The history of placebo research

For over 200 years, a drug without an active ingredient has been called a “placebo”. However, even the physicians of antiquity knew about the placebo effect and used it in their attempts to heal the sick.

Even in ancient times, physicians knew about the placebo effect. The famous physician Galen of Pergamon, for example, considered patients’ trust in medicines and in their physician to be more important than the active substances administered per se. Image: Galen gives a lecture on anatomy in Rome. Print from the book “Vies des Savants Illustres”, re-colored.

"I will please" is the literal translation of "placebo" from Latin. The term appeared in the late Middle Ages to describe mourners who loudly lamented the deceased in exchange for payment. As such, the term already reflected an element of pretence. The term placebo first appeared in a medical dictionary in around 1800 - as the name for a remedy administered as a medicine without an active ingredient.

A placebo (sham drug) refers to a drug that does not contain any pharmacologically active ingredient, e.g., a sugar pill. There are also non-drug placebo treatments, e.g., sham acupuncture. However, research has now provided ample evidence that placebos are by no means purely a sham. What started out with observations in medical practice has how become an intensive branch of research that is increasingly deciphering how the placebo effect comes about and how it works. The research has discovered that patients’ expectations of treatment play a major role, and these expectations are influenced by many different factors of the treatment itself and the context of the treatment. Learning processes are also involved. As a scientific discipline, placebo research – or perhaps described more accurately as research into the expectation effect – is very young, but its contents are as old as medicine itself. Indeed, its story probably already began with mankind’s very first attempts at healing.

Of course, the physicians of antiquity did not use the term placebo, but they were very aware of the placebo effect. For example, the philosopher Plato, a proponent of holistic medicine, described how a medicinal herb for headaches could only be effective if a corresponding charm were uttered at the same time; without the charm, the "leaf" would be useless. Only the charm, which was not medically effective, i.e. a pure placebo, would enable the medicinal herb to drive away the headache.

The famous physician Galen of Pergamon wrote in the 2nd century that he had greater treatment success with patients who truly believed that they would be cured. And he considered a patient’s trust in the medicines and in the doctor to be more important than the administered active substances per se.

In so-called simple archaic social structures and among most Indigenous peoples, illnesses were seen as divine punishments or the work of witches or evil sorcerers. Treatment was performed by medicine men or shamans, who were masters of magical or religious rites. Patients and practitioners firmly believed in the effect of the respect-inspiring rituals, which were used alongside the remedies in nature that had limited effect – and at best activated powers of self-healing.

The renowned placebo researcher Ted Kaptchuk from Harvard Medical School draws comparisons, for instance, between the present-day healing rituals of the Navajo Indians and acupuncture and orthodox medical treatments. What the Navajos have in the way of ceremonies and chants, the acupuncturist has in the way of a chart with needle points, relaxation music or incense sticks, and conventional medics have diplomas on the wall and ultra-modern technical examination equipment. Rituals have always existed in the healing arts, but they have simply changed.

The Scottish physician William Cullen is thought to have been the first to use the word placebo in a medical context. In the late 18th century, he administered mustard powder as an external treatment to patients with no hope of recovery, as a "pure placebo," as he called it. Although he considered the ointment to be ineffective, he saw his medical duty in giving hope to a seriously ill patient through the use of a purportedly effective medicine. Therapeutic options were limited in any case, and no effective remedy was available for many diseases at that time.

Around the turn of the 19th century, the first studies that can be described as placebo-controlled in the broadest sense were carried out. Their main purpose was to convict medical charlatans. For example, an experiment commissioned by the French King Louis XVI, in which the researcher and later statesman Benjamin Franklin was involved, was able to prove that the success of the popular “mesmerism” or “animal magnetism” was based solely on rituals: magnetized water, soothing sounds, incense and magnets. According to the technique of the German physician Franz Anton Mesmer, who often performed his treatments wearing a lavender silk robe and golden slippers, a "mesmerist" was said to positively change the non-specific "fluid” in a patient's body, even from a distance. The sick person felt an improvement if he/she believed the practitioner was behind a curtain – even though nobody was there.

There are several documented placebo-controlled trials from the 19th century, which investigated the – at the time new – system of medicine called homeopathy, created by Samuel Hahneman. These trials sought either to prove the efficacy of Hahneman’s method of healing or to expose it as a humbug. The homeopathic principle of treating "like with like" and using extremely diluted substances for this purpose still resists any scientific proof of efficacy today. The healing power of the remedies is possibly based solely on the placebo effect. In between the homeopathic doses, which he considered to be healing, Hahnemann himself utilised the placebo effect. For instance, in 1814, he recommended that his colleagues give patients "something inconspicuous" (e.g. raspberry juice or sugar of milk) in the meantime, if they were demanding a medicine because they were so accustomed to it from other physicians.

