Molecular classification of the placebo effect in nausea

ABSTRACTNumerous studies have shown that the mere expectation improvement can alleviate symptoms in various conditions. These ‘placebo effects’ often include reliable changes in central and peripheral organ systems. Here, we tested for the first time whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 healthy participants were exposed to a 20-min vection stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and gastric activity could be verified. Using state-of-the-art proteomics, 74 differentially regulated proteins were identified in placebo-treated participants as compared to no-treatment controls. Gene ontology (GO) enrichment analyses of these proteins revealed acute-phase proteins as well as microinflammatory proteins to be reliable plasma correlates of the placebo effect. Regression analyses showed that day-adjusted scores of nausea indices in the placebo group were predictable by the identified GO protein signatures. We next identified specific plasma proteins, for which a significant amount of variance could be explained by the experimental factors ‘sex’, ‘group’, ‘nausea’, or their interactions. GO enrichment analyses of these proteins identified ‘grooming behavior’ as a prominent hit, based on ‘neurexin-1’ (NRXN1) and ‘contactin-associated protein-like 4’ (CNTNAP4). Finally, Receiver Operator Characteristics (ROC) allowed to identify specific plasma proteins differentiating placebo responders from non-responders. These comprised immunoglobulins (IGHM, IGKV1D-16, IGHV3-23, IGHG1) and MASP2, related to regulation of complement activation, as well as proteins involved in oxidation reduction processes (QSOX1, CP TXN). This proof-of-concept study indicates that plasma proteomics are a promising tool to identify molecular correlates and predictors of the placebo effect in humans.

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Choice and the Placebo Effect: A Meta-analysis

Annals of Behavioral Medicine ◽

10.1093/abm/kaab111 ◽

2022 ◽

Author(s):

Biya Tang ◽

Kirsten Barnes ◽

Andrew Geers ◽

Evan Livesey ◽

Ben Colagiuri

Keyword(s):

Placebo Effect ◽

Effect Size ◽

Meta Analysis ◽

Placebo Treatment ◽

Placebo Effects ◽

Sleep Difficulty ◽

Clinical Scenarios ◽

Health Related ◽

Choice Frequency ◽

Improve Patient

Abstract Background Choice has been proposed as a method of enhancing placebo effects. However, there have been no attempts to systematically evaluate the magnitude, reliability, and moderators of the influence of choice on the placebo effect. Purpose To estimate the effect size of choice on the placebo effect and identify any moderators of this effect. Methods Web of Science, PsycINFO, EMBASE, and PubMed were systematically searched from inception to May 2021 for studies comparing placebo treatment with any form of choice over its administration (e.g., type, timing) to placebo treatment without choice, on any health-related outcome. Random-effects meta-analysis was then used to estimate the effect size associated with the influence of choice on the placebo effect. Meta-regression was subsequently employed to determine the moderating effect of factors such as type of choice, frequency of choice, and size of the placebo effect without choice. Results Fifteen independent studies (N = 1,506) assessing a range of conditions, including pain, discomfort, sleep difficulty, and anxiety, met inclusion criteria. Meta-analysis revealed that choice did significantly enhance the placebo effect (Hedges’ g = 0.298). Size of the placebo effect without choice was the only reliable moderator of this effect, whereby a greater effect of choice was associated with smaller placebo effects without choice. Conclusions Treatment choice can effectively facilitate the placebo effect, but this effect appears more pronounced in contexts where the placebo effect without choice is weaker. Because most evidence to date is experimental, translational studies are needed to test whether providing choice in clinical scenarios where placebo effects are weaker may help boost the placebo effect and thereby improve patient outcomes.

