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Placebo Effect

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Last Update: November 13, 2023.


Placebos have been used in medicine since antiquity and may have been significant in improving health and quality of life when little was known about the etiology of most illnesses. Most outcomes were likely due to a placebo effect since the available treatments were unproven or have since been proven invalid. For example, snake oil and bloodletting was a common practice in the past; however, those who responded positively to those treatments likely did so because of a placebo effect. The emergence of placebo-controlled clinical trials in the 1940s reintroduced the placebo effect to the modern day. The classic article "The Powerful Placebo" by Henry Beecher highlighted the placebo effect and emphasized a need to account for it to evaluate the efficacy of a treatment modality properly. Both research and clinical settings utilize the placebo effect.[1][2]

The placebo effect is a fascinating phenomenon that occurs when a sham medical intervention causes improvement in a patient's condition because of the factors associated with the patient's perception of the intervention. Examples of placebo interventions include sugar pills, saline injections, and therapeutic rituals. Placebo pills have even been commercially available in pharmacies in the past, although medical ethics prohibits their use now.[3] Placebo effects are not limited to inert interventions. Proven effective treatments can also generate a placebo effect. Traditionally, the placebo effect was considered a nuisance variable to be controlled for; however, in light of some remarkable research demonstrating its potential to modulate treatment outcomes in recent decades, there has been an increased interest in studying this phenomenon.[4]

The placebo effect can be verbally induced by conditioning and by prior experiences that shape patient expectations. Several research studies have demonstrated the placebo effect's role as a powerful determinant of health in certain disease conditions. Migraines, joint pain, arthritis, asthma, high blood pressure, and depression are some disease conditions that are more sensitive to the placebo effect. The placebo effect is a complex phenomenon with several underlying psychological and neurobiological mechanisms. These underlying mechanisms that mediate placebo responses differ based on the medical condition and the investigated outcomes. Not all results of a placebo are beneficial; as such, placebos can also result in undesirable outcomes. Indeed, the term "nocebo effect," derived from the Latin nocere meaning "harm," is commonly used when a placebo causes an unfavorable outcome. Both placebo and nocebo effects have the same mechanisms, presumably psychogenic, but they can induce measurable changes in the body.[5]

Mechanisms of Placebo Effect

Despite dramatic advances in scientific knowledge surrounding the placebo effect, efforts to characterize this phenomenon are in their primitive stages. The complex nature of mind-body interactions, supplemented by the negative connotations associated with placebo effects in the past, has hampered understanding of the phenomenon. However, researchers are beginning to unravel the neurobiological basis of placebo effects. Classical conditioning and expectancy are 2 hypothesized psychological mechanisms that mediate the placebo effect. Classical conditioning is a form of learning where an association is formed between a stimulus and a response. The association is then remembered, affecting future experiences. Through this process of association, patients may acquire a behavior. For example, a patient may report a decrease in pain after receiving a placebo pill that looks similar to pain medication that was previously effective in easing the pain. Whenever the same stimulus is encountered in the future, the patient conditions himself by shaping expectations and shows a previously imprinted response in his memory. Learning and adaptation, therefore, drive a conditioned response.[6]

Expectations of the patient also play a vital role in mediating a placebo effect.[7] Expectations can impact the course of treatment by affecting the psychological and physiological responses to that treatment. Along with classic conditioning, expectations can be induced by verbal instructions or social learning. For example, a research subject treated for pain with a placebo in the context of a verbal cue that the placebo is an effective analgesic may shape his expectations and elicit an analgesic response. Conditioning and expectancy are often entangled mechanisms mediating placebo responses. Neurobiological mechanisms underlying the placebo effect are best characterized in placebo analgesia.

In addition to these mechanisms, several other influential elements are at work during the placebo effect. These include the patient-physician relationship, the patient's psychological state and personality, the severity of the medical condition, and environmental circumstances. The patient's genetics may also influence the degree of the placebo effect. Researchers are studying how genes influence the placebo effect in various pathways, including dopamine, opioid, serotonin, and endocannabinoid systems. Evidence also indicates that the therapeutic benefits of the placebo effect may not impact the pathophysiology of the underlying disease being studied but rather address the subjective self-appraised symptoms of the disease. Elucidating the underlying mechanisms mediating the placebo effect may benefit clinical practice and drug development.[1]

Issues of Concern

Placebo effects play a vital role in several areas. Placebo interventions primarily serve as control treatments in experimental studies, enabling researchers to determine the specific effects of a particular treatment. Clinical investigators use randomized, double-blind, placebo-controlled trials as a gold standard to validate treatments.[8] Non-blinded trials may result in a disproportionately large placebo effect. In placebo-controlled trials, the placebo effect observed may be more significant for psychological and self-rated measures relative to other more objective measures that are objective. Using a placebo in psychological and medical studies is advantageous as it helps minimize the influence of patient expectations on the outcome.

