By Shayla Love
Nocebo is the evil twin of the placebo effect—and my constant companion. I set out to find out what it is, and how I could learn to harness the more positive effects of medical mind games.
Help me, I took all my pills.” A 26-year-old man in the emergency room fell to the floor, and an empty prescription bottle dropped from his hands.
Mr. A, as he was referred to in his 2007 case study, was still conscious, but pale-faced, drowsy, and lethargic. He told doctors he had impulsively swallowed 29 capsules after a fight with his girlfriend—the pills were an experimental drug for depression he had been given in a clinical trial.
They were clearly having an effect: Mr. A’s blood pressure dropped abnormally low, and his heart rate was a rapid 110 beats per minute. After four hours on an IV, he showed little improvement.
Then, a doctor who oversaw the clinical trial arrived. He said that Mr. A was part of the placebo group—the patients who are selected at random, and without their knowledge, to receive a pill that did nothing at all. Any symptoms he was having weren’t coming from the pills, but from his mind.
Mr. A “expressed surprise then almost tearful relief.” Within 15 minutes, his blood pressure rose and his heart rate returned to normal. He was fine. “Mr. A’s hypotension appears to have occurred as a result of the placebo overdose,” the study wrote. Another name for this phenomenon: the nocebo effect.
You’ve heard of the placebo effect, from the Latin: I shall be pleasing or acceptable—when a person feels better from a drug or treatment that doesn’t have any pharmacological or physiological properties, whether they’re aware it’s a placebo or not. The nocebo effect is sometimes referred to as placebo’s evil twin; it translates to I shall cause harm or be harmful. It’s when a person experiences negative symptoms from an inert pill or treatment, or even from verbal suggestion or observation. As Mr. A showed us, the nocebo effect can be surprisingly powerful.
I’ve always been enamored with the placebo effect, and gobbled up books and studies that explain how it works. It’s been shown to help people with a wide variety of conditions, like chronic pain, IBS, migraine, and depression. I like how it blurs the line between psychology and biology and reminds us that our brains are our bodies; that medicine doesn’t exist in a vacuum, but in a context of expectation, ritual, and person-to-person interaction.
Yet the placebo effect has somehow felt out of my grasp. I’ve looked on with a twinge of jealousy at people who have miraculous experiences with treatments that are often credited as the placebo effect at work, like Reiki or crystal healing. I’ve watched friends find great relief from things with no active ingredient, and yet even when I’ve tried to open my mind and manifest a cure for minor ailments like stomach pains, dizziness, or anxiety, I never have a similar response.
But the nocebo effect and me? We go way back. I have never “overdosed” on a placebo pill, but I relate to Mr. A. From early childhood, if I heard about someone else feeling sick, I would nearly immediately start to feel the same thing. If my doctor told me about side effects of a medicine, like headaches, stomachaches, even fever, like magic, I would start to experience those symptoms.
If the placebo and nocebo effect are opposite sides of the same coin, how could I be so vulnerable to one and not the other? I would love to harness the power of placebo for myself. If I’m a believer, why has the placebo effect forsaken me? I set out to find out why, and learn more about placebo’s evil twin.
Placebo and nocebo pervade the whole history of medicine. In 1807, Thomas Jefferson called placebos a “pious fraud,” and wrote that “one of the most successful physicians I have ever known has assured me that he used more bread pills, drops of colored water, and powders of hickory ashes, than of all other medicines put together.”
Many treatments, and even some surgeries, report improvements from little more than the placebo effect. In a 2009 study on vertebroplasties, an outpatient surgery for spinal pain, there was no significant difference in effect between receiving the procedure and just thinking you had received it—both a placebo group and those who had the procedure showed improvements in their pain, suggesting that the placebo effect could have been a factor. A 2014 review found that about half of placebos worked just as well as the real surgeries investigated.
For a long time, we’ve tried to get rid of the placebo effect, because it can cause confusion. The randomized clinical trial with a placebo group was determined to be the gold standard for science in the 1940s and 50s, and today still helps doctors and pharmaceutical companies know how effective a medication or treatment is all on its own, by accounting for the effects of placebo.
But a rising tide of research is showing us that the placebo effect is not insignificant and not just a nuisance—it can induce real physical changes. Now there is a push not to simply discard the placebo effect, but to understand it and use it to our advantage.
Mr. A wasn't the first to have a nocebo reaction to a placebo pill—many people in clinical trials do. In a study published in 2009 that looked at trials of different anti-migraine drugs, researchers found that a high rate of people in placebo groups were experiencing negative side effects even though they weren’t taking the active drug. The exact effects they suffered from depended on which drug trial they were in, and the side effects of that specific medication—which, again, they were not taking.
