The placebo effect happens when you take an inactive treatment — like a sugar pill — and feel yourself getting better. The nocebo effect is the placebo effect’s evil twin: It’s when you’re warned of an actual drug’s negative side effects and then experience them — even though you received a placebo.

This phenomenon happens frequently in drug trials when patients receiving a placebo experience the same side effects as the patients receiving the actual medication, which obviously makes studying drugs difficult and is worrying for doctors who don’t want to cause their patients any unnecessary distress.

To figure out what drives this phenomenon and how to prevent it, a team of researchers at University Medical Center Hamburg-Eppendorf in Germany put patients in an fMRI machine after giving them different placebos with different price tags to find out whether the price people pay for a drug has any effect on whether they feel its “effects.”

In the team’s paper, published Thursday in Science, they outline an experiment in which they divided 49 healthy subjects into two groups and gave both a placebo skin ointment and told them a side effect of the treatment was increased pain sensitivity. Nobody received any actual medication. The researchers told one group of patients that their skin ointment was more expensive than the other.

“It has been shown that price information or value has an influence on the placebo effect. An expensive medication leads to a greater placebo effect compared to a cheap medication,” Alexandra Tinnermann, a Ph.D. student and first author of the paper, tells Inverse. “So we were interested to find out if value also influences the nocebo effect.”

01 Siemens MAGNETOM Trio
Using fMRI images of patients' brains, scientists found that neurological activity was responsible for the nocebo effect in which patients show side effects when they receive a placebo.

Indeed, their results support the hypothesis that price also has an impact on the nocebo effect. In the paper, they report that patients who received the supposedly more expensive placebo reported more severe sensitivity to pain. By examining the subjects’ brains in action inside an fMRI machine, the researchers gained a greater understanding of how a person’s brain can be primed to experience pain and make them become more sensitive to pain when receiving a placebo treatment. This occurs, the researchers say, because of the way that what a doctor tells a patient about a treatment can prime their brain to expect a certain negative effect.

“There is a set of reactions in the brain and in the spinal cord that show that what patients report — in this case, higher pain — is actually true because there is a larger activation of areas that are critical for saying a stimulus is painful,” Luana Colloca, an associate professor of medicine at the University of Maryland School of Nursing who was not involved in this study, tells Inverse.

Knowing this, Colloca and Tinnermann say, it’s important for researchers and clinicians to figure out how to move forward. This research suggests that when a doctor informs a patient that a procedure might be painful, the doctor could actually be priming a patient for a more severe nocebo effect. But it would be highly unethical for a doctor not to disclose possible side effects. To put it simply, untangling the nocebo effect will require a lot more research.

It’s still pretty early days for this area of study, but Tinnermann says the effect she and her colleagues observed is exactly why they’re conducting this research.

“The goal of nocebo research is to find out which factors might influence nocebo-related effects in patients in order to minimize or prevent them.”