Placebo effect Automatic translate

The placebo effect is a physiologically measurable improvement in health that occurs after the use of a pharmacologically neutral substance or procedure lacking a specific therapeutic effect. It is observed not only in suggestible patients and is not reducible to self-deception — it involves real neurochemical processes, which modern science is increasingly describing.

Origin of the term

The word "placebo" comes from Latin and literally means "I will please" or "I will be pleasing." In medieval liturgical tradition, it was used to describe the funeral hymn sung by hired mourners at funerals — hence the expression’s connotation of something insincere, done for show.

The concept entered medical parlance much later. In the 18th century, Scottish obstetrician William Smellie proposed giving women in labor "some harmless and pleasant counterfeit medicine" to distract them from pain, using the word "placebo." This is one of the first documented examples of the targeted use of an inert substance for therapeutic purposes.

Early evidence and the Perkins extractors

The first documented case of what is now considered the placebo effect is often attributed to the invention of the American physician Elisha Perkins. In the late 18th century, he sold metal rods that supposedly "pulled out" pain, and patients actually reported relief. It was later discovered that wooden replicas of these rods were just as effective as the metal ones.

In 1799, Scottish physician John Haygarth conducted one of the first controlled experiments comparing the effects of real and counterfeit Perkins rods, and found identical results in both groups — thus demonstrating that the relief was due to the patients’ anticipation, not the properties of the metal.

Scientific recognition

Work by Henry Beecher

Systematic scientific understanding of the placebo effect began in the mid-20th century. In 1955, Harvard anesthesiologist Henry Beecher published a review of 15 controlled trials involving 1,082 patients and concluded that placebos produce a therapeutically significant effect in an average of 35.2% of cases. This article became a turning point: it was after this review that the placebo concept became firmly established in clinical trial protocols.

However, Beecher’s methodology has drawn criticism. Patients receiving a placebo were not compared with a group that received no treatment at all. This meant that some of the observed improvements could be explained by the spontaneous course of the disease, regression to the mean, or other nonspecific factors, rather than the effect of the placebo itself.

Criticism and rethinking

In 2001, Danish researchers Asbjørn Hróbjartsson and Peter Gøtzsche published a meta-analysis covering over 150 trials and found that, for objective measurable indicators such as blood pressure or cholesterol levels, placebo was virtually indistinguishable from no treatment. Statistically significant effects were observed primarily in trials in which pain or other symptoms were assessed by patients themselves using subjective scales.

This distinction — between subjective well-being and objective biomarkers — has become central to contemporary discussions of the placebo effect. It should neither be overestimated nor denied: it is a real, but specifically limited, phenomenon.

Neurobiological mechanisms

Modern neuroscience has accumulated compelling evidence that placebos trigger tangible processes in the brain. These aren’t just "imaginary improvements" — the changes are documented using positron emission tomography (PET) and functional MRI (fMRI).

Endogenous opioid system

One of the most well-studied mechanisms is the activation of the brain’s intrinsic opioid system. In studies using PET tracers that bind to μ-opioid receptors, administering a placebo while anticipating analgesia resulted in decreased availability of these receptors — direct evidence of the release of endogenous opioids.

In 2007, Thor Wager and colleagues demonstrated that placebo increases endogenous opioid neurotransmission in several regions rich in μ-receptors: the periaqueductal gray (PAG), dorsal raphe, orbitofrontal cortex, amygdala, and anterior cingulate cortex. The PAG is a key node in descending pain control, so activation of this network explains placebo-induced analgesia at the systemic level.

Dopamine system

In addition to the opioid system, the dopamine system is also involved. In Parkinson’s disease, where dopaminergic neurons degenerate, a placebo can activate the release of endogenous dopamine in the striatum, resulting in a subjective improvement in motor function. This fact is particularly significant: the improvement is observed in a disease in which dopamine deficiency is the underlying cause.