At the beginning of the 20th century, the importance of what we now understand as placebo treatment waned significantly, mainly because physicians were increasingly able to rely on effective pharmacological substances. In addition, there was a prevailing view – now disproven – that placebos could only help against imaginary symptoms.

However, placebos became increasingly relevant as controls in clinical trials testing drug efficacy. By the mid-20th century, placebo-controlled trials had become the standard in clinical research.

Henry Knowles Beecher – Vater der modernen Erforschung der Behandlungserwartung

American physician Henry Beecher ran a hospital for wounded U.S. soldiers during World War II. When the hospital ran out of the painkiller morphine, he administered a saline solution to the suffering men instead, which they believed to be morphine. What was actually an act of desperation had an astonishing effect: Almost half of the wounded men who had received saline said that their pain had lessened or even disappeared.

This experience with the inactive saline led the Harvard Medical School physician to delve deeper into placebo research. In 1955, his manuscript "The Powerful Placebo" was published in the medical journal JAMA. Evaluating 15 placebo studies on the treatment of pain, he concluded that about 35 percent of subjects responded to placebos. Beecher was quoted with this figure for decades, although later research showed that such a sweeping figure could not sustained. **

In the mid-1960s, there was intense debate about which personality factors underlie the placebo effect and whether there is even such a thing as a placebo personality. The latter has been disproven: A "placebo personality" is just as unlikely as a "cancer personality". In contrast, research today is still looking at why people react differently to placebos and which individual factors are involved. And aspects such as optimism or fearfulness might play a role.

Since the 1970s, there has been increasing evidence that placebo effects are associated with (neuro-)biological and physiological processes in the brain and body, such as with the release of endogenous opioids, which can inhibit pain receptors in our body. It has also been shown that substances that inhibit these endogenous pain-reducing substances can block the placebo effect. This finding provided the first evidence for a possible neurobiological mechanism. In the 1990s, placebo effects in pain therapy and depression became a major topic of research. And the placebo effect was increasingly studied in various forms of treatment - from tablets to surgery.

In the early 2000s, placebo research experienced a breakthrough thanks to the development of imaging techniques that can visualize brain activity. Using positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), it was demonstrated that certain areas of the brain are more strongly activated by the administration of placebos. The neurotransmitters involved were also made visible in this way: In PET measurements, subjects were given substances that bind to the body's own opioid or dopamine receptors, for example. This enabled researchers to see that the placebo effect on pain is based on the activation of specific brain areas and the release of complex neurobiological cascades such as the release of endogenous opioids.

Finally, in a statement in July 2010, the Scientific Advisory Board of the German Medical Association attached special importance to the placebo effect: "Since the placebo effect can occur in almost any treatment, it is absolutely necessary and urgent to provide physicians with knowledge of placebo research in order to maximize drug effects, reduce adverse drug effects, and save health care costs."

The boom of studies on the placebo effect, its mechanism of action, its role in any form of treatment, and its targeted use in medical practice, which started in the 1990s, has continued since the 2010s and is currently experiencing a new peak:

Harvard Medical School started its "Program in Placebo Studies and the Therapeutic Encounter" led by Ted Kaptchuk in 2011, Fabrizio Benedetti is a luminary of placebo research in Turin, the doctor-patient relationship is being researched at the Karolinska Institute in Stockholm, and the Universities of Dartmouth, Baltimore, Aarhus, Leiden, and many other internationally renowned researchers are dedicated to researching the placebo effect. Today, Germany enjoys a leading position in placebo research.

The German Research Foundation already funded the Research Group 1328 "Expectations and Conditioning as Basic Processes of the Placebo and Nocebo Response: From Neurobiology to Clinical Application" from 2010 to 2021. Led by Prof. Winfried Rief from Marburg, the group benefited from the combined expertise of scientists throughout Germany. Since 2020, this has developed into the Collaborative Research Centre 289 "Treatment Expectation", with a focal point at the University Hospital Essen led by the neurologist Prof. Ulrike Bingel and the psychologist Prof. Manfred Schedlowski. The main area of research focuses on expectation effects in the area of pain and the immune system, while neuroscientists at the University Medical Center Hamburg-Eppendorf, led by Prof. Christian Büchel, are focusing on innovative imaging of placebo effects. In Marburg, Prof. Winfried Rief and colleagues are concentrating on the topic of "expectation effects in depression therapy". Across these three sites, more than 60 scientists are working in the supraregional Collaborative Research Centre (SFB/TRR 289) "Treatment Expectation". The German Research Foundation (DFG) is funding this research for several years.

You can find a compilation of the projects here.

