The Placebo Effect’s Evil Twin
The Nocebo Effect occurs when we experience pain, depression, or illness based on nothing more than negative expectations.
The term “nocebo effect” derives from the Latin word nocere, which translates roughly as “to harm” (as in the Hippocratic injunction, primum non nocere—first, do no harm). Whereas the better-known placebo effect is typically positive (the alleviation of pain or malaise through treatments that otherwise have no inherent therapeutic value); the nocebo effect is negative, often manifesting as headache, skin irritation, or nausea.
No surprise, then, that the nocebo effect has been called “the placebo effect’s evil twin.” It can be more formally summarized as “the occurrence of a harmful event that stems from conscious or subconscious expectations.” Or, more simply: When you expect to feel sick, you are more likely to feel sick.
Of course, human expectations come up in all sorts of banal, everyday contexts, such as when you tell a friend that you’re stuck in traffic and so he or she should expect your arrival in twenty minutes. But expectation is also an important term of art that academics use (sometimes interchangeably with “expectancy”), having been popularized by Dr. Irving Kirsch, who now serves as Associate Director of the Program in Placebo Studies at Harvard Medical School.
Kirsch’s work built on that of Dr. Henry Beecher, who served with the American military during World War II. While deployed in North Africa and Italy, he gave saltwater to wounded soldiers, but told them they were receiving a powerful painkiller. Beecher did not engage in this deception by choice, but by necessity: As an anesthesiologist treating a flood of battlefield injuries, he faced the difficult task of rationing his supply of morphine.
B.J. Campbell
The roots of our understanding of the nocebo effect are more obscure. But we do find an early precedent involving the work of eighteenth-century German physician Franz Mesmer, best known for his interest in the eponymous proto-hypnotic therapy known as “mesmerism.” In the salons of Paris and Vienna, he promoted the idea that illnesses could be alleviated by using magnets to govern the flow of fluid in patients’ bodies. (If this sounds like obvious quackery, which it is, bear in mind that Mesmer lacked any of our modern-day tools of science. He lived in an era when bloodletting with leeches was still seen as state-of-the-art medical treatment.)
Louis XVI (yes, the French king of guillotine fame) learned of Mesmer’s claims, and (properly) regarded them with skepticism. He established a commission to investigate, led by none other than Benjamin Franklin, who was then serving as the United States Minister to France. The American polymath and Francophile performed what we would now refer to as placebo-controlled studies so as to (as the commission put it) “separate the effects of the imagination from those attributed to magnetism.”
The commissioners led patients to believe they were being magnetized even though they weren’t. Yet the side effects then commonly attributed to magnetism were still often reported. On one occasion, the commission noted, a patient began “shivering, [convulsing], with chattering of her teeth, twisting of her arms and trembling of the whole body.” The commissioners duly concluded that these results attributed to Mesmer’s treatment had been caused by the patients’ “imagination.”
Franklin and the other commissioners had correctly identified nocebo effects—even if they did not use that term. Which is to say that the side effects experienced by Mesmer’s patients were due to the expectation of having such side effects. Magnetism itself could not have caused them, because the patients weren’t actually magnetized.
The second important element that Franklin and his colleagues observed is that desired treatment effects and side effects can emerge at the same time through the effects we now describe, respectively, with the words placebo and nocebo. The patient’s shivers and convulsions were expected side effects of a treatment intended to alleviate suffering. They were viewed as integral to the process, but not as therapeutic in themselves.
This is not untypical. As Charlotte Blease, Cosima Locher, Walter A. Brown, and I show in our forthcoming Mayo Clinic Press book, The Nocebo Effect: When Words Make You Sick, there is a complex relationship between positive treatment effects and negative treatment side-effects. If you’ve ever taken a new medication and concluded that it “must be working” because of the terrible dry mouth it caused, then you’ll instinctively understand this.
Fast-forward a century and a half, when the Journal of the American Medical Association documented the work of Dr. Harold Diehl (1891–1973), an American physician whose work focused on treating the common cold (though he also earned fame as a pioneering anti-smoking activist). Diehl realized that certain people can actually become ill after taking a placebo: In double-blind trials designed to test treatments for the common cold, he noticed that a small portion of people had negative reactions to both a lactose pill and a placebo vaccine.
