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Our findings demonstrate that the participants who showed the most pain reduction with the placebo also showed the largest reductions in brain areas associated with pain construction., study provides deep dive on the neuroscience of placebo effects, posted on march 02, 2021 by amy olson.

A new meta-analysis gives the most detailed look yet at the neuroscience of placebo effects.

Tor Wager is the Diana L. Taylor Distinguished Professor in Neuroscience and co-leader of the Placebo Neuroimaging Consortium. (Photo by Eli Burakian '00)

Much of the benefit that a person gets from taking a real drug or receiving a treatment to alleviate pain is due to an individual's mindset, not to the drug itself, according to previous research. Understanding the neural mechanisms driving this placebo effect has long been a challenge. A meta-analysis published in  Nature Communications  finds that placebo treatments meant to reduce pain, known as placebo analgesia, reduce pain-related activity in multiple areas of the brain.

Previous research of this kind has relied on small-scale studies, so until now, researchers did not know whether the neural mechanisms underlying placebo effects observed to date would hold up across larger samples. This study represents the first large-scale mega-analysis, which looks at individual participants' whole brain images. It enabled researchers to look at parts of the brain they did not have sufficient resolution to see in the past. The analysis comprised 20 neuroimaging studies with 600 healthy participants. The results provide new insight on the size, localization, significance and heterogeneity of placebo effects on pain-related brain activity.

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The research reflects the work of an international collaborative effort by the Placebo Neuroimaging Consortium, led by  Tor Wager , the Diana L. Taylor Distinguished Professor in Neuroscience and Ulrike Bingel, a professor at the Center for Translational Neuro- and Behavioral Sciences in the Department of Neurology at University Hospital Essen, for which Matthias Zunhammer and Tamás Spisák at the University Hospital Essen served as co-authors. The meta-analysis is the second with this sample and builds on the team's  earlier research  using an established pain marker developed earlier by Wager's lab.

"Our findings demonstrate that the participants who showed the most pain reduction with the placebo also showed the largest reductions in brain areas associated with pain construction," explains Wager, who is also the principal investigator of Dartmouth's  Cognitive and Affective Neuroscience Lab . "We are still learning how the brain constructs pain experiences, but we know it's a mix of brain areas that process input from the body and those involved in motivation and decision-making. Placebo treatment reduced activity in areas involved in early pain signaling from the body, as well as motivational circuits not tied specifically to pain."

Across the studies in the meta-analysis, participants had indicated that they felt less pain; however, the team wanted to find out if the brain responded to the placebo in a meaningful way. Is the placebo changing the way a person constructs the experience of pain or is it changing the way a person thinks about it after the fact? Is the person really feeling less pain?

With the large sample, the researchers were able to confidently localize placebo effects to specific zones of the brain, including the thalamus and the basal ganglia. The thalamus serves as a gateway for sights and sounds and all kinds of sensory motor input. It has lots of different nuclei, which act like processing stations for different kinds of sensory input. The results showed that parts of the thalamus that are most important for pain sensation were most strongly affected by the placebo. In addition, parts of the somatosensory cortex that are integral to the early processing of painful experiences were also affected. The placebo effect also impacted the basal ganglia, which are important for motivation and connecting pain and other experiences to action. "The placebo can affect what you do with the pain and how it motivates you, which could be a larger part of what's happening here," says Wager. "It's changing the circuitry that's important for motivation."

The findings revealed that placebo treatments reduce activity in the posterior insula, which is one of the areas that are involved in early construction of the pain experience. This is the only site in the cortex that one can stimulate and invoke the sense of pain. The major ascending pain pathway goes from parts of the thalamus to the posterior insula. The results provide evidence that the placebo affects that pathway for how pain is constructed.

Prior research  has illustrated that with placebo effects, the prefrontal cortex is activated in anticipation of pain. The prefrontal cortex helps keep track of the context of the pain and maintain the belief that it exists. When the prefrontal cortex is activated, there are pathways that trigger opioid release in the midbrain that can block pain and pathways that can modify pain signaling and construction.

The team found that activation of the prefrontal cortex is heterogeneous across studies, meaning that no particular areas in this region were activated consistently or strongly across the studies. These differences across studies are similar to what is found in other areas of self-regulation, where different types of thoughts and mindsets can have different effects. For example, other work in Wager's laboratory has found that rethinking pain by using imagery and storytelling typically activates the prefrontal cortex, but mindful acceptance does not. Placebo effects likely involve a mix of these types of processes, depending on the specifics of how it is given and people's predispositions.

"Our results suggest that placebo effects are not restricted solely to either sensory/nociceptive or cognitive/affective processes, but likely involves a combination of mechanisms that may differ depending on the placebo paradigm and other individual factors," says Bingel. "The study's findings will also contribute to future research in the development of brain biomarkers that predict an individual's responsiveness to placebo and help distinguish placebo from analgesic drug responses, which is a key goal of the new collaborative research center,  Treatment Expectation ."

Understanding the neural systems that utilize and moderate placebo responses has important implications for clinical care and drug-development. The placebo responses could be utilized in a context-, patient-, and disease-specific manner. The placebo effect could also be leveraged alongside a drug, surgery, or other treatment, as it could potentially enhance patient outcomes.

Amy Olson can be reached at  [email protected]

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• Review Article
• Published: 19 June 2015

The neuroscience of placebo effects: connecting context, learning and health

• Tor D. Wager 1 &
• Lauren Y. Atlas 2  

Nature Reviews Neuroscience volume  16 ,  pages 403–418 ( 2015 ) Cite this article

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• Diseases of the nervous system
• Limbic system
• Placebo effect
• Prefrontal cortex

Placebo effects are effects of the context surrounding medical treatment. They can have meaningfully large impacts on clinical, physiological and brain outcomes.

Effects of placebo treatments are consistent across studies from different laboratories. These effects include reduced activity in brain areas associated with pain and negative emotion, and increased activity in the lateral and medial prefrontal cortex, ventral striatum and brainstem.

Placebo effects in pain, Parkinson disease, depression and emotion are enabled by engagement of common prefrontal–subcortical motivational systems, but the similarity across domains in the way these systems are engaged has not been directly tested.

Meaningfully large placebo effects are likely to require a mixture of both conceptual belief in the placebo and prior experiences of treatment benefit, which engage brain learning processes.

In some cases, placebo effects are self-reinforcing, suggesting that they change symptoms in a way that precludes extinction. The mechanisms that drive these effects remain to be uncovered, but doing so could have profound translational implications.

Placebo effects are beneficial effects that are attributable to the brain–mind responses to the context in which a treatment is delivered rather than to the specific actions of the drug. They are mediated by diverse processes — including learning, expectations and social cognition — and can influence various clinical and physiological outcomes related to health. Emerging neuroscience evidence implicates multiple brain systems and neurochemical mediators, including opioids and dopamine. We present an empirical review of the brain systems that are involved in placebo effects, focusing on placebo analgesia, and a conceptual framework linking these findings to the mind–brain processes that mediate them. This framework suggests that the neuropsychological processes that mediate placebo effects may be crucial for a wide array of therapeutic approaches, including many drugs.

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Acknowledgements

The authors thank J. Sills and E. Hitchcock for research support, the members of the Cognitive and Affective Neuroscience Lab, S. Maier and L. Watkins for helpful discussions, and L. Ruzic for help with the summary in Figure 3 . This work was funded by grants NIMH 2R01MH076136 and R01DA027794 (to T.D.W.). This work was also supported in part by the Intramural Research Program of the US National Institutes of Health's National Center for Complementary and Integrative Health.

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Supplementary information

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Supplementary information S1 (table) (PDF 214 kb)

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Neuroimaging studies included in Figure 3 (PDF 170 kb)

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The combination of all of the elements surrounding a given event that can be psychologically meaningful, including interpersonal dynamics, situational features owing to a place or location, memories, goals for the future and internal body or brain states.

