Meet the nocebo effect, the placebo effect's evil twin that makes you feel pain

Some researchers think this is what’s fueling the gluten-free diet fad. People have developed a negative expectation that eating gluten will make them feel bad. And so it does, even though they may not have any biological gluten sensitivity.The placebo effect is one of the most mystifying phenomena in medicine. When we expect a pill to make us feel better, it does. If we see others get better while using a medicine, we will too.

Doctors even see a placebo response in patients who are told they are on a placebo. And the more invasive, expensive, and drastic the placebo intervention, the greater the healing effect. Fake surgeries — where doctors make some incisions but don’t actually change anything — make people feel better than placebo pills alone.
But the placebo effect has an evil twin: the nocebo. It can kick in when negative expectations steer our experience of symptoms and create side effects where none should occur.


This means, incredibly, that you can get side effects from a sugar pill. And sometimes these side effects are so severe that patients drop out of clinical trials, as a 2013 paper in Nature Reviews explains. A review of fibromyalgia drug trials revealed that 72 percent of people who left the trial did so because they felt severe side effects while on placebo.

Or take statins, the most prescribed class of drug in America. They work to lower blood cholesterol and help prevent heart attacks. But people commonly report muscle aches while on the drug. Sometimes the aches are painful enough that people stop taking the drugs, which then puts them at risk for heart disease. Recent evidence suggests that the muscle aches might be a big nocebo.

There’s been a lot of recent fascinating scientific work trying to find ways to maximize the placebo effect, so that doctors can squeeze out the maximum therapeutic benefit from drugs. But scientists are also learning there are ways to minimize or maximize the nocebo effect too.

A fascinating recent study in Science shows one possible way: When patients are led to believe one drug is less expensive than another, they’re also less likely to report painful side effects.

How expensive-looking packaging can alter perception of side effects
In the new experiment published in Science, participants were told they were taking part in a study to test out a new anti-itch cream. They were also told the anti-itch cream had the side effect of making people more sensitive to heat.

The experimenters wondered: Could they manipulate the power of the nocebo effect, and make participants feel more or less pain after using the cream by priming them with an expectation?

In placebo studies, more expensive, involved procedures in which participants are aware of the higher cost and complexity tend to produce a higher placebo response. The researchers here wondered if the same applied to nocebo.

Half the participants were led to believe the drug was expensive. How: It came in a sleek blue packaging and was called “Solestan” — reminiscent of the expensive brand-name drugs you may see advertised on TV.


The other half of the participants were led to believe they were testing an inexpensive generic cream called “Imotadil-LeniPharma Creme,” which came in ugly orange-and-white packaging. It’s giving me a rash just looking at it.



A survey found that the participants did, indeed, rate the blue-packaged drug as costing more than the one in the stripped-down packaging. But in reality, both creams were the same placebo schmear, which contained no active drug whatsoever.

To test the side effect question, the researchers spread some cream on the participants’ arms. Then they hooked up that patch of skin to a device that delivered some mild heat. To fool the participants, they also hooked up another patch of untreated skin to the same machine. But they only turned up the heat on the patch of skin that had the cream. This trick was to ensure that the participants believed they were experiencing the side effect.

Then the trials began. Participants in both the expensive and inexpensive cream groups were exposed to the exact same levels of heat. The scientists kept asking: How much did that hurt?

There was a big, clear, unmistakable difference. The participants who had the “expensive” cream thought it hurt a lot more.

How is this possible?
Like the placebo effect, the nocebo effect is influenced by expectations. And that’s what the researchers think is happening here. People guess a more expensive medication should be more potent and lead to more skin problems.

“The most likely explanation is that participants infer that expensive medication contains a more potent and effective agent and, consequently, produces more side effects,” the researchers conclude.

Some researchers suspect the nocebo effect is partly fueling the gluten-free diet fad. People have developed a negative expectation that eating gluten will make them feel bad. And so it does, even though they may not have any biological gluten sensitivity.

What researchers have realized in the past two decades is that the placebo and nocebo effects don’t just change how we talk about symptoms. Neuroscience studies find evidence that they actually change the way we perceive pain in the brain. And that’s what the researchers in this latest Science paper found too. An fMRI scan of the participants’ brains and spinal cords (which processes our pain response) provided evidence that not only were these participants saying they felt more pain, but they were experiencing it differently too.

Given the real therapeutic power of the placebo effect, there’s been a small but growing thread of research looking into whether it can be harnessed to help treat diseases. It’s surprisingly promising. Through placebo conditioning, it may be possible to maintain the same level of drug effectiveness while taking less of the drug. Overall, this research forces doctors to consider that the context in which medicine is given can make a big difference in how people feel.

But it’s still hard to know the best way to harness the placebo effect and downplay the nocebo effect. This Science study shows the healing power of the placebo isn’t limitless — because where placebo lurks, nocebo may lurk too.