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Choice, Expectations, and the Placebo Effect for Sleep Difficulty

Annals of Behavioral Medicine ◽

10.1093/abm/kaz030 ◽

2019 ◽

Cited By ~ 1

Author(s):

Valerie Yeung ◽

Louise Sharpe ◽

Andrew Geers ◽

Ben Colagiuri

Keyword(s):

Placebo Effect ◽

Sleep Onset ◽

Sleep Time ◽

Placebo Treatment ◽

Sleep Onset Latency ◽

Placebo Effects ◽

Single Session ◽

Sleep Difficulty ◽

Insomnia Severity ◽

Perceived Sleep Quality

Abstract Background Choice has been found to facilitate placebo effects for single-session treatments where standard placebo treatment without choice failed to elicit a placebo effect. However, it is unknown whether choice can enhance the placebo effect for treatments occurring over a period of days and where placebo effects are readily established without choice. Purpose We tested whether single or daily choice between two (placebo) treatments enhanced the placebo effect for sleep difficulty relative to no choice and no treatment over a 1 week period. Methods One-hundred and seventeen volunteers self-identifying with sleep difficulty were recruited under the guise of a hypnotic trial and randomized to one of the four groups. Self-reported outcomes included insomnia severity, fatigue, total sleep time (TST), sleep onset latency (SOL), perceived sleep quality (PSQ), and treatment satisfaction. Objective TST and SOL were assessed in a subsample via actigraphy. Results Overall, placebo treatment significantly improved insomnia severity, fatigue, and PSQ, confirming a placebo effect on these outcomes. However, both traditional and Bayesian analysis indicated no benefit of choice on the placebo effect on any sleep outcome. Mediation analysis of the overall placebo effect indicated that expectancy completely mediated the placebo effects for insomnia severity and PSQ and partially mediated the placebo effect for fatigue. Conclusion These findings suggest that choice does not enhance the placebo effect over longer treatment periods (up to 7 days) when placebo effects are readily established without choice. As such, any benefit of choice on placebo effects may be confined to quite specific circumstances. Clinical Trials Registration ACTRN12618001199202.

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Placebo treatment facilitates social trust and approach behavior

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1800779115 ◽

2018 ◽

Vol 115 (22) ◽

pp. 5732-5737 ◽

Cited By ~ 11

Author(s):

Xinyuan Yan ◽

Xue Yong ◽

Wenhao Huang ◽

Yina Ma

Keyword(s):

Placebo Effect ◽

Social Trust ◽

Real Life ◽

Well Being ◽

Placebo Treatment ◽

Placebo Effects ◽

Approach Behavior ◽

Social Species ◽

Show Evidence ◽

And Behavior

Placebo effect refers to beneficial changes induced by the use of inert treatment, such as placebo-induced relief of physical pain and attenuation of negative affect. To date, we know little about whether placebo treatment could facilitate social functioning, a crucial aspect for well-being of a social species. In the present study, we develop and validate a paradigm to induce placebo effects on social trust and approach behavior (social placebo effect), and show robust evidence that placebo treatment promotes trust in others and increases preference for a closer interpersonal distance. We further examine placebo effects in real-life social interaction and show that placebo treatment makes single, but not pair-bonded, males keep closer to an attractive first-met female and perceive less social anxiety in the female. Finally, we show evidence that the effects of placebo treatment on social trust and approach behavior can be as strong as the effect of intranasal administration of oxytocin, a neuropeptide known for its function in facilitating social cognition and behavior. The finding of the social placebo effect extends our understanding of placebo effects on improvement of physical, mental, and social well-being and suggests clinical potentials in the treatment of social dysfunction.

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Placebos and Movies: What Do They Have in Common?