Stimuli that signify the occurrence, or evoke a representation, of another stimulus or internal experience.

Coordinated responses to biologically relevant events (such as threats and opportunities) that involve changes in multiple systems, including peripheral physiology.

Deleterious outcomes (for example, an increase in pain or an increase in negative side effects) owing to beliefs about the treatment context.

Individuals who show an improvement in symptoms after receiving inert treatments (that is, placebos).

A reduction in pain that can be attributed to the treatment context.

The process of associating neutral stimuli with biologically meaningful outcomes, through which neutral stimuli may begin to induce anticipatory responses that are associated with the outcomes themselves.

A conscious, conceptual belief about the future occurrence of an event. It is a subclass of predictive processes, which may be conscious or unconscious.

Pain relief, which can be caused by many factors, including medical treatments (for example, opioid analgesia), features of the treatment context (placebo analgesia) and affective states (for example, stress-induced analgesia).

Receiving input from stimuli that can cause damage to tissues.

Endogenous, biological mechanisms for suppressing ascending nociceptive information at the level of the spinal cord.

Links between events and/or objects that exist outside conscious awareness. These links are generally created through conditioning procedures or innate (evolutionarily afforded) associations.

Processes that depend on an interpretation of the situational context and its relationship to prior information (for example, memories and rules), including interoceptive cues from the body, and which can be updated in response to verbally presented or symbolic information.

A conceptual, 'situational' pattern — inferred from a combination of sensory cues, internal motivation, interoceptive information and thoughts — that can activate scripts that guide behaviour based on the nature of the situation rather than any single cue.

Inferred causality; the process of assigning an observed effect (for example, a symptom) to an underlying cause or mechanism.

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Wager, T., Atlas, L. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci 16 , 403–418 (2015). https://doi.org/10.1038/nrn3976

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• What Is the Placebo Effect? | Definition & Examples

What Is the Placebo Effect? | Definition & Examples

Published on 17 October 2022 by Kassiani Nikolopoulou . Revised on 6 March 2023.

The placebo effect is a phenomenon where people report real improvement after taking a fake or nonexistent treatment, called a placebo . Because the placebo can’t actually cure any condition, any beneficial effects reported are due to a person’s belief or expectation that their condition is being treated.

The placebo effect is often observed in experimental design s where participants are randomly assigned to either a control or treatment group. 

Table of contents

What is a placebo, what is the placebo effect, how does the placebo effect work, placebo effect examples, downside of the placebo effect, other types of research bias, frequently asked questions about the placebo effect.

A placebo can be a sugar pill, a salt water injection, or even a fake surgical procedure. In other words, a placebo has no therapeutic properties . Placebos are often used in medical research and clinical trials to help scientists evaluate the effects of new medications.

In these clinical trials, participants are randomly assigned to either the placebo or the experimental medication. Crucially, they are not aware of which treatment they receive. The results of the two groups are compared, to see whether they differ.

In double-blind studies , researchers also don’t know who received the actual treatment or the placebo. This is to prevent them from conveying demand characteristics to participants that could influence the study’s results. This is preferred over single-blind studies, where participants do not know which group they have been placed in, but researchers do.

Placebos may help relieve symptoms like pain, fatigue, or stress-related insomnia, but they don’t actually treat a condition or cure a disease. Note that due to ethical considerations , placebos are not always used in clinical trials. For example, as it would be unethical to leave terminal cancer patients untreated, placebos aren’t used in these types of studies.

For some people, just the idea that they are taking medication makes them feel better. This occurs even if the medication is actually just a placebo. This phenomenon is known as the placebo effect . In other words, the perception of feeling better is triggered by the person’s belief in the benefit of the treatment.

When studying a new treatment, researchers must demonstrate that it is more effective than can just be explained by the placebo effect. To do so, they compare the results from those taking the new treatment with those from the placebo. In order to accurately compare the two groups, participants in clinical trials must not know whether they received the treatment or the placebo. If the two groups have the same reaction, the effectiveness of the new treatment is not supported.

Although the exact reasons for the positive effects of placebos are still being researched, a number of factors contribute to the phenomenon. These include:

• A person’s expectations or beliefs that they will get better . People who are motivated and expect their treatment to work are more likely to experience the placebo effect.
• The feeling of receiving attention and care due to participation in the study. This may reduce stress levels and trigger the body’s own pain-relieving chemicals.
• Classical conditioning , or the association people build over the years between a certain action, such as pill-taking, and positive results.
• A trusting relationship between doctors and patients or researchers and study participants from the sample . Listening to an expert you trust talk enthusiastically about a treatment can impact how you respond to it.

However, researchers do not attribute the placebo effect exclusively to psychology. A few other possible explanations include:

• Regression to the mean: When people first visit a doctor or start on a clinical trial, their symptoms might be particularly bad. But in the natural course of an illness, symptoms may subside on their own.
• Confirmation bias : Feelings of hopefulness about a new treatment may lead people to pay more attention to signs that they’re getting better and less attention to signs that they’re getting worse.

The placebo effect illustrates how the mind can trigger changes in the body.

After participants take the pill, their blood pressure and pulse rate increases, and their reaction speeds are improved.

However, when the same people are given the same pill and told it will help them relax and sleep, they report experiencing relaxation instead.

The placebo effect can also explain the popularity of non-FDA-approved products.

Evidence from published studies show that it takes extremely high doses for CBD to be effective. Documented benefits of CBD in placebo-control trials require anywhere from hundreds to thousands of milligrams per day. This is the equivalent of taking almost an entire bottle each day, depending on the concentration.

Most people take 15 milligrams or less per day, far less than what the studies deem an effective dose. The placebo effect seems to play a role here: the expectation is so high that people start to believe it’s working.

The response of people assigned to the placebo control group may not always be positive. They may experience what is called a “nocebo effect,” or a negative outcome, when taking a placebo. The same explanation applies here. If you expect a negative outcome, it’s more likely you’ll have a negative outcome.

For example, in a clinical trial, participants who are given a placebo but are told what side effects the “treatment” may cause. They may have the same side effects as the participants who are given the active treatment, only because they expect them to occur.

Cognitive bias

• Confirmation bias
• Baader–Meinhof phenomenon

Selection bias

• Sampling bias
• Ascertainment bias
• Attrition bias
• Self-selection bias
• Survivorship bias
• Nonresponse bias
• Undercoverage bias
• Hawthorne effect
• Observer bias
• Omitted variable bias
• Publication bias
• Pygmalion effect
• Recall bias
• Social desirability bias
• Placebo effect

Bias affects  the validity and reliability of your findings, leading to false conclusions and a misinterpretation of the truth. This can have serious implications in areas like medical research where new forms of treatment are being evaluated.

Placebos are used in medical research for new medication or therapies, called clinical trials. In these trials some people are given a placebo, while others are given the new medication being tested.

The purpose is to determine how effective the new medication is: if it benefits people beyond a predefined threshold as compared to the placebo, it’s considered effective.

Although there is no definite answer to what causes the placebo effect , researchers propose a number of explanations such as the power of suggestion, doctor-patient interaction, classical conditioning, etc.

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The Placebo Effect: Fake Treatment, Real Response

Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

solidcolours / Getty Images 

The mind can trick you into believing that a fake treatment has real therapeutic results, a phenomenon known as the placebo effect. In some cases, placebos can exert an influence powerful enough to mimic the effects of real medical treatments.

In this phenomenon, some people experience a benefit after the administration of an inactive lookalike substance or treatment. This substance, or placebo, has no known medical effect and can be in the form of a pill (sugar pill), injection (saline solution), or consumable liquid.

In most cases, the person does not know that the treatment they're receiving is actually a placebo. Instead, they believe they've received the real treatment. The placebo is designed to seem exactly like the real treatment, yet the substance has no actual effect on the condition it purports to treat.