Though these findings were reported in his 1930s-era research, little attention was then paid to the topic. That began to change in the 1950s, however, when American hospital administrator and researcher Stewart Wolf reported on an experiment in which inpatients with anxiety were given either a real drug or a placebo to help quell their nervousness.
A scene from Marge in Chains, a 1993 episode of the long-running animated situation comedy The Simpsons; in which agitated residents of the fictional American town of Springfield, unsettled by the spread of a novel Japanese-originated virus, unsuccessfully pillage a truck in search of placebos.
It is in Wolf’s paper on this topic that we observe the first systematic discussion of negative placebo reactions. Wolf and his co-author, researcher Ruth Pinsky, wrote: “Minor reactions—nausea, drowsiness, lightheadedness, and palp[it]ation—were often noticed on placebo administration.” They reported that one patient even developed “a diffuse itchy [rash after] 10 days of taking pills…The patient firmly refused to try another batch of pills. Later, it was learned that the rash had developed while she was taking placebos.”
At this point, the story of nocebos returns to the aforementioned World War II anesthesiologist, Dr. Henry Beecher. In a landmark 1955 paper, Beecher devoted a section to what he called placebos’ “toxic” effects. By his count, there were at least 35 different side effects caused by placebos, including dry mouth, nausea, and headaches.
The mind’s unfortunate ability to create suffering ex nihilo can sometimes affect large groups of people though a process of social contagion (or, in the more indelicate language of the past, hysterical contagion). One such example, known as “The June Bug,” occurred in a U.S. textile mill in 1962. Many employees began to feel dizzy and nauseous. Some vomited. Rumors of a mysterious bug that was biting employees began to circulate, and eventually 62 workers became ill. Yet a subsequent Centers for Disease Control and Prevention investigation determined that no bugs could be identified. Nor could investigators find any other physical cause of the illnesses. This type of phenomenon is now referred to as psychogenic illness—sickness caused by belief.
Over the course of history, there have been countless other examples of psychogenic illness, with symptoms ranging from hysterical laughter to seizures. Aldous Huxley, the famed author of Brave New World, described one such seventeenth-century example in his lesser-known historically-based novel, The Devils of Loudun. In the 1630s, as Huxley documents, an entire convent of Ursuline nuns in the western French community of Loudun became convinced that they’d been demonically possessed (complete with convulsions, and other symptoms recognizable to any connoisseur of the modern exorcism-themed horror-movie genre) due to the unholy machinations of a (genuinely licentious) local priest named Urbain Grandier.
Could such a mass outbreak occur today, in an era when few believe in demonic spirits? Consider that during 2016 and 2017, no fewer than 21 American diplomats serving in Cuba reported a range of bizarre neurological symptoms that later came to be collectively described as “Havana Syndrome.” News of the outbreak spread globally through American diplomatic networks, and eventually more than 200 U.S. diplomats became ill. One leading theory was that the Russian government was attacking American embassies and consulates with microwaves.
To be clear: We do not yet know for certain the cause of these ailments. And it is conceivable that speculation concerning Russian involvement may prove correct (even if the microwave theory is far-fetched). That said, the possibility of psychogenic effects is obvious, and I regard it as concerning that this theory seems to have been rejected out of hand by American officials.
Brenda Breslauer
In 2021, in fact, a senior State Department official who’d been mandated to oversee the task force investigating Havana Syndrome was pushed out of her role when she refused to take psychogenic illness off the menu of potential causes. A former C.I.A. officer who claimed he’d been affected by Havana Syndrome while serving in Moscow declared that failing to rule out “mass hysteria” as a cause was “grotesquely insulting to victims and automatically disqualifying to lead the task force.”
I suspect that if Ben Franklin were alive today, he might take a different view.
Adapted, with permission, from the forthcoming book, The Nocebo Effect: When Words Make You Sick, by Michael H. Bernstein, Ph.D., Charlotte Blease, Ph.D., Cosima Locher, Ph. D., and Walter A. Brown, M.D. Published by Mayo Clinic Press.