In the nucleus accumbens (NAc), placebo causes an increase in both activity (as measured by fMRI) and dopamine levels (as measured by PET). This region is closely linked to the reward system, motivation, and positive emotional states.

The prefrontal cortex and expectation

The prefrontal cortex (PFC) also plays a significant role. Its activity during placebo treatment correlates with the strength of the subsequent analgesic effect. It is believed that the PFC forms the cognitive context of expectancy — the "conviction" that the treatment will work — and translates it into descending modulatory signals.

Placebo-induced neurochemical changes are not a uniform phenomenon: they manifest differently in different brain regions within the same individual. Some subjects show a strong response in the PFC but a weak one in the striatum, and vice versa. This suggests that the placebo effect is mediated by several independent systems.

Psychological mechanisms

Expectation and conditioning

Two mechanisms are most often cited in scientific explanations: expectancy and classical conditioning. Expectancy is a cognitive set: a person believes the treatment will help, and their brain begins to prepare for it in advance. Conditioning works differently: a patient who has already received the real drug maintains the learned response when switching to a placebo — similar to Pavlov’s conditioned reflex.

Both mechanisms operate simultaneously and sometimes reinforce each other. This is especially true in chronic pain, where the history of previous interactions with medicine "trains" the nervous system.

Anxiety reduction and therapeutic ritual

The role of the treatment ritual itself shouldn’t be underestimated. The doctor’s attention, the confidential conversation, the attractive pill packaging, the white coat — all this creates a context of safety, reduces anxiety, and has an anxiolytic effect in itself. Anxiety heightens the perception of pain; its reduction already provides noticeable relief.

This is why an "open" placebo — when the patient knows they’re receiving a dummy — still works, even though the expectation should seemingly disappear. The context of care and therapeutic rituals remain effective regardless of whether the drug’s ingredients are disclosed.

Open placebo

One of the most unexpected areas of modern research has been the study of the so-called open -label placebo (OLP) – when patients are honestly told that they are receiving a pharmacologically inactive substance, and it still has a therapeutic effect.

Evidence base

A 2021 systematic review and meta-analysis found that open-label placebo compared with no treatment produced a standardised mean difference (SMD) of 0.72 (95% CI 0.39–1.05, p < 0.0001) – an effect size larger than many active treatments in certain conditions.

By comparison, the similar value for a hidden (regular) placebo, according to a larger meta-analysis, is only SMD = 0.23. This means that an open placebo is, on average, more effective than a hidden one — a result that contradicts the intuitive notion that the placebo effect relies solely on patient ignorance.

An updated meta-analysis from 2025, which synthesized data from 72 trials, confirmed that open-label placebo is effective in both clinical and non-clinical settings, although the effect is more pronounced in clinical settings. The SMD for subjective measures was 0.39, and for objective measures, 0.09.

Mechanism of action in open placebo

Expectation and the "justifying narrative" appear to play a key role here. If a doctor or researcher doesn’t simply say, "It’s a dummy," but explains how exactly a placebo can activate the body’s own resources, the response is more pronounced. This isn’t deception: the narrative about neurobiological mechanisms is inherently accurate, and it’s precisely this narrative that heightens expectation.

Studies have shown that the type of control group (waiting list, no treatment, standard treatment) influences the size of the observed effect, which is important to consider when interpreting the results.

Factors that enhance or weaken the effect

Several variables modulate the magnitude of the placebo effect. These include the patient, the drug, and the context of the interaction.

Characteristics of the "drug":

• Large tablets work better than small ones.
• Injections provide a more pronounced effect than tablets.
• "Expensive" drugs are perceived as more effective.
• On average, capsules are more effective than homogeneous tablets.
• Red or orange tablets are associated with a stimulating effect, blue ones with a calming effect.

Interaction characteristics:

• The doctor’s clear, warm communication style enhances the effect.
• Longer consultations produce better results.
• Statements like “this will help you a lot” are more effective than neutral ones.