That’s because those were the potential side effects they had been told about in the trial, which tells us something important: It’s not the pill itself in the placebo or the nocebo effect that carries the magic. It’s the meaning placed in the pill, and the context and information that surrounds it.
In one of my favorite apocryphal anecdotes about the nocebo effect, as recounted in 1997, a hex was put on an 18-year-old Maori man in New Zealand. The hexer said if the man ate any wild game hen there would be dire consequences. The man visited a friend who fed him wild game hen, but without his knowledge. Two years later, the friend told him the truth. The “hexed” man died within 24 hours. It wasn’t the pill, or in this case the hen, that killed the man—but the expectation of death.
In our current time, we don’t ascribe much meaning to hexes, but we do put a lot of stock in medicine. Going to the doctor is part of an elaborate medical ritual: the waiting room, the white coat, the feel of the stethoscope, the prescription pad, voicing your fears to an authority figure. These are all important components of how the placebo or nocebo effect will play out.
When a doctor tells someone she’s going to experience a side effect, it can trigger a nocebo effect with real biological consequences. This has a lot to do with what the patient expects to happen, but also the meaning she places in the doctor’s warnings. When people are anxious that something will hurt, it amplifies pain. Studies have shown that when people expect pain they feel more pain, and the increase isn’t merely subjective but can be measured in neural activity. Because I find meaning in a person with a medical license and white coat, his or her words can have just as much influence as a hex against a chicken dinner.
This doesn’t explain why an expectation for bad side effects happens to me so reliably—but it might have to do with exactly how these effects work in the body. It’s currently thought that placebo suggestions activate the brain’s natural opioid systems to provide relief. Nocebo suggestions might work a little differently, Fabrizio Benedetti, a professor of physiology and neuroscience at the University of Turin Medical School in Italy, told me.
His work has found that when the expectation of something bad happening induces anxiety, a chemical in the brain called cholecystokinin (CCK) is activated. CCK helps nerve cells communicate with each other, which can facilitate negative feelings, like pain. When Benedetti gave people a CCK blocker, it stopped nocebo-effect pain. Meanwhile, in a study from 2009, researchers gave people an opioid blocker, naloxone, and found it could reduce the placebo effect. This means there were real biological changes taking place that led to the placebo and nocebo effects, and they could be interfered with by another drug.
But the opioid blocker didn’t reverse the effects of the CCK blocker and the CCK blocker didn’t work for placebo, showing that the placebo and nocebo probably operate in slightly different ways—meaning these effects aren’t exactly like twins, more like cousins. Having a direct line to the nocebo effect, like I do, doesn’t grant me access to the placebo effect too, like I thought it would.
“The mechanism underlying nocebo tends to show different characteristics,” said Luana Colloca, a physician-scientist and an associate professor at the University of Maryland School of Nursing. It’s mostly just convenient to talk about placebo and nocebo as opposites, she said, and their biological differences might explain why they have different triggers. I’m an anxious person, and if I’m always ready to ignite my anxiety, it could lead to more nocebo effects.
“People respond to nocebo even with verbal suggestions,” she told me. “If we just inform a patient ‘You are going to feel more pain,’ they show higher pain.” She said with placebo, it usually doesn’t happen so automatically. Simply telling someone they’ll feel better (or telling yourself, as I’ve tried to do) won’t work. “It suggests that, while nocebo responses are created in a faster and more immediate way, for placebo we need to consolidate an experience before we can show a bene t,” she says.
By “consolidate an experience,” Colloca means that learning is important for how well the placebo effect works for different people. Learning helps decide what meaning a person places in a pill, an interaction with a doctor, or any treatment. For me, it might be that I haven’t had the kinds of experiences in my life that lead to good placebo responses.
People who have had good encounters with doctors and positive medical treatments may respond to the placebo effect more—like Pavlov’s dogs, they learn to associate an environmental clue with a biological one. The dogs started to salivate when they heard a bell, and some people will start to produce a placebo effect in medical contexts if that’s what they’ve been conditioned to do in the past.
In studies, Colloca told me they’re using learning to make placebos more effective by pairing placebos with active drugs and creating these good experiences. For pain, this might look like giving a patient a painkiller for a few days, then throwing a placebo pill into the mix, going back to the drug, then placebo again. Even if a patient knows that he’s taking a placebo, the placebo will produce the same or very similar physiological effect as the painkiller, because the body has learned what to expect and had a positive experience with the ritual of taking the pill.
