Placebo's Invisible Brother

A Restricted Scoping Review of the Biomedical Literature on the Nocebo Effect

Owen J. Sweeney; Sai Arathi Parepalli; Neginsadat Mirtorabi; Kimberley Loo Yong Kee; Benjamin G. Feakins; Jeffrey K. Aronson; Karolina A. Wartolowska


Pain. 2022;163(11):2103-2111. 

In This Article

Abstract and Introduction


Placebos and their beneficial clinical and psychological effects are well-researched, but nocebo effects receive far less attention, despite being highly undesirable. The aim of this restricted scoping review was to examine how nocebo effects are represented in the biomedical literature and to identify the trends and gaps in existing knowledge. After searching 5 biomedical databases and 2 clinical trials registries (from their inception to December 23, 2020) for articles on nocebo effects or negative placebo effects, 1161 eligible publications were identified. The 2 main publication types were nonsystematic reviews (37.7%) and primary research studies (35.6%); only 85 publications (7.3%) were systematic reviews and meta-analyses. The nonsystematic reviews, many of them heavily opinion-based, may contribute to the amplification of narratives, attitudes, and beliefs about nocebo effects that do not objectively reflect the primary research. The primary research articles often used nocebo effects to explain results, rather than as the primary phenomenon under investigation. Most publications were concerned with both positive and negative placebo effects, rather than just nocebo effects. Over half of the abstracts were in the field of neurology, psychiatry, psychology, or neuroscience (52.8%). The nocebo effect was most frequently investigated in the context of pain. Studies were almost exclusively in adults and more often in healthy participants than in patients. In conclusion, in the biomedical literature, there is an overabundance of nonsystematic reviews and expert opinions and a lack of primary research and high-quality systematic reviews and meta-analyses specifically dealing with nocebo effects.


Placebos are a cornerstone of clinical trial design and evidence-based medicine. They typically induce positive outcomes in their recipients, that is, "placebo effects," but they may also have strong negative physiological and psychological effects, that is, "nocebo effects." For example, inhaled isotonic saline may induce an asthma attack or alleviate asthma symptoms, depending on whether patients with asthma were told that they had inhaled an irritant or an effective asthma treatment.[10] Similarly, covert administration of saline instead of remifentanil significantly reduced subject-reported pain ratings. Conversely, when participants were told that their opiate infusion had stopped (when it had actually continued uninterrupted), they reported worse pain than when they were given saline.[2]

The nocebo effect encapsulates any outcome that is detrimental, including both negative effects and the lack of expected positive effects (partially or completely), when it is not a direct physical, biological, or chemical consequence generated by the intervention, whether inert, therapeutic, or harmful. Nocebo effects are associated with poorer treatment efficacy, worse adverse events profiles, and reduced adherence to medications.[7,8,13,15] They can also negatively affect clinical trial outcomes. For instance, reports of erectile dysfunction in beta-blocker trials increased 10-fold when patients were unblinded and told that their medication could cause this effect.[13] Similarly, reports of myalgia after statins increased significantly when patients were unblinded.[7] Therefore, although placebo effects may be harmless or even beneficial, nocebo effects are undesirable and should be mitigated.[15,18,19]

Nocebo effects are less well researched than placebo effects. A PubMed search (on September 8, 2021) returned 230 times more publications on "placebo" or "placebo effects" (n = 209,544) than on "nocebo" or "nocebo effect[s]" (n = 908). It is unclear how the nocebo effect is represented in the biomedical literature, what the main publication trends are, and where gaps exist in the field. To answer this broad and exploratory research question, a scoping review was deemed appropriate.[1,4,5,11,16] Unlike a full systematic review, which aims to test hypotheses and synthesize the existing evidence,[12,16] a scoping review aims to map the key concepts in a particular research area, to describe the range of evidence,[4,12] and to generate new hypotheses.[16] So far, only 1 scoping review on the nocebo effect has been performed, and it reported that the nocebo effect was associated with several psychosocial factors and that there was a need for a consistent definition of the nocebo effect and for increased awareness of it among researchers and clinicians.[14] The scope of this scoping review was narrow—it included only 48 studies and provided a narrative overview rather than a systematic mapping of the evidence using tables and diagrams, as recommended by the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews checklist and explanation.[17] We have performed a broader and more exploratory scoping review,[1,16] investigating how nocebo effects are represented in the biomedical literature, describing the range of evidence, and identifying key concepts, trends, and gaps in knowledge.