Patient characteristics:

• Higher anxiety often means a more pronounced placebo effect in painful conditions.
• On the contrary, the tendency towards somatosensory amplification (increased sensitivity to bodily sensations) weakens placebo analgesia.
• Belief in the effectiveness of treatment is one of the predictors of response.

Nocebo effect

The mirror image of the placebo effect is the nocebo (from the Latin nocebo, meaning "I harm"). This is a worsening of the condition that occurs after the use of a neutral substance, in the presence of negative expectations or anxiety regarding the treatment.

Asymmetry of nocebo and placebo

Studies in healthy volunteers show that negative expectations have a stronger and more persistent effect on pain perception than positive ones. According to data published in 2025, the nocebo effect persisted and increased over the course of a week-long observation period, while placebo analgesia faded more quickly.

The authors attribute this asymmetry to evolutionary logic: avoiding a threat is biologically more important than anticipating a reward. A danger signal must be more persistent for the organism to respond to it even with weak reinforcement.

The clinical significance of nocebo

In clinical practice, the nocebo effect manifests itself as adverse reactions to indifferent medications or as a worsening of symptoms after being warned about possible side effects. This is well documented: patients who were given a detailed explanation of the possible side effects of statins report muscle pain significantly more often than those who were not warned about them, even when both groups receive the same treatment.

Nocebo and placebo mechanisms appear not to be simple inversions of the same process: they are supported by partially different neural pathways and exhibit different extinction dynamics.

Placebo in clinical trials

A double-blind, randomized, placebo-controlled trial (RCT) is the gold standard for evaluating drug efficacy. In this study, neither participants nor researchers know which group receives the drug being studied and which receives a placebo: this allows for the separation of the specific drug effect from the non-specific contextual effect.

Design and interpretation

RCT methodology requires that the actual drug outperform the placebo on measurable endpoints. If the difference is statistically insignificant, the drug is not considered effective, even if both groups improved. This improvement may be explained by the non-specific context of the treatment.

An important caveat: when Hróbjartsson and Gøtzsche conducted a placebo versus no treatment comparison, they found that a significant portion of the effect attributed to placebo in classic studies actually described spontaneous recovery. This led the researchers to distinguish between the "placebo effect" and the "treatment context effect."

Types of placebo in research

In clinical trials, different types of placebo are used depending on the intervention being studied:

• Pharmacological placebo - tablets or capsules with inert fillers (starch, lactose).
• Procedural placebo is a sham operation or invasive procedure without actual therapeutic effect (e.g., "sham" arthroscopy).
• Psychological placebo is non-specific supportive talk as opposed to structured psychotherapy.
• Physiotherapy placebo - switched off devices simulating ultrasound or laser treatment.

Each type has its limitations: perfect blindness is not always achieved, and participants often guess which group they are in.

Application in clinical practice

The use of placebos by doctors in real-world practice is the subject of both ethical and epidemiological research. Surveys show that a significant proportion of doctors in various countries occasionally use "pure" placebos (neutral pills) or "impure" placebos — that is, real medications prescribed without specific indications (for example, vitamins for fatigue).

Ethical framework

Until the 2000s, medical ethics clearly categorized the use of placebos without informing the patient as deception. In 2008, the American Medical Association (AMA) formulated conditions for the permissible use of placebos, which require at least minimal disclosure.

The advent of open-label placebos has redefined this debate. If a patient knows they are receiving an indifferent drug and still experiences a therapeutic effect, the question of deception is eliminated. Authors of relevant reviews conclude that open-label placebos comply with current AMA standards because they do not violate the principle of informed consent.

Psychotherapeutic context and medical communication

Understanding the mechanisms of placebo leads to a practical conclusion: the quality of therapeutic communication is itself a therapeutic factor. Empathy, attentiveness, and trust — these elements of clinical style have measurable clinical value, and do more than just improve compliance.

Placebo and individual diseases

Pain syndromes

Placebo analgesia is the most studied type of effect. It is partially blocked by naloxone, an opioid receptor antagonist, directly confirming the involvement of endogenous opioids. This phenomenon has been replicated in dozens of studies.