That’s the most promising use of placebos in routine clinical practice, Benedetti told me. Placebos could help someone take less of a drug overall, but likely not replace it completely. “If you give a placebo for the first time, some patients respond, some others do not,” Benedetti explained. “But if you give a placebo after repeated effective treatments, you can bet that virtually all patients will respond.”
My casual attempts at the placebo response have never incorporated this kind of learning and conditioning, or tapped into any preexisting rituals I had ascribed deep meaning to. I wanted the placebo effect to simply work automatically for me, the way I thought I saw it work for others. What I was ignoring was a lifetime of history and meaning that each person carries with them when they encounter a potential placebo.
Still, the question of who innately responds best to placebo is one of the key questions that placebo researchers continue to ask. There are some people who seem more open to a placebo right off the bat.
Those who are sensitive to incentives and rewards might be better responders, Benedetti told me. A recent study found that people who responded to placebo pills for chronic back pain were more emotionally aware, unable to distract themselves from painful situations, and clued in to their environments. Other studies have shown that nocebo effects engage a brain region called the hippocampus, but there’s little evidence that the placebo effect does. The hippocampus is related to anxiety, which is at play in nocebo but generally not placebo, Ted Kaptchuk, the director of the Program in Placebo Studies at Beth Israel Deaconess Medical Center, told me. The research isn’t conclusive, but it hints that there may be some personality traits that are more likely to respond to placebo or nocebo.
There is also some preliminary evidence that there might be different genetic variants that influence placebo response—these have been dubbed the “placebome.” Work led by the molecular biologist Kathryn Hall at Brigham and Women’s Hospital has found that the placebome could lead to changes in the brain’s opioid and dopamine functions; both are associated with how the placebo effect works.
It is important to know who is a placebo and nocebo responder so that we can better design trials for drugs, and so that doctors know the best way to interact with patients. For a person like me, if I was known to have a strong nocebo response, it might change the way my doctor told me test results or administered medication.
But Kaptchuk told me that we’re at early stages of all this. “Research has still failed to provide reproducible and consistent correlations with personality or circumstances for placebo,” he said.
For now, if I sense an imbalance in how I respond to placebo and nocebo, it probably isn’t an accurate way to gauge my true response. But it still might be a way to discover something about myself, my own expectations and life experience.
I grew up in a family of scientists who, I can now recognize, had complicated relationships with health and their bodies. Small symptoms were catastrophized and worried over. Visits to the doctor were fraught with expectations of the worst possible outcome, and any little ache or pain meant the end could be near. From this upbringing, I likely learned to feat and expect the worst when it comes to health, medicine, or sensations in my body. Throw that in a pot with some anxiety and OCD, and it’s no wonder it feels like I’m a prime candidate for the nocebo effect.
As much as I dislike that fact, Colloca wrote in a 2017 Science magazine article that evolutionarily speaking, nocebo is around for a reason. It’s there to teach me to anticipate and avoid an approaching threat, just as the placebo effect is there to promote behaviors that are good for me, or healing.
There likely isn’t a person who is completely immune to either effect, though I feel especially susceptible to it. Benedetti told me that we are all sensitive to nocebos in everyday life. If I want camaraderie, I can look to the many documented instances of mass psychogenic illnesses, when whole groups of people become sick because of the nocebo effect. Most recently, in Cuba, it’s thought that the diplomats who developed puzzling symptoms of memory loss, headaches, and hearing loss may have actually been victims of the nocebo effect. Another recent study found that learning the results of a DNA test can influence your body independently of your actual genes. People who were told they had a high risk of obesity because of a lower genetic capacity for exercise experienced a decline not only in perception of their exercise ability but in their physiological capacity for it as well.
The placebo effect will never be a cure-all, but Colloca said she looks forward to a day when doctors don’t just unwittingly nocebo their patients by rattling off potential side effects, but actively try to harness the placebo effect, too. And we know that placebos can work, even without what Jefferson called a “fraud”: In recent years, researchers like Kaptchuk have even been informing their subjects that what they were taking was a placebo, and found that the placebo could still work. They called them “open-label” or “honestly prescribed” placebos. Given that, doing all we can to access the effect feels like a no-brainer to me.
"It will be nice, actually, to start to educate patients, to learn about the resources in our brain that we do not fully use," Colloca said. "As placebo scientists, we should try to provide a sort of tool kit to patients so that they can learn by themselves to use these self-healing strategies.”
I can’t change my experience with medicine, doctors, and my body overnight, so I’m probably stuck with the nocebo effect for a while. But I can try to teach myself to have new associations and experiences, and can try to access for myself that “tool kit” Colloca is talking about. It’s a nice thought: That anyone can be guided toward changing their experiences, even if they’re more prone to negative effects than positive ones.