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INSIGHTS BLOG > The Art and Science of the Placebo Effect

The Art and Science of the Placebo Effect

Written on 14 September 2023

Ruth Fisher, PhD. by Ruth Fisher, PhD

Introduction

Most people are probably familiar with the concept of a placebo effect. The general idea is that, loosely speaking, it is a trick of the mind that leads people to feel better after taking what they think is a medicine, but is actually a sugar pill. In other words, simply believing that you’ll feel better is enough to make it happen.

The notion of the placebo effect rarely appeared in the medical literature before the 1950s. Yet, throughout history and up until then, the placebo effect pervaded the practice of medicine, invoked by doctors as an art form.

In contrast to its lack of discussion historically, since the 1950s until quite recently, the placebo effect was widely discussed in the pharmaceutical literature. In this context, the placebo effect was considered in a negative light, as a complicating factor that gets in the way of establishing the efficacy of drugs during testing, that is, the placebo effect was something to be minimized, if not eliminated. The research during this time examined the placebo effect from as much of a pure science perspective as possible and focused on how best to control for its effect in clinical trials. Additionally, most studies reporting on clinical trials of specific drugs devoted space to discussing methodologies used in their trials to account for the placebo effect.

More recently, attitudes about the placebo effect have changed yet again. Currently, the placebo effect is seen as something much deeper and more nuanced, to be explored and exploited. In its current inception, researchers are treating the placebo effect as a mixture of both art and science, trying to figure out how to use it to optimize mental and physical well-being. Interestingly, there are three separate contexts driving this new perspective. First, there is the health and wellness literature discussing the mind-body connection, that is, the idea that physical and mental/emotional well-being are interconnected. In this context, the existence of a placebo effect is evidence that positive attitudes can improve physical health. Second, there is a blossoming body of neuroscience research building on evidence that some people are more prone to experience placebo effects than others. These researchers are examining the genetic underpinnings of this predisposition, with implications for personalized medicine. And third, there is a growing literature on the importance of proper set and setting in psychotherapy and psychedelic therapy in contributing to patient outcomes. 

Defining the Placebo Effect

Before examining the historical differences in the attitudes toward the placebo effect in greater detail, let’s start by more precisely defining the concept. The definition of the placebo effect associated with using some therapeutic has been considerably debated. There is general agreement that the placebo effect includes any increase in a patient’s well-being that’s not directly attributable to the pharmacological effect of the treatment. Here’s a meaty description provided by Arthur Shapiro (1960), citing a description provided by Pierre Janet (1925):

He [Janet] discusses the factors in the patient, physician and situation which are thought to underlie these [suggestibility and hypnosis therapies] successes: In the patient – enthusiasm, faith, belief, feelings in general, power of the imagination, expectant attention, faith in authority, the importance to the patient of being the object of investigation; in the physician-undoubting enthusiasm, faith, and belief, the unconscious personality of the healer; in the situation-the ritual, mystery and strangeness of the proceedings and the situation, changed environment, repetitive education, and suggestibility factors.[1]

Daniel Moerman and Wayne Jonas (2002) describe the placebo effect as including any meaning patients attribute to any and every aspect of the treatment process:

The physician’s costume (the white coat with stethoscope hanging out of the pocket), manner (enthusiastic or not), style (therapeutic or experimental), and language are all meaningful and can be shown to affect the outcome; indeed, we argue that both diagnosis and prognosis can be important forms of treatment.[2]

Moerman and Jonas’s meaning response can include seemingly innocuous factors. For example, Alan Leslie (1954) suggests that colors and sizes of medications have associated properties, which can induce psychological effects in patients: 

When we decide to prescribe a placebo capsule we need not be concerned over the taste, since gelatin capsules are considered to be tasteless. Color, however, is important. A capsule colored red, blue or yellow suggests specific attributes which a transparent, colorless capsule containing a white powder might seem to lack... 

Size of medication should be a consideration. Tiny or oversize tablets and capsule may be more impressive than average sized ones, the tiny one suggesting great strength, the jumbo one impressing by its heroic size. Aspirin, although a valuable drug, by being available without prescription has come to be regarded by the public as only a mild remedy. A tablet which resembles aspirin, even if quite potent, will therefore appear undistinguished and consequently lose much of its psychotherapeutic punch.[3]

These descriptions of factors included in the placebo effect suggest the phenomenon involves a wide variety of highly nuanced factors.

