Nocebo responses explain up to 76% of COVID vaccine side effects

A drive-up COVID-19 vaccine site is located in Reno, Nevada.

The tendency to cause mild symptoms that signal immune responses firing up after a shot has been a feature of safe and effective COVID-19 vaccines. Families, friends, and coworkers swapped stories of their harrowing post-jab days as vaccine supplies were unleashed in the US last year.

The experiences may not be connected to the vaccines. As more and more results from randomized-controlled vaccine trials hit science journals, researchers kept noting that, while trial participants often reported mild symptoms after shots, so too did the participants who received placebos.

When an intervention leads people to report health benefits that couldn't possibly have been caused by a fake treatment, it's known as a "placebo effect." People can experience a certain amount of psychosomatic benefits from the placebo effects. A placebo will not cure cancer, but it can lead people to feel better, for example.

There is a dark side to placebos. When people are expecting harmful side effects, the harmless interventions can lead to them reporting them. The phantom adverse reactions are called "nocebo responses." Nocebo responses are thought to stem from expectations of side effects, anxiety-induced effects, and the mistaken attribution of common, nonspecific ailments, like headaches, to the placebo.


The vaccine nocebos.

A new study quantified the role that nocebo responses played in the trials of COVID-19 vaccines. The meta-analysis looked at side-effect data from 12 high-quality randomized clinical trials testing various COVID-19 vaccines against placebo control groups. After the first vaccine dose, 76 percent of adverse reactions were caused by nocebo, while 52 percent of adverse reactions were caused by the second vaccine dose.

The researchers concluded that the rates of side effects in the placebo groups were very high. The study found that fatigue and headaches are associated with nocebo, and are among the most common side effects.

The point of this analysis is not to make you question your sanity. The main point is that these nocebo responses are making safe, life-saving vaccines seem less pleasant than they actually are, and that is a reason why some people choose not to get vaccine.

"Informing the public about the potential for nocebo responses may help reduce worries about COVID-19 vaccination, which might decrease vaccination hesitancy," they wrote. According to some clinical evidence, making people aware of nocebo responses can also lower their expectation for side effects.

Real effects.

Local reactions and side effects after the second dose of a COVID-19 vaccine are real, and not all side effects are nocebo responses.

About 35 percent of placebo recipients reported at least one systemic side effect after their first faux dose, according to the meta-analysis. After getting their first real dose, 46 percent of vaccine recipients reported at least one systemic side effect. The researchers looked at the severity levels of the side effects and found that they were similar to the severity levels of the vaccine groups. The vaccine group didn't collectively report more severe side effects than the placebo group. The local side effects were different. Only 16 percent of placebo recipients reported local side effects, like pain or swelling at the injection site, while 67 percent of the vaccine group reported such effects.

There were more differences after the second dose. The placebo group reported at least one systemic effect, while the vaccine group reported at least one systemic effect. The vaccine group reported more moderate to severe systemic effects than the placebo group. The vaccine group had more local side effects than the placebo group, with 73 percent reporting them, and only 12 percent reporting them.

The nocebo responses seem to be skewing our experience with the COVID-19 vaccines, which are being used around the world. The researchers argue that highlighting the potential for nocebo responses could reduce side effects.