What causes the placebo effect and how strong is it?

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1. 1

   Placebo (Wikipedia)

   WikipediaPublished Oct 1, 2026Checked Oct 3, 2026

   “A placebo ( pluh-SEE-boh) is a medicine or treatment intended to appear genuine to its recipient, but which has no pharmaceutical effect. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials to test the efficacy of medical treatments. In a placebo-controlled trial, any change in the control group is known as the placebo response, and the difference between this and the result of no treatment is the placebo effect. Placebos in clinical trials should ideally be indistinguishable from so-called verum treatments under investigation, except for the latter's particular hypothesized medicinal effect. This is to shield test participants (with their consent) from knowing who is getting the placebo and who is getting the treatment under test, as patients' and clinicians' expectations of efficacy can influence results. The idea of a "placebo effect" was discussed in 18th century psychology, but became more prominent in the 20th century.”

2. 2

   Magnitude of the placebo response across non-surgical treatment modalities used for knee osteoarthritis: A meta-analysis with meta-regression.

   Osteoarthritis and cartilage open (Holtedahl et al.)Published Aug 12, 2026Checked Oct 3, 2026

   “Searches of the PubMed and Embase databases were conducted through May 2025. Hedges' g was calculated as the effect size for pre-to-post change in pain outcomes using a random-effects model. Heterogeneity was assessed using the I2 statistic, and sources of variance were analyzed with multivariate meta-regression.ResultsOne hundred and seventy-nine RCTs were included. Four trials also included a no-treatment arm. A Hedges' g of 0.5 or greater for improvement from baseline was observed in the placebo arm of 109 (60%) trials, while 15 (8%) reported worsening. Substantial heterogeneity was present (I2 = 88%, p ConclusionMost trials reported moderate to large effect sizes for improvement in the placebo group. Treatment modality did not significantly affect outcomes and most of the variance in the placebo response remained unexplained. Important limitations include substantial statistical heterogeneity, the lack of data on psychological variables and few trials with a no-treatment group.”

3. 3

   Beyond control in psychiatric research: systematic review and meta-analysis of placebo treatment responses across major psychiatric conditions in citalopram and escitalopram RCTs.

   The British journal of psychiatry : the journal of mental science (Ahmadzad-Asl et al.)Published Aug 25, 2026Checked Oct 3, 2026

   “A large placebo response was observed (effect size: 1.01; 95% CI: 0.93-1.10) with significant heterogeneity (I2: 99.61%). Significant differences in placebo responses were noted across clinical conditions, independent of the medication type. PTSD and depressive disorders exhibited the highest placebo effect size (1.14 and 1.02, respectively), whereas OCD showed the lowest (effect size: 0.62, P P I2: 99.76%) but was not significantly different across psychiatric conditions (P = 0.61). Placebo response magnitude was larger in studies with more study arms (b: 0.181, P b: -0.010, P v. 0.76, P p v. 0.86, P = 0.01) were associated with larger placebo effect size.ConclusionsThis study used a unique approach to examine placebo responses from the same interventions across multiple major psychiatric disorders. We found substantial placebo responses across psychiatric conditions and significant heterogeneity, influenced by a range of study-related and demographic factors. The findings underscore the complexity of placebo responses and highlight the importance of considering these variances in both research design and clinical translation.”

4. 4

   Meta-analytic evidence for distinct neural correlates of conditioned versus verbally induced placebo analgesia.

   Nature communications (Spisak et al.)Published Jul 17, 2026Checked Oct 3, 2026

   “Both techniques increase activity during pain in the dorsolateral prefrontal and inferior parietal cortices and decrease activation in the insula, putamen, and primary sensory areas. Adding conditioning enhances engagement of regions associated with context representation and pain modulation (e.g., dorsolateral/dorsomedial prefrontal cortices) and decreases in nociceptive regions (e.g., primary sensory and insular areas). Conditioning also strengthens the negative association between analgesia and nociceptive activity, as quantified by the Neurologic Pain Signature. Combining conditioning with instructions yields greater placebo analgesia, mediated by increased ventromedial prefrontal and dorsal caudate activity, alongside decreased sensory-nociceptive and cerebellar activity. These findings suggest the two strategies rely on partially distinct mechanisms in the brain.”

5. 5

   A Comprehensive Scientometric Analysis of Placebo and Nocebo Effects in Pain Research: From Placebo Mechanisms to Clinical Trials.

   Journal of evaluation in clinical practice (Borghesi et al.)Published Sep 1, 2026Checked Oct 3, 2026

   “Mechanistic studies grew 3.97% annually, focusing on expectation, conditioning, and pain modulation, with key contributions from Benedetti, Colloca, and Wager, concentrated in the USA, Germany, Italy, and the UK. RCTs grew 3.52% per year, emphasising systematic reviews and methodological standards (Jadad scale, PRISMA), led by Moore and Manchikanti, with the USA, China, and the UK dominating output. Co-citation analyses identified mechanistic clusters around opioidergic and dopaminergic pathways and prefrontal-cingulate circuits, and RCT clusters emphasising methodological rigour and pain outcomes. Keyword analyses highlighted pain, analgesia, and expectation as central themes, with emerging trends reflecting evolving clinical applications and innovative trial designs. This scientometric mapping underscores the dual role of placebo as a neurobiological phenomenon and methodological cornerstone, offering a comprehensive overview of the evolution, structure, and thematic organisation of placebo and nocebo research in pain.”

6. 6

   Placebo and nocebo effects on pain through the lens of the predictive brain: Neurobiological mechanisms and translational implications.