Pre-1950s: The Art of the Placebo Effect

Most early doctors did not know how to cure diseases, and most early “medicines” were tonics or potions with no redeemable active ingredients, and thus with no ability to physiologically treat illness or disease. Arthur Shapiro (1960) describes some early medications given to patients by their doctors:

Patients in ancient Egypt, according to the Ebers Papyrus, in 1500 B.C., were often treated with medication such as “lizard’s blood, crocodile dung, the teeth of swine, the hoof of an ass, putrid meat arid fly specs”. No treatments of specific value are found in all the pages of Hippocrates [460 – 370 B.C.]. Despite this, and the continued prescription of the “flesh of vipers, the spermatic fluid of frogs, horns of deer, animal excretions, holy oil” and other bizarre substances, the physician continued to be a useful, respected and a highly honored member of society.[4]

From the time of Ancient Egypt over the next 3,000 years medical treatments didn’t improve much. Charles II (1630 – 1685), King of England, Scotland, Ireland, would presumably have had access to the best medical care available at the time. Perhaps he would have lived longer had he not been so fortunate. Shapiro continues:

Consider the treatment that Charles II endured by the physicians of his day: “A pint of blood mas extracted from his right arm, and a half-pint from his left shoulder, followed by an emetic, two physics, and an enema comprising fifteen substances; the royal head was then shaved and a blister raised; then a sneezing powder, more emetics, and bleeding, soothing potions, a plaster of pitch and pigeon dung on his feet, potions containing ten different substances, chiefly herbs, finally forty drops of extract of human skull, and the application of bezoar stone; after which his majesty died.” [5]

It wasn’t until the late-19th to early-20th century that medications started to become available that contained active ingredients that provided a true potential for generating pharmacological relief.[6]

Why, then, did patients turn to doctors to help them with their medical problems if doctors had no “real” treatments to provide? In the majority of cases, doctors and patients both were drawing on the doctor-patient relationship to generate placebo effects to help patients find relief. Shapiro describes this phenomenon when he quotes W. Houston (1938) in The Doctor Himself as a Therapeutic Agent. Houston describes the art of creating a placebo effect as “a skill in dealing with the emotions of men”:

The great lesson, then, of medical history is that the placebo has always been the norm of medical practice, that it was only occasionally and at great intervals that anything really serviceable, such as the cure of scurvy by fresh fruits, was introduced into medical practice. . . . Their skill was a skill in dealing with the emotions of men. They themselves were the therapeutic agents by which cures were effected. Their therapeutic procedures, whether they were inert or whether they were dangerous, were placebos, symbols by which their patients’ faith and their own was sustained.[7]

While practitioners have always recognized that they were invoking placebo effects in their treatment of patients, the term was rarely used or mentioned in the medical literature until the 1950s, when the issue of a placebo effect began to be hotly discussed.[8]

1950s – 2000s: The Science of the Placebo Effect

During the mid-1800s, Robert Koch and Louis Pasteur “demonstrated that specific bacteria could cause specific diseases.” Newly developed remedies, including insulin and antibiotics, “were so dramatically effective that they became the sole treatments utilized in modern scientific medicine and changed attitudes toward the nature of healing. Medicine began to value and rely exclusively on the specific effects of pharmacologic and surgical interventions rather than on combinations” of pharmacologic and placebo therapies.[9] In other words, “real” therapeutics weren’t introduced until the mid 1800s. (I recognize that herbal remedies have been used effectively throughout history. However, Western medicine tends to dismiss them.)

By the 1950s, roughly a century after Koch and Pasteur, increasingly more drugs were being developed and introduced, and pharmaceutical companies sought to establish the credibility of their products.[10] These companies sponsored clinical trials of their drugs, which employed placebos to specifically screen out non-drug effects. That is, “The placebo effect was a problem to be eliminated rather than an important aspect of clinical care.”[11] Articles, and even full book chapters, on the placebo effect began to appear in medical journals, exploring methodological problems – including placebo effects – encountered in clinical trials.[12]

There is some interesting discussions in the literature about why, despite understanding the historical role of the placebo effect in medicine, the subject had not been openly discussed until the 1950s. The explanation I found most convincing is that there was a sense of guilt or shame by doctors who were not able to help their patients with a “real” treatment, so-to-speak. However, once medications became available that could actually treat the patient “legitimately”, again my term, the placebo was no longer needed:

Placebos are often given to demanding and difficult patients, when the physician is frustrated personally and professionally, when the physician’s knowledge, or medical knowledge in general, is inadequate to the presenting problem, when the doctor-patient relationship is deteriorating … Physicians often prescribe with the full knowledge, or at least the suspicion, that these substances are placebos, although communicating to the patient, by omission, or commission, that these inert substances are active.[13]

In short, during the 1950s, the issue of the placebo effect had been transformed from the art of manipulating the “the emotions of men” into a science of controlling for “a problem to be eliminated.”

