‘Nocebo effect’ may be behind two-thirds of Covid vaccine symptoms, study suggests

Nearly one-third of all participants who received a placebo in 12 vaccine trials reported at least one adverse event

Nearly two-thirds of reported adverse effects to vaccination against Covid-19, such as headaches and fatigue, could be due to the “nocebo” effect – a negative version of the placebo effect – a new study has suggested.

While under the placebo effect, a person’s health improves after taking treatment with no pharmacological therapeutic benefit, such as a sugar pill, or a syringe full of saline, the nocebo effect occurs when individuals experience unpleasant side effects after a similar treatment, the scientists at Beth Israel Deaconess Medical Center (BIDMC) in the US said.

The researchers assessed data from 12 clinical trials of Covid-19 vaccines, and compared the rates of adverse events reported by participants who received the vaccines to the rate of side effects experienced by those who received a placebo injection containing no vaccine.

While a significant number of those who received the vaccine reported side-effects, the study, published in the journal JAMA Network Open on Tuesday, reported that nearly a third of trial participants who got the placebo jab also reported at least one adverse event.

In the 12 trials, the researchers say, adverse effects were reported by 22,578 placebo recipients and 22,802 vaccine recipients.

Over 35 per cent of placebo recipients reported experiencing symptoms affecting the entire body, such as fever – with headache and fatigue most common at 19.6 percent and 16.7 percent.

Scientists noted that 16 per cent of placebo recipients reported at least one local event, such as pain at site of injection, redness, or swelling.

In comparison, they said, 46 per cent of vaccine recipients experienced at least one systemic adverse event and two-thirds of them reported at least one local event after the first jab.

While this group received the actual vaccine active treatment, researchers said that at least some of their reported side effects are attributable to the nocebo effect given that many of these same effects also occurred in the placebo group.

The study suggested that nocebo effect could account for over three-quarters of all adverse events in the vaccine group and nearly a quarter of all local effects reported.

“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,” the study’s senior author Ted J Kaptchuk, professor of medicine at Harvard Medical School, said in a 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,” Dr Kaptchuk added.

After the second dose, the analysis found that adverse events among the placebo group dipped to 32 per cent reporting any systemic events, and 12 per cent reporting any local effects.

In contrast, researchers said that the participants who received the vaccine reported more side effects, with 61 per cent reporting systemic adverse events and 73 per cent reporting local adverse events.

The study estimated that nocebo could account for nearly half of the side effects reported after the second dose.

While the reason for this relative decline in nocebo effects between the two doses could not be confirmed in the study, researchers suspect the higher rate of adverse events in the vaccine group the first time may have led participants to anticipate more the second time.

However, the scientists also advised caution while interpreting the results. They said that the relatively small number of included trials in the analysis and the high level of heterogeneity between the trials are some of the study’s limitations.

For instance, some of the included trials in the study adopted different methods to assess adverse events in patients with different symptom checklists, and also involved different types of Covid-19 vaccines – mRNA, protein-based, and viral vector-based.

While the researchers believe the findings of high nocebo responses are still relevant for everyday health care, they have called for larger meta-analyses to further investigate the role of these adverse event causes noted in the study.

“Our findings lead us to suggest that informing the public about the potential for nocebo responses could help reduce worries about Covid-19 vaccination, which might decrease vaccination hesitancy,” Dr Kaptchuk concluded.