Current Directions in Psychological Science ◽

10.1177/09637214211003892 ◽

2021 ◽

pp. 096372142110038

Author(s):

Fabrizio Benedetti

Keyword(s):

Everyday Life ◽

Common Sense ◽

Placebo Effect ◽

Psychological Factors ◽

General Framework ◽

Physiological Responses ◽

Therapeutic Effects ◽

Physiological Effects ◽

Placebo Effects ◽

What Matters

Placebos are fake therapies that can induce real therapeutic effects, called placebo effects. It goes without saying that what matters for inducing a placebo effect is not so much the fake treatment itself, but rather the therapeutic ritual that is carried out, which is capable of triggering psychobiological mechanisms in the patient’s brain. Both laypersons and scientists often accept the phenomenon of the placebo effect with reluctance, as fiction-induced clinical improvements are at odds with common sense. However, it should be emphasized that placebo effects are not surprising after all if one considers that fiction-induced physiological effects occur in everyday life. Movies provide one of the best examples of how fictitious reality can induce psychological and physiological responses, such as fear, love, and tears. In the same way that a horror movie induces fear-related physiological responses, even though the viewer knows everything is fake, so the sight of a syringe may trigger the release of pain-relieving chemicals in the patient’s brain, even if the patient knows there is a fake painkiller inside. From this perspective, placebos can be better conceptualized as rituals, actions, and fictions within a more general framework that emphasizes the power of psychological factors in everyday life, including the healing context.

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Reactivity in social scientific experiments: what is it and how is it different (and worse) than a Placebo effect?

European Journal for Philosophy of Science ◽

10.1007/s13194-021-00350-z ◽

2021 ◽

Vol 11 (2) ◽

Author(s):

María Jiménez-Buedo

Keyword(s):

Experimental Data ◽

Conceptual Framework ◽

Placebo Effect ◽

Placebo Effects ◽

Causal Inferences ◽

Scientific Experiments ◽

Social Scientific ◽

The Many ◽

Definition Of ◽

In Virtue Of

AbstractReactivity, or the phenomenon by which subjects tend to modify their behavior in virtue of their being studied upon, is often cited as one of the most important difficulties involved in social scientific experiments, and yet, there is to date a persistent conceptual muddle when dealing with the many dimensions of reactivity. This paper offers a conceptual framework for reactivity that draws on an interventionist approach to causality. The framework allows us to offer an unambiguous definition of reactivity and distinguishes it from placebo effects. Further, it allows us to distinguish between benign and malignant forms of the phenomenon, depending on whether reactivity constitutes a danger to the validity of the causal inferences drawn from experimental data.

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Endotoxemia and hepatic injury in a rodent model of hindlimb unloading

Journal of Applied Physiology ◽

10.1152/japplphysiol.00302.2003 ◽

2003 ◽

Vol 95 (4) ◽

pp. 1656-1663 ◽

Cited By ~ 17

Author(s):

C. A. Rivera ◽

M. H. Tcharmtchi ◽

L. Mendoza ◽

C. W. Smith

Keyword(s):

Acute Phase ◽

Hepatic Injury ◽

Acute Phase Proteins ◽

Elevated Serum ◽

Hindlimb Unloading ◽

Low Grade ◽

Systemic Blood ◽

Blood Samples ◽

Amyloid A ◽

Organ Systems

Hindlimb unloading (HU) is known to induce physiological alterations in various organ systems that mimic some responses observed after exposure to microgravity. In the present study, the effects of up to 4 wk of HU on the liver were assessed in male Wistar rats and two mouse strains: endotoxin-sensitive C57BL/6 mice and endotoxin-resistant C3H/HEJ mice. Plasma levels of endotoxin, a known stimulator of hepatic injury, were measured in portal and systemic blood samples. Endotoxin was elevated by ∼50% in portal blood samples of mice and rats but was not detectable in systemic blood. This low-grade portal endotoxemia was associated with hepatic injury in rats and C57BL/6 mice as indicated by inflammation and elevated serum transaminase activities. Blood levels of the cytokine TNF-α were increased by ∼50% in C57BL/6 mice; no significant elevation of this cytokine was detected in rats. Messenger RNA levels of the acute-phase proteins serum amyloid A, haptoglobin, and lipopolysaccharide binding protein were significantly enhanced after 3 wk of HU in endotoxin-sensitive rodents. In contrast, no histological changes or significant increases in serum enzyme activity were detected after HU in C3H/HEJ mice despite portal endotoxin levels of 222 ± 83.4 pg/ml. At the 3-wk time point, expression of acute-phase proteins was not elevated in C3H/HEJ mice; however, expression after 4 wk of HU was similar to endotoxin-sensitive rodents. In conclusion, these findings indicate that HU induced mild portal endotoxemia, which contributed to the observed hepatic injury in endotoxin-sensitive rodents.

