Those adverse COVID-19 vaccine side effects your friend told you they experienced may have been all in their head, according to a recent study conducted by researchers at Harvard Medical School and Beth Israel Deaconess Medical Center. 

The study represents a meta-analysis of 12 vaccine trials with a total of 45,380 participants. The researchers found that 76% of the adverse side effects (such as fatigue or headache) that people experienced after receiving their first COVID-19 vaccination were also reported by participants who received a placebo shot. Such results are known as the placebo (or nocebo) effect — meaning the purported side effects were not caused by the vaccine itself.

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What’s more, while the study showed that mild adverse side effects were more common among participants who received the vaccine, more than a third of participants who received the placebo shot also reported at least one adverse side effect. 

A placebo is an inactive treatment or substance (a sugar pill or a syringe full of saline, for instance) commonly used in medical research to establish a control group and to help scientists determine the safety and effectiveness of a treatment. The placebo effect in a person “is a phenomenon where the body has a reaction or response to that inactive treatment,” said Dr. Richard Dang, president of the California Pharmacists Association and assistant professor of clinical pharmacy at the University of Southern California.

Our minds are impressionable, and placebos have been shown to be beneficial such as when a restless patient is given the equivalent of a sugar pill but told it would help them sleep better. ”People taking a placebo may rest better simply because that is expected,” explained Dr. Joseph Larkin, a microbiologist at the University of Florida. But when a patient expects pain or harm to come from a treatment, they experience something known as the nocebo effect — basically a negative placebo effect. 

While placebos are commonly used in clinical trials, the statistic citing 35% of placebo recipients in the Beth Israel study reporting adverse side effects is unusually high. Dr. Julia W. Haas, an investigator in the Program in Placebo Studies at Beth Israel Deaconess and the study’s lead author said she was “surprised by how large the nocebo responses actually were.” 

One explanation multiple experts provided for such a high number of placebo recipients claiming adverse side effects is the rampant misinformation circulating on social media about the purported dangers of COVID-19 vaccines and the sheer volume of media coverage devoted to the topic of vaccination throughout the pandemic. ”Negative information in the media may increase negative expectations towards the vaccines and may therefore enhance nocebo effects,” Haas said, adding: “Anxiety and negative expectation can worsen the experience of side effects.” 

“After receiving a placebo, the body or mind may believe that it is receiving a treatment and react in a way that it thinks it should,” Dang offered. He explained that placebo recipients who were told on social media that the vaccines were unsafe may have been looking for problems that weren’t actually there. ”Confirmation bias could absolutely be a factor in the rates of side effects reported after (receiving) a placebo,” he said. 

Placebo or nocebo responses are also known to be connected to how a clinician administers the treatment and whether they demonstrate empathy, warmth or competence to the patient or participant. One’s individual misdiagnosis is another potential explanation. “Individuals tend to be more hyperaware of their body after receiving a treatment and may attribute something like a headache (that would have occurred anyway) to a treatment received,” Dang said. 

While this study shows a shockingly high number of placebo responses to COVID-19 vaccines, valid side effects do occur for many individuals. The CDC lists common mild vaccine side effects a person may experience, including pain/swelling at the injection site, or fatigue, headache or nausea throughout one’s body for a day or two following vaccination. Serious adverse side effects such as an allergic reaction are very rare. 

Studies like this are nonetheless important because research has shown that informing patients about potential placebo/nocebo responses and providing an accurate framing of possible effects may reduce levels of anxiety and vaccine hesitation. 

“This study shows that side effects that are expected from a COVID-19 vaccine may actually be attributed to the placebo effect, and not the vaccine itself,” Dang said. “This information can be used to reassure individuals that the side effects from the vaccine may actually not be as common as previously believed. This, along with all of the safety data generated from the clinical trials and CDC surveillance systems, paints a clear picture that the COVID-19 vaccine remains to be a safe, and important, tool in our battle against the pandemic.”