Many of the questions that are addressed by placebo research are still waiting for clear and reliable answers. However, since the scientific study of this topic has gained momentum over recent decades, many exciting aspects have already been investigated. Here is a selection of important findings:

• Placebo effects are not tied to the administration of placebo drugs. Rather, any treatment, be it a medicine, acupuncture, or surgery, is accompanied and modulated by placebo effects, or more precisely expectation effects.
• Placebo effects can lead to clinically relevant improvements in symptoms and diseases. This was impressively demonstrated, for instance, for the highly effective painkiller remifentanil: A positive treatment expectation was found to double the pain-relieving effect, while a negative expectation, coupled with concerns that the pain might get worse, caused this highly effective drug to lose its effect. As another example, British rheumatologists analysed placebo-controlled trials in osteoarthritis patients and showed that a placebo not only reduced pain but also improved function and reduced joint stiffness.
• Placebo effects have been described in all physical systems. Placebo effects seem to be particularly strong in the areas of pain and depression, where they contribute to treatment success to a considerable degree. But placebo effects also occur in other systems, such as the gastrointestinal tract and even the immune system.
• The driving force of placebo effects is the expectation attached to the treatment. This is shaped by patients’ previous experiences or by information they have been given, and even by having observed treatment successes or failures in other patients.
• The type of treatment and the general treatment conditions play a role. The placebo effect is stronger for invasive procedures (e.g., an infusion) compared to merely swallowing a pill. Expensive pills bring about a greater placebo effect than cheap ones, and their size and colour also have an impact. Not only drugs, but also invasive treatments, come with a dose of placebo effect. In an experiment in Houston, 120 patients with knee osteoarthritis underwent an operation, but half of them only received superficial incisions on the skin and no real surgery. After two years, 90 percent of patients in both groups were satisfied with the surgery. The only difference between the two groups was that the non-operated patients were experiencing even less pain than the operated group.
• Attentive communication and a relationship of trust between patient and practitioner can enhance the placebo effect. In a randomized trial at Harvard Medical School, patients with irritable bowel syndrome felt best after receiving sham acupuncture with warm, empathetic communication from the practitioner. Sham acupuncture without communication brought significantly less improvement, but was still significantly better than purely being examined.
• Placebo effects are not imaginary, and nor can they be entirely described on the psychological level. In the brain, the expectation of improvement or healing triggers a complex neurobiological cascade. For example, the brain releases pain-relieving opioids when a patient is supposedly given a painkiller.
• It isn’t just subjective symptoms like pain, depression and chronic fatigue that respond to placebo and expectation effects. Breathing, the stomach, bowel movements and even the immune system are also affected. In a study of patients with hypertension, a placebo was shown to lower systolic and diastolic blood pressure. Systematic studies are currently investigating how differently placebo effects influence subjective symptoms and objectifiable physiological processes. Beyond the already convincing findings in the field of pain, the neurobiological and peripheral physiological mechanisms underlying these effects are also unclear.

For a very long time, it was believed that a placebo could only work if patients actually believed they were receiving the real active drug. This is why for research purposes, even in science, so-called covert placebos are often given, which are presented as real drugs. However, placebos even work when patients know that they are receiving a drug without an active substance. In so-called open-label placebo studies, patients with back pain, migraine, and irritable bowel syndrome have reported significant improvements in pain, even when they knew they were taking placebos. It is suggested that the mere act of swallowing a tablet may activate the symptom-relieving cascade. However, the exact mechanisms underlying the open-label placebo effect remain to be clarified. In particular, unconscious expectation and learning processes are being discussed.

How can we use placebo effects in a way that exploits their full potential? How can doctors guide their patients towards better treatment outcomes through communication and managing expectations? Why do some patients respond well to placebos while others do not respond at all? What role do cultural and social factors play? – We still have many scientific questions about the placebo effect. Answering these questions is the task of today’s and tomorrow’s research, especially in the Collaborative Research Centre "Treatment Expectation".

**Unfortunately, a shadow has been cast on the moral integrity of the former Harvard professor, with critics accusing him of being involved in human experiments conducted by the CIA in post-war Germany, involving psychoactive substances such as LSD and mescaline. For this, he also collaborated with a German doctor who had been involved in human experimentation in concentration camps during the Nazi era.

U. Bingel, M. Schedlowsi, H. Kessler: Placebo 2.0 - The power of expectation. Rüffer & Rub, Zurich 2019

Placebo in medicine. Ed. by the German Medical Association. Deutscher Ärzte-Verlag, Cologne 2011

C. Guijarro: A History of the Placebo. In: Neuroscience and History, 2015

R. Jütte: The early history of the placebo. In: Complementary Therapies in Medicine, April 2013.

M. Breidert, K. Hofbauer: Placebo - Misunderstandings and prejudices. In: Deutsches Ärzteblatt, November 2009

The power of expectation: How placebo and nocebo work. In: Zeit Online, 13.1.2021

M. McKechneay: The power of nothing. In: Impuls Wissen, Wiener Städtische 2021