Post – 2000s: The Art and Science of the Placebo Effect

Since about the early 2000s, the placebo effect is seen as a phenomenon in which mental attitudes and mindsets cause physiological changes in the body. Researchers are investigating how exactly the mind controls physiological functions, while health and wellness coaches are helping people exploit this control to help patients improve their mental and physical health. The goal of all these placebo researchers is to understand how to better understand and utilize – through both art and science – the mind-body connection to improve health and well-being. 

The Mind-Body Connection

In the context of the mind-body connection, the existence of a placebo effect is evidence that positive attitudes can improve physical health. This mind-body link involves various physiological systems, including 

  • The nervous systemserves as the communication system in your body that transmits signals between the brain and the rest of the body.[14]It makes sense, then that the nervous system should be central to the mind-body connection. 
  • The endocrine systemserves as the basis for hormone signaling within your body, which controls bodily functions. Many hormones, including dopamine, cortisol, serotonin, and adrenaline, regulate mental health directly, and they are activated by the immune system.[15]
  • The immune systemserves as your body’s defense system to fight against internal and external threats. When a threat activates the immune system, your body’s fight-or-flight response triggers hormonal release.[16]

Positive attitudes (mental states) improve mental and physical well-being, for example, by triggering release of dopamine and serotonin, and by preventing the immune system from triggering (e.g., stress-induced) release of cortisol and adrenaline. 

Genetic Underpinnings

Researchers are examining genetic underpinnings to understand why some people experience larger placebo effects than others. What they have discovered is that when certain receptors in the body are activated, higher placebo response individuals release greater amounts of chemicals than do lower placebo response individuals. Furthermore, these researchers have traced back these greater activation response levels as being linked to specific genetics. 

For example, in response to dopamine receptor activation, certain people release more dopamine than others. Here’s how the study worked. Study participants are given a series of drugs designed to activate dopamine release. The researchers observe that some participants release more dopamine than others in response to the drug. After the individuals have been trained using the dopamine drugs, the researchers then give the individuals sugar pills, and they found that the high dopamine releasers tended to exhibit greater placebo effects than did the low dopamine releasers. The researchers then traced back the genes responsible for activating dopamine response and found different gene variants for the high dopamine releasers than the low releasers. Finally, the researchers found these same types of genetic-placebo associations for people with certain genes associated with dopamine, opioid, serotonin, and/or endocannabinoid receptors.  

This research has implications for personalized medicine by being able to tailor drugs and doses to individuals who are more likely – due to their genetic predispositions – to respond.[17]

Set and Setting

Ido Hartogsohn, an Israeli researcher and professor, has published several insightful articles on the subject of set and setting in the context of psychedelics. The information in this section comes larges from his works:

  • Hartogsohn I. (2016). Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology. Journal of Psychopharmacology. Hartogsohn I (2017). Constructing drug effects: A history of set and setting. Drug Science, Policy and Law. 
  • Pronovost-Morgan C, Hartogsohn I, and Ramaekers JG (2023). Harnessing placebo: Lessons from psychedelic science. Journal of Psychopharmacology.

The idea that set and setting influence outcomes associated with the use of psychotropic substances has existed “since the prehistory of medicine”. However, the concept of set and setting formally emerged within the medical community during the 1960s with research into psychedelic drugs, where Timothy Leary, the infamous Harvard psychedelics researcher, is credited with coining the phrase. 

During the 1950s and 1960, psychedelics were administered in many different contexts and generated a wide variety of different outcomes. For example, 

Some claimed that LSD was primarily an anxiety-provoking agent, while others believed it imbued a sense of wholeness. Some claimed that LSD invoked psychosis, while others that it was a harbinger of a ‘new sanity’. Some said it caused retardation of thought, while others presented it as a cognitive enhancer. Finally, some maintained that no one who had the LSD experience wanted to repeat it, while others claimed those who had the LSD experience wish to repeat it regularly.

These puzzling differences in effects led some to conclude that set and setting was “the most important determinant of the contents of psychedelic experiences”. 