The placebo effect is much more than just positive thinking , however. When this occurs, many people have no idea they are responding to what is essentially a sugar pill. Placebos are often used in medical research to help doctors and scientists discover and understand the physiological and psychological effects of new medications.

Here's why the placebo effect is important, how it happens, and why it works.

Placebo vs. Placebo Effect

It is important to note that a "placebo" and the "placebo effect" are different things. The term placebo refers to the inactive substance itself, while the term placebo effect refers to any effects of taking a medicine that cannot be attributed to the treatment itself.

Causes of the Placebo Effect

Although researchers know that the placebo effect is real, they do not yet fully understand how and why it occurs. Various factors might contribute to this phenomenon.

Hormonal Response

One possible explanation is that taking the placebo triggers a release of endorphins. Endorphins have a structure similar to that of morphine and other opiate painkillers and act as the brain's own natural painkillers.

Researchers have demonstrated the placebo effect in action using brain scans, showing that areas with many  opiate  receptors were activated in both the placebo and treatment groups. Naloxone is an opioid antagonist that blocks both natural endorphins and opioid drugs. After people received naloxone, placebo pain relief was reduced.

Conditioning

Other possible explanations include classical conditioning , or when you form an association between two stimuli resulting in a learned response. In some cases, a placebo can be paired with an actual treatment until it evokes the desired effect.  

For example, if you're regularly given the same arthritis pill to relieve stiff, sore joints, you may begin to associate that pill with pain relief. If you're given a placebo that looks similar to your arthritis pill, you may still believe it provides pain relief because you've been conditioned to do so.

Expectation

Expectations, or what we believe we will experience, have been found to play a significant role in the placebo effect. People who are highly motivated and expect the treatment to work may be more likely to experience a placebo effect.

A prescribing physician's enthusiasm for treatment can even impact how a patient responds. If a doctor seems very positive that a treatment will have a desirable effect, a patient may be more likely to see benefits from taking the drug. This demonstrates that the placebo effect can even take place when a patient is taking real medications to treat an illness.

Verbal, behavioral, and social cues can contribute to a person's expectations of whether the medication will have an effect.

• Behavioral : The act of taking a pill or receiving an injection to improve your condition
• Social : Reassuring body language, eye contact, and speech from a doctor or nurse
• Verbal : Listing to a health care provider talk positively about treatment

Genes may also influence how people respond to placebo treatments. Some people are genetically predisposed to respond more to placebos. One study found that people with a gene variant that codes for higher levels of the brain chemical dopamine are more prone to the placebo effect than those with the low-dopamine version. People with the high-dopamine version of this gene also tend to have higher levels of pain perception and reward-seeking.

The Nocebo Effect

Conversely, individuals can experience more symptoms or side effects as a response to a placebo, a response that is sometimes referred to as the " nocebo effect ." For example, a patient might report having headaches, nausea, or dizziness in response to a placebo.

The placebo effect can be used in a variety of ways, including in medical research and psychology research to learn more about the physiological and psychological effects of new medications.

In Medical Research

In medical research, some people in a study may be given a placebo, while others get the new treatment being tested. The purpose of doing this is to determine the effectiveness of the new treatment. If participants taking the actual drug demonstrate a significant improvement over those taking the placebo, the study can help support the claim for the drug's effectiveness.

When testing new medications or therapies, scientists want to know if the new treatment works and if it's better than what's already available. Through their research, they learn the sort of side effects the new treatment might produce, which patients may benefit the most, and if the potential benefits outweigh the risks.

By comparing the effects of a treatment to a placebo, researchers hope to be able to determine if the effects of the medicine are due to the treatment itself or caused by some other variable.

In Psychology Experiments

In a psychology experiment, a placebo is an inert treatment or substance that has no known effects. Researchers might utilize a placebo control group , which is a group of participants who are exposed to the placebo or fake independent variable . The impact of this placebo treatment is then compared to the results of the  experimental group .

Even though placebos contain no real treatment, researchers have found they can have a variety of both physical and psychological effects. Participants in placebo groups have displayed changes in heart rate, blood pressure, anxiety levels, pain perception, fatigue, and even brain activity. These effects point to the brain's role in health and well-being.

Benefits of Using a Placebo

The major advantage of using a placebo when evaluating a new drug is that it weakens or eliminates the effect that expectations can have on the outcome. If researchers expect a certain result, they may unknowingly give clues to participants about how they should behave. This can affect the results of the study.

To minimize this, researchers sometimes conduct what is known as a double-blind study . In this type of study, neither the study participants nor the researchers know who is getting the placebo and who is getting the real treatment. By minimizing the risk of these subtle biases influencing the study, researchers are better able to look at the effects of the drug and the placebo.

One of the most studied and strongest placebo effects is in the reduction of pain. According to some estimates, approximately 30% to 60% of people will feel that their pain has diminished after taking a placebo pill.

For example, imagine that a participant has volunteered for a study to determine the effectiveness of a new headache drug. After taking the drug, she finds that her headache quickly dissipates, and she feels much better. However, she later learns that she was in the placebo group and that the drug she was given was just a sugar pill.

Placebo Effect Outcomes

While placebos can affect how a person feels, studies suggest that they do not have a significant impact on underlying illnesses. A major review of more than 150 clinical trials involving placebos found that placebos had no major clinical effects on illnesses. Instead, the placebo effect had a small influence on patient-reported outcomes, particularly of perceptions of nausea and pain.

However, another review conducted nearly 10 years later found that in similar populations, both placebos and treatments had similar effects. The authors concluded that placebos, when used appropriately, could potentially benefit patients as part of a therapeutic plan.

• Depression : The placebo effect has been found to impact people with major depression disorder. In one study, participants who weren’t currently taking any other medication were given placebo pills labeled as either fast-acting antidepressants or placebo for one week. After the week, the researchers took PET scans and told the participants they were receiving an injection to improve mood. Participants who took the placebo labeled as an antidepressant as well as the injection reported decreased depression symptoms and increased brain activity in areas of the brain linked to emotion and stress regulation.
• Pain management : A small 2014 study tested the placebo effect on 66 people with episodic migraine, who were asked to take an assigned pill—either a placebo or Maxalt (rizatriptan), which is a known migraine medication—and rate their pain intensity. Some people were told the pill was a placebo, some were told it was Maxalt, and others were told it could be either. Researchers found that the expectations set by the pill labeling influenced the participants responses. Even when Maxalt was labeled as a placebo, participants gave it the same rating as a placebo that was labeled Maxalt.
• Symptom relief : The placebo effect has also been studied on cancer survivors who experience cancer-related fatigue. Participants received three weeks of treatment, either their regular treatment or a pill labeled as a placebo. The study found that the placebo (despite being labeled as such) was reported to improve symptoms while taking the medication and three weeks after discontinuation.

A Word From Verywell

The placebo effect can have a powerful influence on how people feel, but it is important to remember that they are not a cure for an underlying condition.

Healthcare providers aren't allowed to use placebos in actual practice without informing patients (this would be considered unethical care), which reduces or eliminates the desired placebo effect.

However, by using placebos in research, during which they don't have to inform the participant, scientists are able to get a better idea of how treatments impact patients and whether new medications and treatment approaches are safe and effective.

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Bąbel P. Classical conditioning as a distinct mechanism of placebo effects .  Front Psychiatry . 2019;10:449. doi:10.3389/fpsyt.2019.00449

Brown WA. Expectation, the placebo effect and the response to treatment .  R I Med J (2013) . 2015;98(5):19-21.