Additionally, studying the placebo effect at its core can help clinicians and researchers understand the context of how beliefs can shape various sensory and emotional perceptions. Identifying a physiological basis for the placebo effect may open doors to modulating processes that can improve mental and physical health. A clear understanding of the underlying mechanisms of placebo response with scientific work may enable clinicians to harness the placebo effect and enhance patient care.

It is challenging for medical professionals to sidestep the placebo effect and only measure the intrinsic activity of the tested treatment. Therefore, therapeutic evaluations become difficult in medical conditions sensitive to the placebo effect. Interindividual differences also complicate the studies of the placebo effect. Physicians must separate the placebo effect from the treatment. Placebo research is challenging because of a certain degree of deception.

Clinical Significance

Understanding how the placebo responses form is vital for clinical practice and can be crucial in determining the patient's therapeutic outcome. Although placebo effects frequently occur in clinical practice, they often go under-recognized. The therapeutic rituals and the psychosocial context surrounding the patient can mediate a placebo effect. The placebo effect is considered a melting pot of ideas in neuroscience. Translating the knowledge of the placebo effect to benefit the patient requires a thorough evaluation of the clinical effectiveness of the intended effect. Therefore, attempts to generate beneficial placebo responses should be made only under strict professional, legal, and ethical norms after obtaining appropriate informed consent.[9]

Placebo effects have also been a subject of ethical concern in clinical practice. Additionally, the ethical dimensions of placebo-controlled trials, such as using sham invasive procedures, withholding potential proven treatments, or deception, are issues of concern in studying the placebo effect.[10]

Nursing, Allied Health, and Interprofessional Team Interventions

An understanding of the placebo effect and a coordinated team effort must be made by prescribers, nursing staff, and pharmacists to ethically treat patients, particularly during the design and performance of placebo-controlled trials.

Review Questions


Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev. 2013 Jul;93(3):1207-46. [PMC free article: PMC3962549] [PubMed: 23899563]
BEECHER HK. The powerful placebo. J Am Med Assoc. 1955 Dec 24;159(17):1602-6. [PubMed: 13271123]
Chua SJ, Pitts M. The ethics of prescription of placebos to patients with major depressive disorder. Chin Med J (Engl). 2015 Jun 05;128(11):1555-7. [PMC free article: PMC4733778] [PubMed: 26021517]
Dodd S, Dean OM, Vian J, Berk M. A Review of the Theoretical and Biological Understanding of the Nocebo and Placebo Phenomena. Clin Ther. 2017 Mar;39(3):469-476. [PubMed: 28161116]
Colagiuri B, Schenk LA, Kessler MD, Dorsey SG, Colloca L. The placebo effect: From concepts to genes. Neuroscience. 2015 Oct 29;307:171-90. [PMC free article: PMC5367890] [PubMed: 26272535]
Jakovljevic M. The placebo-nocebo response: controversies and challenges from clinical and research perspective. Eur Neuropsychopharmacol. 2014 Mar;24(3):333-41. [PubMed: 24393653]
Basedow LA, Fischer A, Benson S, Bingel U, Brassen S, Büchel C, Engler H, Mueller EM, Schedlowski M, Rief W. The influence of psychological traits and prior experience on treatment expectations. Compr Psychiatry. 2023 Nov;127:152431. [PubMed: 37862937]
Serrano C, Rothschild S, Villacampa G, Heinrich MC, George S, Blay JY, Sicklick JK, Schwartz GK, Rastogi S, Jones RL, Rutkowski P, Somaiah N, Navarro V, Evans D, Trent JC. Rethinking placebos: embracing synthetic control arms in clinical trials for rare tumors. Nat Med. 2023 Oct 12; [PubMed: 37828359]
Meissner K, Kohls N, Colloca L. Introduction to placebo effects in medicine: mechanisms and clinical implications. Philos Trans R Soc Lond B Biol Sci. 2011 Jun 27;366(1572):1783-9. [PMC free article: PMC3130411] [PubMed: 21576135]
Barman-Aksözen J, Andreoletti M, Blasimme A. Current trials in erythropoietic protoporphyria: are placebo controls ethical? Orphanet J Rare Dis. 2023 Oct 16;18(1):325. [PMC free article: PMC10580501] [PubMed: 37845740]

Disclosure: Swapna Munnangi declares no relevant financial relationships with ineligible companies.

Disclosure: Joshua Henrina Sundjaja declares no relevant financial relationships with ineligible companies.

Disclosure: Karampal Singh declares no relevant financial relationships with ineligible companies.

Disclosure: Anterpreet Dua declares no relevant financial relationships with ineligible companies.

Disclosure: Lambros Angus declares no relevant financial relationships with ineligible companies.

Copyright © 2023, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK513296PMID: 30020668


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