Set and setting can be more explicitly described as follows:  

Set is understood as anything related to the internal state of a person, including personality, preparation for the experience, intention, as well as ‘‘mood, expectations, fears, wishes’’. Setting is understood as anything related to the environment in which the experience takes place, including the physical environment, the emotional/social environment, and finally the cultural environment—the ideas and beliefs which are prevalent in the society regarding drug effects and the world in general.

I had delved into the literature on set and setting while trying to get a better understanding of psychedelics. At the time, I was very familiar with the concept of a placebo effect. Perhaps it was the different context in which I had come across the concepts of “set and setting” vs. “the placebo effect” that prevented me from making an immediate connection between the two. However, more recently I was researching the mind-body connection, when it occurred to me that the mind-body connection sounded a lot like the placebo effect, which led me to investigate this connection. My investigation into the placebo effect in that context then led me to connect it to the idea of “set and setting”. Hartogsohn has some of the best articles on the subject, and as you see, his articles are all very recent.

The notion of using art and science to exploit the placebo effect — or, if you prefer, set and setting — to personalize medicine and improve health and wellness is new and, I believe, a very exciting area with huge amounts of potential. The more we learn about the brain/the mind, the more mysterious it becomes.

 

References

[1] Shapiro AK (1960). A Contribution to a History of the Placebo Effect. Behavioral Science. https://onlinelibrary.wiley.com/doi/abs/10.1002/bs.3830050202

[2] Daniel E. Moerman and Wayne B. Jonas (2002). Deconstructing the Placebo Effect and Finding the Meaning Response. Ann Intern Med. https://www.acpjournals.org/doi/epdf/10.7326/0003-4819-136-6-200203190-00011

[3] Leslie A (1954, Jun). Ethics and Practice of Placebo Therapy. American Journal of Medicine. https://www.sciencedirect.com/science/article/abs/pii/0002934354904507

[4] Shapiro AK (1960). A Contribution to a History of the Placebo Effect. Behavioral Science. https://onlinelibrary.wiley.com/doi/abs/10.1002/bs.3830050202

[5] Shapiro AK (1960). A Contribution to a History of the Placebo Effect. Behavioral Science .https://onlinelibrary.wiley.com/doi/abs/10.1002/bs.3830050202

[6] Pina AS et al (2009). An Historical Overview of Drug Discovery. Methods in Molecular Biology. https://pubmed.ncbi.nlm.nih.gov/20694682/

[7] Shapiro AK (1960). A Contribution to a History of the Placebo Effect. Behavioral Science .https://onlinelibrary.wiley.com/doi/abs/10.1002/bs.3830050202

[8] Shapiro AK (1960). A Contribution to a History of the Placebo Effect. Behavioral Science. https://onlinelibrary.wiley.com/doi/abs/10.1002/bs.3830050202

[9] Herbert Benson and Richard Friedman (1996). Harnessing the Power of the Placebo Effect and Renaming It “Remembered Wellness”. Annu Rev Med. https://drdgoodman.com/wp-content/uploads/2016/02/fordyce_placebo_effect.pdf

[10] Meldrum ML (2000, Aug). A Brief History of the Randomized Controlled Trial. Hematology/Oncology Clinics of North America. https://www.sciencedirect.com/science/article/abs/pii/S0889858805703099

[11] Herbert Benson and Richard Friedman (1996). Harnessing the Power of the Placebo Effect and Renaming It “Remembered Wellness”. Annu Rev Med. https://drdgoodman.com/wp-content/uploads/2016/02/fordyce_placebo_effect.pdf

[12] Shapiro AK (1960). A Contribution to a History of the Placebo Effect. Behavioral Science. https://onlinelibrary.wiley.com/doi/abs/10.1002/bs.3830050202

[13] Shapiro AK (1960). A Contribution to a History of the Placebo Effect. Behavioral Science. https://onlinelibrary.wiley.com/doi/abs/10.1002/bs.3830050202

[14] Cherry K (2023, May 4). Structure and Function of the Central Nervous System. Very Well Mind. https://www.verywellmind.com/what-is-the-central-nervous-system-2794981

[15] Gupta S (2023, Jun 11). Structure and Function of the Central Nervous System. Very Well Mind. https://www.verywellmind.com/how-your-endocrine-system-affects-your-mental-health-7506208

[16] Gupta S (2023, Jun 11). Structure and Function of the Central Nervous System. Very Well Mind. https://www.verywellmind.com/how-your-endocrine-system-affects-your-mental-health-7506208

[17] Colagiuri B et (2015). The Placebo Effect: From Concepts to Genes. Neuroscience. https://www.sciencedirect.com/science/article/abs/pii/S030645221500740X