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Howick J, Friedemann C, Tsakok M, et al. Are treatments more effective than placebos? A systematic review and meta-analysis . PLoS One . 2013;8(5):e62599. doi:10.1371/journal.pone.0062599

Peciña M, Bohnert ASB, Sikora M, et al. Association between placebo-activated neural systems and antidepressant responses: Neurochemistry of placebo effects in major depression .  JAMA Psychiatry . 2015;72(11):1087. doi:10.1001/jamapsychiatry.2015.1335

Kam-Hansen S, Jakubowski M, Kelley JM, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks . Science Translational Medicine . 2014;6(218):218ra5-218ra5. doi:10.1126/scitranslmed.3006175

Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR. Open-label placebo treatment for cancer-related fatigue: A randomized-controlled clinical trial .  Sci Rep . 2018;8(1):2784. doi:10.1038/s41598-018-20993-y

Weiner IB, Craighead WE.  The Corsini Encyclopedia of Psychology, Volume 3 . Hoboken, NJ: John Wiley & Sons. 2010.

By Kendra Cherry, MSEd Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

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Colagiuri, Ben. "Expectancies in Double-Blind Randomised Placebo-Controlled Trials and Placebo-Induced Side Effects." Thesis, The University of Sydney, 2009. http://hdl.handle.net/2123/8595.

Lärkefjord, Gabriel. "Provoking Placebo : A Literature Study About Placebo Response in Nursing." Thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-322165.

Brewer, Steve T. "The Influence of Dopamine on the Magnitude and Duration of the Placebo Effect." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1905.

Fenchel, Monika, and Therese Hermansen. "Omvårdnad med placeboeffekt : En litteraturstudie om hur omvårdnadsåtgärder kan skapa placebo och nocebo." Thesis, Röda Korsets Högskola, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:rkh:diva-2563.

Johnson, Ian Thomas. "Organisation change prescriptions as placebo and side effect." Thesis, University of Hertfordshire, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275141.

Argus, Emmie, and Camilla Hägerbäck. "Omvårdnad som optimerar placeboeffekt : en litteraturöversikt om omvårdnadens möjligheter att modulera placeboeffekt." Thesis, Sophiahemmet Högskola, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:shh:diva-4004.

Chung, Valerie Yeung Shi. "The Effect of Choice on Placebo Treatment for Sleep." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/16928.

Tolusso, Danilo V. "The Placebo Effect: Influence on Recovery During Repeated Intermittent Sprints." Bowling Green State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1395323451.

Watkinson, Andrew. "The role of treatment beliefs in the placebo effect." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10041639/.

Sawkins, Kate. "The Placebo Effect of Ankle Taping on Ankle Instability." Thesis, Physiotherapy, 2007. http://hdl.handle.net/2123/3574.

Karlsson, Pontus. "Modern Research into The Placebo Effect, and its Ethical Implications." Thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-73000.

Lidstone, Sarah Christine. "Expectation, the placebo effect and Parkinson's disease : an investigation using high-resolution positron emission tomography." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/971.

Kauffman, Erin E. "The Role of Expectations on Attention Performance." Thesis, University of North Texas, 2012. https://digital.library.unt.edu/ark:/67531/metadc149618/.

Antonova, Alexandra, and Josefin Ceder. "The Placebo Effect of Eco-Labelling on Consumer Attitudes : An Explanatory Study." Thesis, Linnéuniversitetet, Institutionen för marknadsföring (MF), 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-44519.

Johal, Jaspreet. "Placebo expectancy effect of consuming psychoactive beverages on cognition and mood." Thesis, Aston University, 2015. http://publications.aston.ac.uk/27179/.

Lazzari, Fernanda. "O efeito placebo do país de origem sobre o desempenho de produtos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/72772.

Carvalho, Isnard da Silva. "Resposta a placebo em ensaios clínicos com antidepressivos: análise de características de personalidade e variáveis genéticas." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-10092008-162457/.

Magalhaes, De Saldanha D. Pedro. "The power of suggestion: placebo, hypnosis, imaginative suggestion and attention." Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209119.

Brown, Jill Anne. "The Effect of Culture and Advisor Characteristics on Treatment Outcomes." University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1429967404.

Vieira, Alessandra Helen Magacho. "AvaliaÃÃo da eficiÃncia de agentes anti-hiperestÃsicos no tratamento da hiperestesia dentinÃria." Universidade Federal do CearÃ, 2007. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=1027.

Graham, Cynthia Anne. "Treatment of premenstrual syndrome with a triphasic oral contraceptive : a double-blind placebo-controlled trial." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74262.

Haile, Anja [Verfasser], and Karin [Akademischer Betreuer] Meißner. "Neurophysiological correlates of the placebo effect in nausea / Anja Haile ; Betreuer: Karin Meißner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/124014525X/34.

Burke, Eric, and Matthew Garvin. "The Effect of Placebo on Weight Loss in Obese Patients: A Meta-analysis." The University of Arizona, 2008. http://hdl.handle.net/10150/624317.

Honoré, Margaux. "L'effet hypoalgésique de la manipulation vertébrale The regional effect of spinal manipulation on the pressure pain threshold in asymptomatic subjects: a systematic literature review How big is the effect of spinal manipulation on the pressure pain threshold and for how long does it last? – secondary analysis of data from a systematic review Wedderkopp Chiropractic & Manual Therapies volume 27, Article number: 22 (2019) What is the effect of spinal manipulation on the pressure pain threshold in young, asymptomatic subjects? A randomized placebo-controlled trial, with a cross-over design." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS131.

Pereira, Roy Jawahar Joseph. "The Chemistry of Attention: Neuro-Quantum approaches to Consciousness." Thesis, Boston College, 2011. http://hdl.handle.net/2345/3714.

Belanger, Annie. "Brain Basis of the Placebo Effect: A Proposed Integrative Model Implicating the Rostral Anterior Cingulate." Scholarship @ Claremont, 2013. http://scholarship.claremont.edu/scripps_theses/272.

Belazarė, Odeta. "Lazerio terapijos poveikis skausmui ir kaklinės stuburo dalies judėjimo funkcijai esant kaklinės stuburo dalies radikulopatijai." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2014. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2014~D_20140618_150913-89917.

Brewer, Steve T. "Factors that Contribute to Susceptibility of the Placebo/Nocebo Effect in Experimentally Induced Ischemic Arm Pain." ScholarWorks@UNO, 2011. http://scholarworks.uno.edu/td/1410.

Brackenridge, Anna. "The effect of thiazolidinediones on lipoprotein metabolism : a double blind randomised placebo controlled trial using stable isotopes to investigate the effect of pioglitazone, rosiglitazone and placebo on lipoprotein (apolipoprotein B100, VLDL, IDL and LDL) metabolism." Thesis, University of Surrey, 2005. http://epubs.surrey.ac.uk/843498/.

Faria, Vanda. "Mind really does matter : The Neurobiology of Placebo-induced Anxiety Relief in Social Anxiety Disorder." Doctoral thesis, Uppsala universitet, Institutionen för psykologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-181548.

Lee, Sandra. "Does elimination of placebo responders in double-blind placebo-controlled randomized clinical trials of SSRI antidepressants in depression influence the size of the treatment effect?, a meta-analytic evaluation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ62778.pdf.

Bojanowicz, Weronika, Lina Mattsson, and Heidi Nilsson. "Going Lean and Green on Your Mobile Machine : A Quantitative Marketing Placebo Effect Study on Eco-Labelled Technology." Thesis, Linnéuniversitetet, Institutionen för marknadsföring (MF), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-54342.

Ashirova, Margarita Olegovna. "Utilization of Placebo Response in Double-Blind Psychopharmacological Studies, Contextual Perspective." Antioch University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=antioch1445977459.

Grahl, Arvina [Verfasser], and Christian [Akademischer Betreuer] Büchel. "Experiencing Pain - The Impact of Variability on Pain Perception and the Placebo Effect / Arvina Grahl ; Betreuer: Christian Büchel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://d-nb.info/1171988427/34.

Chen, Xi. "The placebo effect and its determinants in fibromyalgia : a systematic review and meta-analysis of randomised controlled trials." Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/28254/.

Hafizi, Kaamel. "The effect of Methylphenidate on Energy Expenditure in Individuals with Obesity: A Randomized, Double-Blind, Placebo Controlled Pilot Trial." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39265.