   Experimental physiology (Zamfira et al.)Published Aug 28, 2026Checked Oct 3, 2026

   “In contrast, nocebo hyperalgesia involves increased activity in limbic-interoceptive networks, recruitment of stress-related systems and cholecystokinin-mediated facilitation of nociceptive transmission. Within this framework, placebo and nocebo effects emerge as precision-dependent modulations of predictive signals that shape both central processing and peripheral physiological outputs, including autonomic and neuroendocrine responses. We further identify methodological approaches to operationalize priors, precision and prediction errors, and discuss how inter-individual variability may reflect differences in computational and physiological phenotypes. This integrative review offers a mechanistic bridge between cognitive context and physiological regulation, offering a novel perspective on how endogenous predictions can be harnessed to enhance treatment efficacy and mitigate adverse outcomes in clinical practice.”

7. 7

   Clinical neuroscience and neurobiology of placebo and nocebo effects.

   International review of neurobiology (Raghuraman & Colloca)Published Oct 1, 2025Checked Oct 4, 2026

   “The neurochemical basis of placebo analgesia is also examined, with a central role identified for endogenous opioids, and additional contributions from the endocannabinoid and dopaminergic systems. Neuroimaging studies reveal brain networks and structural markers that predict placebo responsiveness. Genetic and transcriptomic insights add a molecular layer to this understanding as well as RNA expression profiles, helping to identify placebo responders. Finally, the chapter emphasizes the clinical relevance of nocebo effects, detailing how negative expectations and communication can worsen outcomes. We also discuss the clinical relevance of these mechanisms, particularly in rheumatology, where both functional and structural brain changes have been observed. It advocates for improved communication strategies, personalized consent, and ethical integration of placebo science to optimize pain care and clinical trial designs. Future research should focus on translating individual variability in placebo and nocebo effects into strategies for advancing personalized and precision medicine.”

8. 8

   The neuropharmacological basis of placebo analgesia: Mechanisms and clinical applications in the context of chronic pain.

   Pharmacological reviews (Boorman et al.)Published Dec 23, 2025Checked Oct 4, 2026

   “Finally, we discuss the range of therapeutic possibilities for placebo interventions to provide clinically relevant and meaningful pain relief to chronic pain patients, many of which could be quickly, easily, and ethically implemented into clinical practice today. SIGNIFICANCE STATEMENT: Chronic pain remains a significant global health challenge as it is often resistant to conventional treatments. This review synthesizes our current knowledge of the neurobiology of acute and chronic pain and highlights key overlaps in the mechanisms of placebo analgesia. We highlight how placebo-based strategies, including expectancy modulation, pharmacological conditioning, and open-label placebos, could be ethically integrated into clinical practice to enhance pain management. These approaches offer a promising avenue to activate endogenous pain relief systems, reduce opioid reliance, and personalize treatment for both placebo responders and nonresponders. Harnessing placebo mechanisms presents a largely underused yet promising approach to chronic pain management, with the potential to refine existing treatment strategies and address the global burden of chronic pain.”

9. 9

   Placebo Response in Randomised Controlled Trials of Systemic Therapies for Cutaneous Lupus Erythematosus: A Systematic Review and Meta-Analysis.

   Pharmaceutical medicine (Légaré et al.)Published Aug 18, 2026Checked Oct 4, 2026

   “At the primary endpoint timepoint, the pooled proportion of placebo-treated participants (n = 424 in 14 trials) achieving ≥ 50% reduction in CLASI-A (CLASI‑A50) was 42% (95% CI, 35-50). The CLASI‑A50 placebo responses were 21% at Week 8, 33% at Week 24, and reached 46% at Week 52 for up to 8 trials (n = 150 to 278). Univariate analyses revealed higher placebo responses in studies initiated after 2016, those with follow‑up durations > 24 weeks, and those requiring stable background therapy. Study start year and primary endpoint timepoint were identified as the most influential predictors of placebo response in a meta-regression analysis. A positive correlation was also observed between the proportion of White participants and CLASI-A50 placebo responses.ConclusionsThese findings suggest that limiting background therapy, shortening follow-up durations, and ensuring balanced racial representation should be further explored to reduce placebo responses in future CLE trials. Such strategies may improve signal detection and accelerate the development of effective systemic therapies for cutaneous lupus. PROSPERO record: CRD42024558334.”

10. 10

    Meta-Analysis: The Placebo Response in Modern Treatments for Cholestatic Pruritus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

    Alimentary pharmacology & therapeutics (Silveira et al.)Published Sep 24, 2026Checked Oct 4, 2026

    “We used random-effects models with Hartung-Knapp adjustment and meta-regression.ResultsThirteen trials (n = 548) were analysed. Across placebo groups, pruritus intensity decreased significantly from baseline during follow-up periods of up to 52 weeks. The pooled SMC was -0.49 (95% CI, -0.72 to -0.27) overall, and -0.57 (95% CI, -0.81 to -0.33) for moderate-to-severe pruritus. Pooled response rates were 30.0% (overall) and 27.4% (moderate-to-severe). In moderate-to-severe patients, NRS showed a significant mean reduction of -1.62, whereas the WI-NRS change (-0.65) was not statistically significant. Significant reductions occurred in the PBC-40 itch domain (-2.02) and overall score (-9.13), while 5-D Itch changes were non-significant. None of the evaluated moderators were statistically significant.ConclusionsThe magnitude of placebo-associated improvement differed across outcome instruments and may affect estimates and interpretation of treatment effects in cholestatic-pruritus trials. These findings may inform endpoint selection and assumptions used in future trial design.Trial registrationPROSPERO registration number: CRD420261385974.”