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Pemeriksaan Laboratorium sebagai Indikator Sepsis dan Syok Septik

JURNAL BIOMEDIK (JBM) ◽

10.35790/jbm.11.1.2019.23204 ◽

2019 ◽

Vol 11 (1) ◽

pp. 1

Author(s):

Diana S. Purwanto ◽

Dalima A.W. Astrawinata

Keyword(s):

Septic Shock ◽

Acute Phase ◽

Laboratory Tests ◽

Acute Phase Proteins ◽

Cell Surfaces ◽

Tissue Hypoperfusion ◽

Organ Systems ◽

Almost All ◽

Sepsis And Septic Shock ◽

Bacterial Products

Abstract: The complexity of the pathogenesis and pathophysiology of sepsis involves almost all types of cells, tissues, and organ systems. Therefore, there are numbers of laboratory tests that can be used as biomarkers of sepsis and septic shock. Some widely used biomarkers are divided into groups of bacterial products, acute phase proteins, tissue hypoperfusion, coagulation mediators, cell surfaces, and cytokines.Keywords: sepsis, septic shock, biomarkersAbstrak: Kompleksnya patogenesis dan patofisiologi sepsis melibatkan hampir semua jenis sel, jaringan, dan sistem organ. Oleh karena itu, terdapat banyak parameter laboratorik yang dapat dijadikan biomarker sepsis dan syok septik. Berbagai biomarker yang banyak digunakan terbagi dalam kelompokan produk bakteri, protein fase akut, hipoperfusi jaringan, mediator koagulasi, permukaan sel, dan sitokin.Kata kunci: sepsis, syok septik, biomarker

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Mental and behavioural disorders

10.1093/oso/9780198843177.003.0012 ◽

2020 ◽

pp. 333-365

Author(s):

Fabrizio Benedetti

Keyword(s):

Clinical Trials ◽

Mental Disorders ◽

Placebo Effect ◽

Crucial Role ◽

Drugs Of Abuse ◽

Placebo Treatment ◽

Brain Regions ◽

Psychotherapeutic Interventions ◽

Psychotherapeutic Outcome ◽

The Brain

In this chapter some mental disorders are described. For example, in depression, fluoxetine treatment and a placebo treatment affect similar brain regions. In anxiety, patients’ expectations play a crucial role, as covert (unexpected) administration of anti-anxiety drugs is less effective than overt (expected) administration. The disruption of prefrontal executive control in Alzheimer’s disease decreases the magnitude of placebo responses. In addition, expectations appear to be particularly important when associated with the effects of drugs of abuse. Placebo effects appear to be powerful in psychotherapy as well, and the brain areas involved in the psychotherapeutic outcome are different from those involved in the placebo effect. As clinical trials for psychotherapeutic interventions represent a major problem, new recommendations are presented.

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Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice

BMJ ◽

10.1136/bmj.m1668 ◽

2020 ◽

pp. m1668 ◽

Cited By ~ 1

Author(s):

Ted J Kaptchuk ◽

Christopher C Hemond ◽

Franklin G Miller

Keyword(s):

Chronic Pain ◽

Clinical Practice ◽

Predictive Coding ◽

Evidence Theory ◽

Placebo Treatment ◽

Placebo Effects ◽

Unified Framework ◽

Open Label ◽

Double Blind ◽

Bayesian Brain

ABSTRACTDespite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights “predictive coding” and “bayesian brain” as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.

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