Hellmann, Andreas [Verfasser], and Ulrike [Akademischer Betreuer] Bingel. "The effect of Open-Label-Placebo on physical functioning in chronic low back pain / Andreas Hellmann ; Betreuer: Ulrike Bingel." Duisburg, 2021. http://d-nb.info/1229350071/34.

Lussana, F. "EFFECT OF PRASUGREL IN PATIENTS WITH ASTHMA: RESULTS OF PRINA, A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,CROSS-OVER STUDY." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/264155.

Lynöe, Niels. "Theoretical and empirical aspects of the assessment and practice of alternative medicine." Doctoral thesis, Umeå universitet, Socialmedicin, 1991. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-100579.

Diss. (sammanfattning) Umeå : Umeå universitet, 1991, härtill 6 uppsatser

Medeiros, Camila Andrade Mendes. "Effect of the melatonine on sleep and the motor function in the parkinson illness: a randomized, double-blind, placebo-controlled trial." Universidade Federal do CearÃ, 2005. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=445.

Drayson, Hannah Elizabeth. "Gestalt biometrics and their applications : instrumentation, objectivity and poetics." Thesis, University of Plymouth, 2011. http://hdl.handle.net/10026.1/866.

Roderjan, Douglas Augusto. "Estudo clínico comparativo de dose única pré-operatória de 50mg de rofecoxib ou diclofenado sódico no controle da dor após tratamento endodôntico." UNIVERSIDADE ESTADUAL DE PONTA GROSSA, 2004. http://tede2.uepg.br/jspui/handle/prefix/1811.

Govender, Yolin. "Is conventional sugar-free chewing gum effective in the management of orthodontic pain associated with fixed appliances? A randomised clinical trial comparing the pain-reducing effects of sugar-free chewing gum versus a placebo medicament." University of the Western Cape, 2020. http://hdl.handle.net/11394/7536.

Kalos, Alex Peter. "The effect of azithromycin on the non-surgical treatment of peri-implantitis. A prospective double blind placebo controlled randomised clinical trial. A pilot study." Thesis, Faculty of Dentistry, 2015. http://hdl.handle.net/2123/13447.

Morral, Fernández Antoni. "Tratamiento de la fascitis plantar crónica mediante ondas de choque: ¿Influye la apariencia externa del equipo en los resultados clínicos? Ensayo clínico controlado aleatorizado." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/377450.

Bani, Fatemi Shakibasadat. "The Effect of Methylphenidate (MPH) on Appetite, Energy Intake, and Body Composition in Individuals Living with Obesity: A Randomized, Double-Blind, Placebo-Controlled Pilot Study." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38676.

Teixeira, Marcus Zulian. "Ensaio clínico quali-quantitativo para avaliar a eficácia e a efetividade do tratamento homeopático individualizado na rinite alérgica perene." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5159/tde-10062009-102220/.

Boussageon, Rémy. "L'efficacité thérapeutique : objectivité curative et effet placebo." Lyon 3, 2010. https://scd-resnum.univ-lyon3.fr/out/theses/2010_out_boussageon_r.pdf.

Albuquerque, Assis Filipe Medeiros. "Effect of preemptive analgesia on tissue levels of interleukin-1 beta and tumor necrosis factor alpha in third molar surgery: a triple-blinded randomized placebo-controlled study." Universidade Federal do CearÃ, 2016. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=16231.

Michel, Karin. "Effect of Rennie liquid TM vs Maalox liquid TM on the intragastric pH in a double-blind, randomized placebo controlled triple cross-over study in healthy volunteers /." Bern : [s.n.], 1996. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

Definition of the Placebo Effect in Medicine Essay

Introduction, placebo effect.

A placebo is an inert substance that is administered to medical patients as a form of disease management. Some patients may experience positive changes in their ailment owing to administration of the placebo. It is presumed that because disease is a combination of mental and physical factors, then the placebo plays into the psyche of the patient and causes positive results.

Medical practitioners and researchers usually create the placebo effect by making the patients believe that they may be receiving treatment for their disease, yet this is not true. Thereafter, the practitioners will reinforce the effects by reassuring the subjects that they are already seeing positive improvements in the patient’s conditions. Expectancy and false feedback combine to create improved outcomes in the patient’s health (Colagiuri & Boakes, 2009)

Price et. al. (2008) explain that the placebo effect is not just a response bias. It emanates from emotional changes in the patient. These, eventually, affect the patient’s neurological system and thus lead to noted changes in the patient’s body. Therefore, emotions play an important role.

Psychological factors may also be used to explain how body functions change. Sometimes classical conditioning occurs, thus affecting the body’s immunity, respiratory or even hormonal systems. These alterations are manifested as improvements in symptoms of the disease.

In medical research, placebos are used to demonstrate the effect of an intervention. These studies are often called randomised controlled trails. Andrews (2001) explains that placebos illustrate the usefulness of a new drug by comparing its effects with those that belong to randomized groups. If a drug has results that are weaker than the placebo, then the drug is labelled ineffective. Scholars argue that such drugs may have a mild effect on patients, but the result is not strong enough to overpower those that emanate from the placebo effect.

Consequently, the failed drug should not be made available to the public because a non-interventionist effect is more powerful. A lot of psychologists have carried out research on antidepressants and found that their effects are less effective than placebos. This has reduced use of the drugs in treatment of depression.

However, some ethical concerns exist concerning the use of placebos for drug-treatment research. By its very definition, placebos are inert, so they should create no psychological or biological change in the concerned individuals.

Therefore, medical practitioners who endorse such a strategy are using a non –scientific, hence an objectionable approach in medicine. Andrews (2001) explains that placebos should be used only when no other proven alternative exists in the market. Starting with the placebo when there are other options is unethical to this author and several others.

Additionally, problems also arise for researchers who carry out placebo-controlled trials. All scholars must get informed consent from subjects as long as they are human. This is an ethical prerogative that every one must abide by. However, telling participants about the consumption of a placebo could minimise its effects because they will already know that they are taking an inert substance.

Therefore, in order to meet this ethical standard while maintaining research blindness of the participants, most scholars tell all participants about the existence of a placebo (Colagiuri & Boakes, 2009). They also add that the participants have a 50-50 chance of belonging to a placebo group (control) or to the test group. As a result, the placebo effect will still arise as patients would peg on the hope of belonging to the test group.

The placebo effect is useful in medicine because it leads to positive outcomes; it eliminates ineffective drugs in the market and also creates positive outcomes in patients. However, researchers must address ethical concerns such as informed consent and availability of other alternatives when dealing with placebos.

Andrews, G. (2001). Placebo response in depression: Bane of research, boon to therapy . British Journal of Psychiatry , 178, 192-194. Web.

Colagiuri, B. & Boakes, R. (2010). Perceived, treatment, feedback, and placebo effects in double blind RCTs : An experimental analysis. Psychopharmacology , 208(3), 433-441. Web.

Price, D., Finiss, D. & Benedetti, F. (2008). A comprehensive review of the placebo effect: Recent advances and current thought. The Annual Review of Psychology , 59, 565-590. Web.

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1. IvyPanda . "Definition of the Placebo Effect in Medicine." February 28, 2024. https://ivypanda.com/essays/placebo-effect/.

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IvyPanda . "Definition of the Placebo Effect in Medicine." February 28, 2024. https://ivypanda.com/essays/placebo-effect/.

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Nocebo ― a placebo's evil twin

You've heard of the placebo effect: when positive thinking makes you believe your meds are working. Nocebo is the power of negative thinking. Wait, what?

"Somebody tells you 'God, you look terrible, are you going to be sick?' and then suddenly you are," said Charlotte Blease, recalling a recent bus trip in Ireland, from Belfast to Dublin. "You have this expectancy and it ramps up the symptoms."

