The Nuance

The ‘Nocebo Effect’ May Be Even Stronger Than Placebo

Belief is a powerful drug

Illustration: Kieran Blakey

“Help me. I took all my pills.”

According to a 2007 case report in the journal General Hospital Psychiatry, those were the words a 26-year-old man spoke to a hospital’s emergency department staff just before collapsing. An empty pill bottle skittered from one of his hands.

Nurses checked the man’s vitals; while his heart was racing, his blood pressure was dangerously low. The man was barely conscious. He was pale and sweaty. He said he’d swallowed all 29 of his antidepressant pills after having a fight with his girlfriend.

He received saline infusions, which over the next four hours mildly improved his blood pressure and heart rate. Meanwhile, his doctors examined his pill bottle, which confirmed that he was taking drugs as part of an experimental trial for a new antidepressant drug. They called the physicians running the trial, and one of them soon arrived at the hospital. The physician let the man know he had received a placebo, not the active antidepressant drug. The pills he swallowed were shams. Within 15 minutes, the man was fully alert and overcome with relief. His heart rate and blood pressure had returned to normal.

Most people know about the placebo effect, which refers to the power of positive expectations to induce pleasant sensations or symptom improvements. (Placebo roughly translates to “I shall please.”) The placebo effect is well studied, and its benefits are often significant. To gain FDA approval, a new drug often has to beat out a placebo in clinical trials, which is a high bar to hurdle.

Nocebo translates to “I shall harm.” The nocebo effect is “the opposite side of the placebo coin,” says Vitaly Napadow, an associate professor at Harvard Medical School and director of the Center for Integrative Pain NeuroImaging at Massachusetts General Hospital. “In the same way the brain’s circuitry can downregulate pain or the severity of other aversive sensations — that’s the placebo effect — the brain can also upregulate these sensations, and that’s nocebo effect,” he explains.

While the placebo effect has traditionally enjoyed greater public recognition and medical interest, Napadow says the nocebo effect is likely stronger, and its implications for public health are potentially far broader.

For a 2015 study in the journal Allergy, Napadow and colleagues injected people’s skin with either a harmless saltwater solution or an itch-triggering allergen. In some cases, the people knew they were getting saltwater; in others, they thought the saltwater was an allergen. Compared to those who knew they were getting saltwater, people who thought the water was an allergen reported twice as much itch intensity. “The itch response wasn’t as high as it was with the actual allergen, but it was substantial,” Napadow says.

Research on pain, fatigue, nausea, stomachache, and other subjective symptoms has consistently uncovered a significant nocebo effect, he says. While many regard these effects as imagined or somehow pretend, this is a misconception. Napadow says “top-down” symptoms manifested by the brain are just as real and unpleasant as “bottom-up” symptoms that are induced by some kind of injury or illness.

“Neuroscientists are starting to appreciate that the brain operates like a great Bayesian prediction machine,” he says. In statistics, Bayesian prediction describes a model or algorithm’s ability to anticipate an outcome based on incomplete data. And this is just what the brain does all the time. “The brain has all these inputs coming in from the senses, but there’s always missing info,” Napadow says. “So the brain has to fill in missing pieces, and how it fills those in becomes your reality or what you perceive.” This makes room for both placebo and nocebo effects.

While the placebo effect has traditionally enjoyed greater public recognition and medical interest, Napadow says the nocebo effect is likely stronger, and its implications for public health are potentially far broader.

Researchers aren’t exactly sure how the brain manifests these effects. But some who have studied nocebo say they’ve identified at least two underlying explanations. “At the molecular level, we know the body releases cholecystokinins, or CCKs, in anticipation of increased pain,” says Luana Colloca, MD, PhD, MS, an associate professor of pain science at the University of Maryland School of Nursing. CCKs act on dopamine and serotonin receptors in the brain, both of which play a role in pain perception. And while the release of CCKs seems to hypersensitize a person to pain, some of Colloca’s research has found that drugs that block the action of CCKs can effectively blunt the nocebo effect.

Apart from the action of CCKs, heightened activity in the brain’s hippocampus seems to ratchet up a person’s perception of unpleasant sensations, Colloca says. Her research has found that even when people are taking some of the strongest pain-killing drugs in the world — including morphine— they still exhibit dramatic nocebo and placebo responses. “For one study, we treated postoperative patients with morphine,” she says. When the patients were told that their morphine medication would be interrupted, they reported a spike in pain even if there was no change to their drug regimen. On the other hand, when Colloca and her colleagues interrupted morphine therapy without telling patients, few of them noticed or complained, she says.

The human brain may possess this nocebo function in order to detect and plan for negative events, she says. Just as anxiety in small doses can help people anticipate and avoid trouble, a heightened response to painful or otherwise unpleasant stimuli may help a person steer clear of that source of unpleasantness before it can do them lasting harm. But just as anxiety can run amok and cause much more anguish that it prevents, the nocebo effect can also rage out of control.

Napadow says that, more and more, doctors are discussing the role of the nocebo effect in patient care and informed consent. For example, when a person is told the drug they’re starting may lead to depression, upset stomach, or other side effects, nocebo research shows they’re much more likely to experience them. “Expectation leads to perception, which becomes reality,” he says. “What we believe may happen becomes much more apt to happen.”

This presents doctors with a thorny ethical dilemma: Do they have an obligation to disclose all available information to their patients, or does their oath to “first, do no harm” obligate them to withhold information that might cause their patients pain or other negative experiences? “It’s a hard question, because we don’t want to deceive patients, but at the same time, we don’t want to tap into this nocebo circuitry,” Napadow says.

Outside of doctor-patient conversations, the implications of the nocebo effect on human health are much broader. “Nocebo has a huge role in what we’re learning from and how we’re affected by what we observe online and on social media,” Colloca says. “Merely observing someone else’s experience can produce a nocebo or placebo response.”

A recent study in the Clinical Journal of Pain found that when people watched a video of a woman reacting to a skin-pressure test with winces and other outward signs of pain, they reported feeling pain in response to the same pressure test — even though the test was painless. Meanwhile, if the woman in the video did not show any pain, the study participants likewise felt none.

Colloca says that if someone is diagnosed with a medical condition and then reads about another person’s experience with the same condition on a blog or social media feed, this is very likely to influence that person’s symptoms. And the same nocebo and placebo effects surely extend to people’s experiences with diets, health supplements, exercise routines, and pretty much anything else that purportedly hurts or heals.

“How many people out there are really intolerant to gluten or lactose, and how much of that is nocebo effect?” she asks. No one knows. Expectation, Colloca adds, creates not just psychosocial but also neurobiological events that shape how a person feels.

Belief is a powerful drug.

I write about health and science. I live in Detroit with my wife and kids. I’m trying to learn German, but my progress so far is nicht gut.

Get the Medium app

A button that says 'Download on the App Store', and if clicked it will lead you to the iOS App store
A button that says 'Get it on, Google Play', and if clicked it will lead you to the Google Play store