Nearly One-Third of Individuals Report Systemic Adverse Events With COVID-19 Placebo Vaccine


A sizable number of clinical trial participants say they had at least 1 AE, with fatigue and headaches the most common.

In a new meta-analysis of placebo-controlled, randomized COVID-19 vaccine trials investigators from Beth Israel Deaconess Medical Center (BIDMC) compared the rates of adverse events (AEs) reported by individuals who received the vaccines to the rates of AEs reported by those who received a placebo injection containing no vaccine.

Although investigators found significantly more individuals who received the vaccine reported AEs, approximately one-third of individuals who received the placebo also reported at least 1 AE, with fatigue and headaches the most common.

“Adverse events after placebo treatment are common in randomized controlled trials,” Julia Haas, PhD, an investigator in the program in placebo studies at BIDMC, said in a statement. “Collecting systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide, especially because concern about side effects is reported to be a reason for vaccine hesitancy.”

The placebo effect is a well-known phenomenon of an individual’s mental or physical health improving after taking a treatment with no pharmacological therapeutic benefit. However, some placebo effects can also cause harm, called the nocebo effect, which occurs when an individual experiences unpleasant AEs after taking a treatment with no pharmacological effects.

The investigators analyzed data from 12 clinical trials of COVID-19 vaccines. The 12 trials included AE reports from 22,578 individuals who received the placebo and 22,802 individuals who received the vaccine.

After the first injection, more than 35% of individuals who received the placebo experienced systemic AEs with headaches occurring in approximately 19.6% of individuals and fatigue occurring in approximately 16.7%. Approximately 16% of individuals who received the placebo reported at least 1 local event, such as pain at the injection site, redness, or swelling. By comparison, approximately 46% of individuals who received the vaccine experienced at least 1 systemic AE after the first injection, and about two thirds reported at least 1 local event.

Although this group received a pharmacologically active treatment, at least some of these AEs are attributable to the placebo/nocebo effect, given that many of these effects also occurred in the placebo group. The analysis suggested that the nocebo effect accounted for approximately 76% of all AEs in the vaccine group and nearly one-quarter of all local effects reported.

After a second dose, AEs among the placebo group declined to approximately 32% in systemic events reported and about 12% in any local events reported. However, individuals from the vaccine group reported more AEs, with approximately 61% reporting systemic events and approximately 73% reporting local events.

Investigators estimated that the nocebo effect accounted for nearly 52% of the AEs reported after the second dose. Although the reason for this decline in the nocebo effect cannot be confirmed, the investigators thought that the higher rate of AEs in the vaccine group the first time may have led individuals to anticipate more the second time.

“Nonspecific symptoms like headache and fatigue, which we have shown to be particularly nocebo sensitive, are listed among the most common adverse reactions following COVID-19 vaccination in many information leaflets,” Ted Kaptchuk, director of the program in placebo studies and the therapeutic encounter at BIDMC, said in the statement. “Evidence suggests that this sort of information may cause people to misattribute common daily background sensations as arising from the vaccine or cause anxiety and worry that make people hyper alert to bodily feelings about adverse events.”.

The findings were published in JAMA Network Open.


Placebo effect accounts for more than two-thirds of COVID-19 vaccine adverse events, researchers find. EurekAlert. News release. January 18, 2022. Accessed January 19, 2022.

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