Blease ― a health researcher at Uppsala University, Sweden, and one of the authors of "The Nocebo Effect: When Words Make You Sick" ― was  feeling nauseous with motion sickness . 

She was trying to distract herself with any other thought, and knew that if someone interrupted her, it would trigger the nocebo effect. 

"The nocebo effect [is] negative health outcomes that arise from negative expectations," Blease told DW. It can exacerbate feelings of pain, anxiety, nausea and fatigue.

Nocebo: Not placebo

The nocebo effect is the negative mirror image of the placebo effect.

Imagine a medical trial. One group is given a real medication to treat headaches. The other group gets sugar pills, without an active ingredient.

When patients in this second group report an alleviation of their headaches, doctors say the patients are experiencing  a placebo effect ― because they thought they were taking painkillers, like the patients in group one, positive thinking led to a positive outcome in their treatment.

It's a medically recognized phenomenon. And the nocebo effect is slowly gaining a similar recognition by health professionals, except it's the exact opposite: it's when negative thinking influences your outcomes, negatively.

Nocebo effect, COVID and vaccine hesitancy

During the coronavirus pandemic , researchers found that people's expectations before a  COVID-19 vaccination  could be linked to how they felt afterwards.

A team of scientists from Israel and the UK looked at a group of 756 Israeli adults over the age of 60 years. Each had received a booster shot ― a third vaccine against COVID-19 .

"We measured both vaccine hesitancy ― one's negative attitude or expectations towards the vaccine ― and the number of subjectively reported side effects," said Yaakov Hoffman, lead author of the study and a professor in the Department of Social and Health Sciences at Bar-Ilan University, Israel.

Published in the journal Scientific Reports in December 2022 , their results indicated that people who had negative expectations before their second shot were more likely to experience side effects after their third.

"The more anxiety about the vaccine, its safety and its side effects [one felt], the greater one would actually experience side effects," Hoffman told DW. 

And when the nocebo effect and vaccine hesitancy were combined, he said, it had the potential to become a vicious circle: A person who was hesitant to get vaccinated, perhaps because they had read about side effects online, would be more likely to experience side effects. Those side effects would then be recorded and reported by their doctor. That, in turn, would contribute to more media coverage about side effects, and more people feeling hesitant about vaccines… and so on, and so on.

How doctors deal with the nocebo effect

Talking to patients without triggering the nocebo effect can be a challenge.

"Doctors are obligated not to harm the patient, or to mitigate harm where possible, but they also have an obligation to tell the truth," said Blease.

In the case of a vaccine with relatively minor side effects, said Hoffman, addressing the nocebo effect head-on could make sense.

"Perhaps it's better to call a spade a spade and say, 'There's a certain percent of side effects which you are experiencing that are nocebo effects. Which means you are really experiencing them, but it doesn't necessarily signify danger,'" he said.

Hoffman stressed, however, that this was only speculation and that further research was needed to provide firm evidence.

Importance of framing health information

Other experts in the field agree the way that doctors communicate with patients can help prevent nocebo effects.

"How doctors talk to patients can influence therapy outcomes," said Ulrike Bingel, a clinical neurosciences professor who heads a pain research unit at University Hospital Essen, Germany.

"So far, communication has been mostly viewed as a feel-good issue. We need a higher awareness of how crucial it is," Bingel said.

When it comes to vaccines, for example, doctors are required to disclose any possible side effects.

But instead of rattling off a list of side effects that might scare a patient, Bingel said doctors should frame side effects as a sign that the immune system is working well.

This way, the patient might have fewer negative expectations and experience fewer or less-pronounced side effects.

Nocebo effect may be evolutionary

But how can negative ideas in our mind affect what's going on in our body?

First, it's important to understand that the nocebo effect is real. It's not a figment of a patient's ― pessimistic — imagination. 

"The nocebo and placebo effects involve complex neuroscientific processes," Bingel told DW. "When you're experiencing a nocebo effect, your body stops pumping its pain brakes. Your brain receives more brain impulses and you feel more pain."

The problem is, researchers can't explain why this happens. Not yet. But they do believe it may have something to do with our evolution.

"It was important that our ancestors learned from coming into contact with a wild animal or a poisonous plant," said Bingel. "The body [got] prepared for next time."

In other words, an early human's negative expectations would have prepared them, just in case they had to run for their lives.

"The nocebo effect could be a hangover from the past," said Blease, [but] that's a mismatch for today's modern medical environment."

Edited by: Zulfikar Abbany

The Nocebo Effect: When Words Make You Sick by Michael Bernstein, Charlotte Blease, Cosima Locher, Walter Brown. Mayo Clinic Press, March 19, 2024.

Vaccine hesitancy prospectively predicts nocebo side-effects following COVID-19 vaccination by Y.S.G. Hoffman, Y. Levin, Y. Palgi et al. Scientific Reports, 2022:  https://doi.org/10.1038/s41598-022-21434-7

Explore more

Covid-19 vaccines and the 'nocebo' effect, is there a right way to convey bad news, placebos and nocebos - new insights, related topics.

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Placebo, nocebo: Believing in the field of medicine

Karin meissner.

1 Division of Health Promotion, Coburg University of Applied Sciences and Arts, Coburg, Germany

2 Medical Faculty, Institute of Medical Psychology, Ludwig-Maximilians-University Munich, Munich, Germany

Introduction

A medical treatment is regarded efficacious if it induces a larger improvement than an inert placebo treatment. The efficacy of the active treatment is usually tested in randomized placebo-controlled trials, which are expensive but necessary because also placebo treatments are associated with large improvements. This improvement is due in part to the occurrence of a “placebo effect.”

The placebo effect is a genuine phenomenon that has been intensively researched in recent decades. A placebo treatment is by definition an inert treatment without specific ingredients, for example, a pill without pharmacologic ingredients. The placebo effect is best conceptualized as the effect of the informational context in which a (placebo or active) treatment is embedded and which consists of internal and external cues ( 1 ). External cues comprise, for example, the care provider's verbal suggestions about the effects of a treatment (e.g., “this drug is a powerful painkiller”) as well as associated non-verbal cues conveyed through body language and facial expression. External cues include also the characteristics of a particular treatment, such as its invasiveness, price, color, and the medical setting in which it is applied ( 2 ). Internal cues that play a role in the formation of placebo effects comprise pre-existing expectancies, previous experience and the affective state of a patient. Internal and external cues interact with each other, and the resulting informational context can be considered the “active ingredient” of placebo interventions ( 1 ).

Typically, the informational treatment context translates into specific treatment expectations. Positive treatment expectations are thought to trigger placebo effects, that is, beneficial effects on health-related outcomes. When negative treatment expectations arise, so-called “nocebo effects” can occur, resulting, for example, in the occurrence or aggravation of symptoms. Treatment expectations are also able to modulate the effects of active treatments ( 3 , 4 ). Negative treatment expectations are typically elicited by information about the risks of a treatment, communicated through healthcare professionals, medication leaflets, mass media, social media, and other patients ( 5 ). Nocebo effects have often been studied by analyzing the adverse events in the placebo arms in clinical trials. For example, a recent meta-analysis on the side effects of COVID-19 vaccination found that 76% of the systemic side effects after the first dose of vaccine, such as headache and fatigue, were also seen in the placebo groups, suggesting that the majority of systemic side effects were due to nocebo effects ( 6 ).

Placebo and nocebo effects can affect almost any medical symptom, including but not limited to pain, itch, nausea, depression, and motor symptoms ( 7 ). Notably, also physiological parameters, such as autonomic activity ( 8 , 9 ) and plasma proteins ( 10 ) have been shown to be affected by placebo interventions. Furthermore, placebo effects can be surprisingly system specific: According to the content of the accompanying verbal suggestion, placebo interventions specifically affected gastric activity but not cardiovascular activity ( 11 ), and blood pressure but not gastric activity ( 12 ).

