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A new study has found that a significant number of people who were given a placebo during a COVID-19 vaccine trial reported experiencing side effects after receiving their shot. FG Trade/Getty Images
  • A significant number of people included in a new study reported experiencing unpleasant side effects after receiving the COVID-19 vaccine despite only receiving a placebo.
  • Researchers say this may be due to the “nocebo effect.”
  • The “nocebo effect” occurs when people perceive they’ve had negative effects from a treatment simply because they expect them to occur.
  • COVID-19 vaccine side effects are usually nonexistent to mild. Severe side effects are quite rare.

A group of American researchers say a portion of reported COVID-19 vaccine side effects may not be from the vaccines themselves.

Rather, the effects may be from what is known as the “nocebo effect.”

In fact, their research found that a significant number of people reported experiencing side effects despite having only received an inactive placebo injection.

The team came to the conclusion that there was a nocebo effect after performing a systematic review and meta-analysis of 12 articles including adverse event (AE) reports for 45,380 people.

Systemic AEs were reported by 35.2 percent of those who received their first dose of a placebo, while 16.2 percent reported at least one local AE.

Systemic AEs are those that occur away from the injection site, like having a headache after receiving an injection in your arm. Local AEs occur near the injection site.

Following the second dose, 31.8 percent of study participants said they had at least one systemic AE, while 11.8 percent reported at least one local AE.

Significantly more study participants reported an AE among those who did receive the vaccine, with 46.3 percent reporting at least one systemic AE and 66.7 percent reporting at least one local AE following the initial dose.

Following the administration of the second dose, 61.4 percent of study participants reported systemic AEs, while 72.8 percent reported local AEs.

When the researchers looked at the ratios between the vaccine and placebo groups, however, what stood out was that, after the first dose, the placebo groups accounted for 76 percent of all reported systemic side effects and 24.3 percent of local side effects.

Following the second dose, these figures dropped to 51.8 percent and 16.2 percent, respectively.

From this, the team concluded that the people who reported side effects after placebo injections must be experiencing a nocebo effect.

Dr. Nicholas Kman, an emergency medicine physician at The Ohio State University Wexner Medical Center, explained that the nocebo effect is related to the better-known placebo effect.

“Placebo effects are when an inert substance is given to someone and it provokes perceived medical benefits,” he said.

A placebo can be something like a sugar pill or an injection made with saline solution (salt water). It doesn’t have medicinal effects, but people may perceive that it does because they believe they have received the active treatment.

The nocebo effect is the opposite of this: The person receives an inert substance, but they believe it has caused them to experience negative effects.

Kman said there are a number of factors that can contribute to a person experiencing a nocebo effect.

This includes a person’s expectation that they will have an adverse reaction because they’d heard about another case in which one occurred.

It can also include people who may have had an adverse reaction to the first vaccination and anticipate the second dose or booster will cause the same.

Among other reasons Kman cited that influence a nocebo effect are:

  • drug packaging inserts
  • TV commercials highlighting possible side effects of drugs
  • information found on the internet and social media
  • anecdotes or comments from friends or relatives

He said these factors “can all contribute to the high incidence of nocebo responses to various treatments.”

However, Kman pointed out it’s unclear what, if any, role misinformation campaigns associated with COVID-19 vaccines might play in experiencing a nocebo effect.

Dr. Sanjeev Gupta, professor of medicine and pathology at Albert Einstein College of Medicine and member of the American Physiological Society, said the issue has not yet been studied.

However, he feels misinformation campaigns probably didn’t play a role in this particular study.

Gupta noted that, while fear and misinformation have been major reasons for vaccine hesitancy, study participants were volunteers, so they most likely would not have had the same concerns about vaccine side effects.

While reports of severe vaccine side effects have drawn a lot of attention, Gupta said the majority of people will have either no or minimal side effects from COVID-19 vaccines.

The more common side effects, according to Gupta, include:

  • injection site discomfort
  • feeling feverish
  • general aches and pains
  • transient fatigue lasting for a few hours.

“The likelihood of severe side effects is small, perhaps 1 in a million or fewer,” Gupta said.

“Interferences in physiological aspects of blood clotting have been reported in a handful of people with blockages of blood vessels or internal bleeding in the brain,” he added.

Gupta further explained that any allergic reactions can be identified within minutes and are typically treated shortly after vaccination.

In fact, in a recent study involving 19,586 adults who received a COVID-19 vaccine, it was found that allergic reaction or anaphylaxis was reported in only 0.3 percent of participants after partial vaccination and 0.2 percent of participants after full vaccination.

Kman noted that myocarditis and pericarditis have been reported, especially in adolescents and young adult males, within several days after COVID-19 vaccination.

“This is also rare and more likely to happen after COVID infection,” he said.

“Further, most patients with myocarditis or pericarditis who received care responded well to medicine and rest and felt better quickly,” Kman added.

Both Kman and Gupta agree that the benefits of COVID-19 vaccination greatly outweigh the small degree of risk associated with them.

“Not receiving it has serious implications, not only for the individual who refuses potentially lifesaving medication, but for the community,” said Kman.

He also pointed out that getting vaccinated reduces the risk of severe disease, hospitalization, and death.

“This has been shown over and over with real world experience,” he said.

Kman also noted that studies like this show that the perceived adverse reactions are not always causally related to the vaccine.

This suggests that some vaccinated people may believe they’ve had vaccine-related symptoms simply because they expect to, or because the event happened near the time of the vaccination.

Gupta added he believes the vaccines “absolutely and unequivocally” are worth it, especially for certain groups of people.

“The benefits of vaccination increase markedly for anyone at risk for severe disease, including those with many chronic conditions, immune deficiency states, organ transplantation, advanced age, and others,” said Gupta.