In fibromyalgia, chronic back pain, and migraine, the placebo response is often comparable to or greater than the response to active drugs, significantly complicating the development of new analgesics and antimigraine agents.

Depression

In psychopharmacology, the placebo effect is particularly strong. Meta-analyses conducted in the early 2000s showed that for mild to moderate depression, the difference between antidepressants and placebo in controlled trials is minimal, and by some estimates, clinically insignificant. This doesn’t mean antidepressants don’t work, but it does indicate that a significant portion of their observed effect may be nonspecific.

Parkinson’s disease

Neuroimaging studies in Parkinson’s disease have provided particularly compelling evidence of dopamine’s role in the placebo effect. The anticipation of motor improvement activated the endogenous dopaminergic system in the striatum, which was accompanied by actual improvement in motor performance. This finding has become one argument in favor of the neurobiological, rather than purely psychological, nature of the phenomenon.

Irritable bowel syndrome

Open-label placebos were among the first to be studied in functional gastrointestinal disorders. In a 2010 study by Kaptchuk and colleagues, patients with irritable bowel syndrome who were honestly told they were receiving a placebo still showed a significant reduction in symptoms compared to a control group without treatment.

Limits of the effect

Placebos don’t cure tumors, lower glucose levels in type 1 diabetes, or repair broken bones — this is well documented. Their effect extends to subjective symptoms: pain, fatigue, anxiety, nausea, some movement disorders, and mood. For objective biomarkers — blood pressure, hormone levels, and biopsy results — the effect is mostly minimal or nonexistent.

This distinction is crucial: it explains why placebos should not be offered as a substitute for specific treatments for serious illnesses, but also why contextual factors matter in any treatment — symptomatic relief is facilitated by concomitant therapeutic interactions.

Individual differences

Not all people respond to placebos the same way. Research has identified several predictors of response, although none is powerful enough to predict individual outcomes.

Functional connectivity between the dorsolateral prefrontal cortex, anterior cingulate cortex, and nucleus accumbens predicts the strength of placebo analgesia: the better these regions communicate at rest, the more pronounced the response tends to be. This suggests a neurobiological predisposition, which is partly heritable.

Genetic studies have found associations between polymorphisms in the genes encoding catechol-O-methyltransferase (COMT) and the severity of the placebo response. The COMT enzyme influences the breakdown of dopamine in the prefrontal cortex: carriers of the "slow" gene variant, in whom dopamine is broken down more slowly, exhibit a more pronounced placebo effect in certain pain conditions.

Placebo surgery

A special category is constituted by so-called placebo surgeries — surgical interventions in which the patient is anesthetized and undergoes incisions, but the specific part of the procedure is not performed. Such studies are extremely difficult to justify ethically, but several trials have yielded unexpected results.

A 2013 Finnish study (FIDELITY) compared knee arthroscopy with sham surgery in patients with a meniscus tear and found that both groups improved similarly after a year of follow-up. Similar results were obtained with vertebroplasty, a procedure to cement vertebrae for compression fractures: in several trials, the pain-relieving effects of the real and sham procedures were not statistically different.

These data do not mean that surgery is useless; they indicate that some of the effect of some surgeries may be non-specific and dependent on the context of the treatment intervention.

Historical perspective and place in medicine

Before the era of evidence-based medicine, most therapeutic methods used for centuries — bloodletting, potions made from exotic ingredients, cauterization — likely worked primarily through non-specific mechanisms. Scottish medical historian A.K. Shapiro suggested that Thomas Sydenham’s discovery of quinine in the 17th century may have been the first use of a drug with a truly specific mechanism of action.

This puts the placebo effect in a different perspective: for most of medical history, it was the dominant therapeutic mechanism. Respecting this fact doesn’t mean rejecting modern pharmacology. It means recognizing that the therapeutic ritual and the doctor-patient relationship are not an optional addition to treatment, but rather an integral part of it.