Neurobiological mechanisms

The neurobiological mechanisms underlying placebo effects differ depending on the conditions and paradigms used to induce placebo effects. According to their diversity, different neurochemical systems are known to be involved, including the opioid, dopamine, cholecystokinin, and oxytocin systems ( 1 ). For example, the opioid antagonist naloxone partially blocks placebo analgesia, whereas the cholecystokinin-antagonist proglumide inhibits the nocebo hyperalgesia, suggesting the involvement of opioidergic and cholecystokininergic pathways ( 13 , 14 ). A recent meta-analysis of individual patient data from fMRI studies focusing on pain provided strong evidence for placebo-associated reductions of pain-related activity in areas linked to nociception and pain, such as the insular and thalamic regions. These changes, in turn, correlated with the magnitude of behavioral pain reduction ( 15 ). Effect sizes, however, were small, suggesting that further mechanisms underly placebo effects in pain. The meta-analysis also revealed increased activity in front-oparietal brain regions during placebo analgesia, particularly in the dorsolateral prefrontal cortex (DLPFC). This activation is thought to mirror the construction of top-down representations of context, including expectations and beliefs ( 15 ). The pivotal role of the DLPFC for placebo effects is nicely illustrated by an experimental study showing that the disruption of the DLPFC by repetitive transcranial magnetic stimulation completely blocked the placebo analgesic effect ( 16 ). In addition, the meta-analysis of placebo brain imaging studies showed a reduction of activity in brain areas related to negative affect ( 15 ). Accordingly, experimental evidence suggests that placebo effects on pain are partly mediated by reduced negative affect ( 17 , 18 ), possibly induced by cognitive re-appraisal strategies ( 15 ). A further brain region frequently activated during placebo hypoanalgesia is the ventromedial prefrontal cortex (vmPFC), an area with a prominent role in decision making, valuation, and choice ( 1 ). VmPFC activation during placebo analgesia may reflect the occurrence of a decision bias evoked by the brain in an ambiguous situation. When positive treatment expectations, for example, let expect less pain while the nociceptive stimulus actually remains the same, a prediction error occurs. The brain may resolve this prediction error by a placebo hypoalgesic effect ( 19 ).

The majority of placebo effects are likely to be due to emotional re-appraisal strategies and cognitive-evaluative processes. Only very strong placebo interventions, such as induced by classical conditioning or powerful manipulations of belief, may affect early sensory processes in a significant manner ( 1 ).

Social neuropeptides and placebo effects

Allo-grooming in animals signals intense social relationships, and it has been postulated to constitute an important evolutionary trace of the placebo effect in humans ( 20 – 22 ). Indeed, empathetic behavior can enhance placebo effects. In a randomized controlled clinical trial on irritable bowel syndrome, for example, sham acupuncture was administered by a healthcare provider who was either instructed not to talk to the patients, or to interact with patients in an empathetic manner. Addition of empathy further enhanced the magnitude of the placebo effect induced by sham acupuncture ( 23 ). Furthermore, there is experimental evidence that neuropeptides released during social interactions, including oxytocin and vasopressin, can modulate placebo hypoalgesia ( 24 , 25 ). For example, Colloca et al. ( 25 ) performed a randomized, placebo-controlled trial, in which nasal vasopressin agonists were administered to healthy volunteers before placebo analgesia was induced. The results showed that vasopressin remarkably enhanced the analgesic effect of the placebo intervention in women. By using plasma proteomics, we recently provided first evidence that the neuropeptides neurexin 1 (NRXN1), contactin-associated protein-like 4 (CNTNAP4), and reelin (RELN) play a role for the placebo effect in nausea ( 10 ). The cell adhesion molecules NRXN1 and CNTNAP4 are involved in mirror neuron activity and empathic behavior and have been linked to grooming behavior, and RELN is known to functionally interact with oxytocin. These preliminary results of an unbiased methodological approach (i.e., without a priori hypotheses) are promising, as they confirm previous findings that trust and a good doctor-patient relationship can improve medical outcomes and that such effects have a biological basis.

Open-label placebos

One of the most spectacular results of recent placebo research was the discovery that the open-label administration of placebos, where the patient is truthfully informed that the pill contains no pharmacological substance, produces a placebo effect. Since the first pilot study in patients with irritable bowel syndrome ( 26 ), numerous trials have confirmed that open-label placebos can positively affect a variety of medical conditions, including but not limited to chronic low back pain, chronic knee pain, episodic migraine, allergic rhinitis, depression, attention deficit hyperactivity disorder, and cancer-related fatigue ( 27 – 32 ). There is even evidence that the beneficial effects of open-label placebos can last for several years ( 33 ).

The mechanisms underlying the effects of open-label placebos are largely unknown. A qualitative study in patients receiving open-label placebo within a clinical trial suggested that hope, rather than expectation, may play a role ( 19 ). While expectations refer to a relatively high (assumed) likelihood of the desired outcome and represent a rather cognitive construct, hope can also be present when the likelihood is very low and has often been conceptualized as an emotional state ( 34 ). Hope can drive patients to seek treatment even from a counterintuitive intervention such as open-label placebos ( 19 ).

Kaptchuk et al. ( 19 ) suggested that prediction error processing could explain the hypoalgesic effects of both deceptive and open-label placebos: In the case of deceptive placebo administration, positive expectations primarily lower the level of predicted pain, resulting in a prediction error which is resolved by the brain through a perceived hypoalgesic effect. In the case of OLP treatment, the placebo effect could be primarily due to reduced precision of the predicted pain signal, i.e., increased uncertainty resulting from the paradox information of receiving “substances that have no active ingredients.” According to Bayesian brain models, the lowered precision of the “prior” (i.e., predicted pain) also leads to a prediction error, which in turn is resolved by a perceived hypoalgesic effect ( 19 ). Previous research on open-label placebos thus suggests that placebo effects can be elicited also in the absence of expectations, for example, when the patient is in an affective state of hope and increased uncertainty. Bayesian brain models provide a comprehensive model to explain both types of placebo effects.

The temporal dynamics of placebo effects

The multitude of mechanisms involved in placebo effects shows that this neurobiological phenomenon is complex and multifaceted. The temporal dynamics of placebo effects, however, have rarely been studied. Several authors suggested that perceived active treatment assignment may increase expectations, and thus placebo effects over time ( 35 – 37 ). In a randomized controlled trial in depression, for example, perceived treatment assignment affected symptom improvement only in the second half of the trial ( 37 ). “Active” placebo interventions that deliver non-specific sensory stimuli may be particularly useful in initiating such reinforcement processes. For example, adding electrotactile stimulation to a sham electrical nerve stimulation intervention for nausea significantly increased study participants' belief that they had received the “active” intervention. Although the magnitude of the placebo effect at the first placebo administration did not differ between the two placebo conditions, the difference in perceived treatment assignment could well lead to higher treatment expectations and thus placebo effects at subsequent placebo administrations ( 36 ). The long-lasting improvements in chronic low back pain observed during the 5-year follow-up of an open-label placebo study ( 33 ) furthermore suggests that placebo interventions can trigger strong and salient changes in patients' belief systems that may have long-term health effects. Altered cognitions, emotions and re-appraisal strategies, as well as changes in health behavior, may mediate such long-lasting placebo effects. Finally, also nocebo effects are most likely subject to changes over time, although empirical evidence in this area is limited due to ethical constraints.

Placebo effects and the process of believing

As outlined above, placebo research indicates that treatment expectations and related beliefs are not stable but are subject to change. Recently, a new area of research has emerged that aims to better understand beliefs as a function of “credition,” that is, the “process of believing” (derived from the Latin verb “credere” - “to believe”) ( 38 ). The process of believing is conceptualized as a basic brain function with neurophysiological underpinnings ( 39 ) that links past experience with predictions about the future and enables individuals to make sense of signals in the environment and ascribe personal meaning to them ( 38 ). Beliefs are the neural representations that result from the ongoing process of believing and can be reinforced and updated through learning processes. The model of credition thus shares many similarities with recent concepts in placebo research and offers a promising approach to better understand the dynamic formation of treatment-related beliefs and expectations as well as their clinical effects.

