is required for clinical advancements, and the problem of too much medicine. With over 60 academic publications (including two books), I have been funded by the Medical Research Council and the National Institutes of Health Research (both in the United Kingdom) and my research has been used to shape policy. I am also a dedicated teacher who has won four teaching awards. More recently I have expanded my public engagement activities and give regular talks to lay audiences, my social media platform has over 5000 followers, and I have written a popular science book (April 2017) called Doctor You, which explains the science behind the problem of too much medicine for a lay audience.