How do they add up? The interaction between the placebo and treatment effect: A systematic review
Open accessAbstract
AIM: The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. METHODS: We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance. RESULTS: Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). CONCLUSION: Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo-sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity.
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Findings of balanced placebo designs that included other interventions and drug effects have been mixed regarding whether effects were additive or interactive.
“Still, findings of balanced placebo designs that included other interventions and drug effects have been mixed regarding whether effects were additive or interactive (Boussageon et al., 2022; Metrik et al., 2009).”
From Mindfulness Effects on Anxiety: Disentangling the Role of Decentering and Treatment Expectations (2024) · cites this paper as Boussageon et al., 2022
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Zhang, M., Zhang, B., & Morice, A. H. (2024) · ERJ Open Research · doi:10.1183/23120541.00335-2024 · Cited by 15 · see citing works
“Some conditions that are more defined by symptoms rather than objective pathophysiology, and are sensitive to the placebo effect, usually in perceived disorders such as neuropathic pain, negative emotion, irritable bowel syndrome (IBS) and coughing [33].”
Contextual effects in musculoskeletal pain: are we overlooking essential factors?
Poulter, D. C., Palese, A., Rodeghiero, L., Carlino, E., Esteves, J. E., Cook, C. E., & Rossettini, G. (2025) · Frontiers in Psychology · doi:10.3389/fpsyg.2025.1537242 · Cited by 12 · see citing works
The Relevance Of Real-World Data For The Evaluation Of Neuropathic Pain Treatments
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Tesfaye, S. H., Saravanan, P., Ehler, E., Zinek, K., Palka-Kisielowska, I., Nastaj, M., Sérusclat, P., Lipone, P., Vergallo, A., Quarchioni, E., et al. (2024) · Pain and Therapy · doi:10.1007/s40122-024-00624-3 · Cited by 8 · see citing works
“…psychological factors and lack of biomarker‑based: eligibility criteria, phenotypic profiling and outcome measures (to name a few) – which are all likely to influ‑ ence treatment outcomes and may account for the moderate trial outcomes and dilute results through large placebo responses [31, 32].”
ResultHohenschurz‐Schmidt, D., & Liem, T. (2025) · International journal of osteopathic medicine · doi:10.1016/j.ijosm.2025.100762 · Cited by 7 · see citing works
Mindfulness Effects on Anxiety: Disentangling the Role of Decentering and Treatment Expectations
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Placebo and nocebo effect in pain
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“Effective assessment of change expectations often necessitates focusing on the symptomatic domains of the intervention 17 .”
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Is It All in Your Head? Placebo Effects in Concussion Prevention
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“A further consideration is that active and contextual effects may not just be additive, they may also interact to either enhance (synergistic) or reduce (antagonistic) the effects of a given treatment [13].”
The Elastic Ruler: Placebo Responses, Clinical Trials, and Medical Knowledge
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“…suggest that from clinical trials, the relationship between effects is not a simple addition or subtraction as the effect interplay to procure larger (super-additive or synergistic), smaller (sub-adaptive or antag-onistic) or even reverse effect (qualitative interaction) (Boussagen et al., 2022).”
BackgroundOpen-label placebos for low back pain: unresolved challenges and next steps
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Some additional considerations on the evidence for fluoxetine in pediatric depression
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Mindfulness Effects on Anxiety: Disentangling the Role of Decentering and Treatment ExpectationsPreprint
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Problems with placebo-control studies of functional foods
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“…the case when the combined effect exceeds the sum of individualized effects of active treatment and placebo which can lead to an overestimation of active treatment’s efficacy in RCTs, or even a reverse reaction to the treatment (De La Fuente-Fernández et al., 2001; Rémy Boussageon et al., 2022).”
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“[15] According to the published literature, it has been stated that the amount of saliva secretion is inversely proportional to the sIgA.”
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“Our findings are comparable but smaller than the results previously described and may support the subadditivity effect (Boussageon et al. 2022) between the effect promoted by the positive/neutral expectations and the effect of SMT.”
- Authors
- Boussageon, R., Howick, J., Baron, R., Naudet, F., Falissard, B., Harika‐Germaneau, G., Wassouf, I., Gueyffier, F., Jaafari, N., & Blanchard, C.
- Affiliations
- Laboratoire de Biométrie et Biologie Evolutive (FR)
- University of Oxford (GB)
- Université de Lyon (FR)
- Centre Hospitalier Universitaire de Rennes (FR)
- Inserm (FR)
- Centre Hospitalier Henri Laborit (FR)
- Unité de recherche clinique intersectorielle en psychiatrie à vocation régionale Pierre Deniker du Centre Hospitalier Henri Laborit France
- Université de Poitiers (FR)
- Corresponding author
- Blanchard, Clara
- ORCID
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2022-05-02
- Volume
- 88
- Issue
- 8
- Pages
- 3638-3656
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC9545282
- OpenAlex
- W4225318411
- Cited by
- 36
- References
- 74
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 9 · 2023: 4 · 2022: 4 · 2021: 1
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Clinical Pharmacology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- HAL (submittedVersion)
- Funders
- Medical Research Council (MR/V020706/1)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Keywords
- placebo effect, additivity, generalizability
- MeSH terms
- Humans, Placebo Effect
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