Concluding remarks

Placebo effects are not unique responses, but comprise a variety of mechanisms that differ between conditions and research paradigms. They rely on the brain's ability to actively integrate contextual information with prior experiences, conceptual knowledge, beliefs, and emotions, resulting in brain responses that promote health and well-being ( 1 ). There is considerable overlap with emerging concepts such as predictive coding and the process of believing. Integrating these concepts into placebo research could provide a better understanding of the fluid nature of beliefs and expectations and their role in maintaining health and combating disease.

Author contributions

The author confirms being the sole contributor of this work and has approved it for publication.

This paper was funded by Rüdiger Seitz, via the Volkswagen Foundation, Siemens Healthineers, and the Betz Foundation. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Conflict of interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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An Ozempic Relative Slowed Parkinson’s Disease in a Small Study

The trial lasted only one year but offered embers of hope to some experts.

By Gina Kolata

In 1817, James Parkinson expressed a hope about the disease that is named after him. He thought that at some point there would be a discovery and “the progress of the disease may be stopped.”

Now, nearly 200 years since Parkinson expressed his hope, and after four decades of unsuccessful clinical trials, a group of French researchers reports the first glimmer of success — a modest slowing of the disease in a one-year study.

And the drug they used? A so-called GLP-1 receptor agonist, similar to the wildly popular drugs Ozempic, for diabetes, and Wegovy, for obesity .

As many as half a million Americans have been diagnosed with Parkinson’s disease, a degenerative brain illness second only to Alzheimer’s in prevalence.

Symptoms include tremors, slowness and stiffness, and difficulty with balance. That can lead to difficulty walking, talking and swallowing. Many patients develop dementia.

But there are drugs and treatments, like deep brain stimulation, that help, said Dr. David Standaert, a Parkinson’s expert at the University of Alabama at Birmingham.

“You will look and feel much better,” Dr. Standaert said. The problem is that the disease inexorably progresses.

“When you get five or 10 years into Parkinson’s, a lot of problems emerge,” he said.

The new study gave researchers cautious hope.

It is not a slam dunk, but it is “nibbling at the edges of disease modification,” said Dr. Michael S. Okun, a Parkinson’s disease expert at the University of Florida who was not involved in the study.

Dr. Standaert, who also was not involved in the trial, said it was “a really encouraging step forward.”

“There were so many trials that showed no success,” he added.

Dr. Hyun Joo Chu at the National Institute of Neurological Disorders and Stroke said the study was “very important” but cautioned that it was a Phase 2 study, designed to test a hypothesis but not big enough or long enough to be definitive.

“There are many many examples of very promising Phase 2 trials,” she said. “People get very excited, and then it doesn’t pan out.”

The paper , published Wednesday in The New England Journal of Medicine, involved 156 people with early Parkinson’s disease who were randomly assigned to take the drug — lixisenatide, made by Sanofi — or a placebo and followed for a year. The trial was funded by the French government and Cure Parkinson’s, a British charity.

During that time, Parkinson’s symptoms like tremor, stiffness, slowness and balance worsened in those taking the placebo but not in those taking the drug.

The drug also caused gastrointestinal side effects like nausea and vomiting in more than half of the participants, perhaps because the researchers started with the highest dose instead of gradually increasing it as is done with GLP-1 drugs like Ozempic or Wegovy. In a third of participants, whose side effects became intolerable, the researchers halved their dose.

For the European researchers, led by Dr. Wassilios G. Meissner of the University of Bordeaux and Dr. Olivier Rascol of the University of Toulouse, it made sense to see if a GLP-1 drug could slow Parkinson’s.

Studies have repeatedly found that people with Type 2 diabetes are at increased risk for Parkinson’s disease, Dr. Rascol said. But that increased risk declines in those who take a GLP-1 drug to treat their diabetes.

He added that post-mortem studies of brain tissue from Parkinson’s patients had found abnormalities related to insulin resistance, even though the patients did not have diabetes. GLP-1 drugs treat insulin resistance.

Finally, he said, GLP-1 drugs can attach to proteins in neurons, so they may affect the brain in different ways.

The French group says it wants to do a larger and longer study if it can get funding, and if it can get more of the drug. At the start of this year, Sanofi withdrew the drug in the U.S. and said it has started withdrawing it worldwide. The move was made for business reasons, a company spokesman said.

But what about Parkinson’s patients who have diabetes or obesity? They are eligible for a GLP-1 drug. Should they take one in the hopes it will slow their Parkinson’s?

“It is reasonable” for them to take the drugs, said Dr. Standaert, who wrote an editorial accompanying the study.

But, he cautioned, they will not be able to tell if the drugs have caused their disease progression to slow because they won’t know what would have happened if they had not taken it.

“We won’t learn anything from it,” he said.

Gina Kolata reports on diseases and treatments, how treatments are discovered and tested, and how they affect people. More about Gina Kolata

A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer's Disease

• PMID: 38562783
• PMCID: PMC10984053
• DOI: 10.1101/2024.03.20.24304638

Background: Amyloid beta protein (Aβ) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.

Methods: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) with positive CSF biomarkers were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13 C 6 -leucine, and CSF sampling for 36 hours. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.

Results: From June 2017 to December 2021, 19 participants were enrolled, in dose cohorts (6 active: 2 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs placebo groups.

Conclusions: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.

Trial registration: NCT02925650 on clinicaltrials.gov.

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Associated data.

• ClinicalTrials.gov/NCT02925650

Food & Function

Effect of the probiotic weissella cibaria cms1 on the immune response and the oral microbiome: a randomized, double-blind, placebo-controlled, parallel study †.

* Corresponding authors

a Department of Food Science and Biotechnology, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea E-mail: [email protected] Fax: +82-2-976-6460 Tel: +82-2-970-6740

b Department of Nano Bio Engineering. Seoul National University of Science and Technology, Seoul 01811, Republic of Korea

c Department of Family Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea

The oral cavity connects the external environment and the respiratory and digestive systems, and the oral microbial ecosystem is complex and plays a crucial role in overall health and immune defense against external threats. Recently, the potential use of probiotics for disease prevention and treatment has gained attention. This study aimed to assess the effect of Weissella cibaria CMS1 ( W. cibaria CMS1) consumption on the oral microbiome and immune function in healthy individuals through a 12-week clinical trial. This randomized, double-blind, placebo-controlled, parallel trial enrolled 90 healthy subjects. The consumption of W. cibaria CMS1 significantly increased salivary immunoglobulin A ( p = 0.046) and decreased tumor necrosis factor-α (TNF-α) levels ( p = 0.008). Analysis of the oral microbiota revealed changes in beta diversity, increased abundance of Firmicutes and Actinobacteria, and decreased abundance of Bacteroidetes and Fusobacteria after 12 weeks of consuming W. cibaria CMS1. Significant increases in various strains, including Lactobacillales, Bacilli, Streptococcaceae, Streptococcus, and Firmicutes, were observed in the W. cibaria CMS1 group after 12 weeks of intake. Additionally, Fusobacteriia Fusobacteriales Fusobacteriaceae and Fusobacteriia Fusobacteriales Fusobacteriaceae Fusobacterium exhibited a positive correlation with TNF-α. These findings demonstrate the positive effect of W. cibaria CMS1 on the oral environment and immune function.

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Effect of the probiotic Weissella cibaria CMS1 on the immune response and the oral microbiome: a randomized, double-blind, placebo-controlled, parallel study

M. J. Park, S. Park, K. J. Kim, B. Oh and J. Y. Kim, Food Funct. , 2024, Advance Article , DOI: 10.1039/D4FO00195H

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