More Than Two-Thirds of Adverse COVID-19 Vaccine Events Are Due to Placebo Effect

One-third of clinical trial participants who received no vaccine reported systemic adverse advents like headache and fatigue.

The placebo effect is the well-known phenomenon of a person’s physical or mental health improving after taking a treatment with no pharmacological therapeutic benefit – a sugar pill, or a syringe full of saline, for example. While the exact biological, psychological, and genetic underpinnings of the placebo effect are not well understood, some theories point to expectations as the primary cause and others argue that non-conscious factors embedded in the patient-physician relationship automatically turn down the volume of symptoms. Sometimes placebo effects can also harm –the so-called “nocebo effect” occurs when a person experiencing unpleasant side effects after taking a treatment with no pharmacological effects. That same sugar pill causing nausea, or that syringe full of saline resulting in fatigue.

In a new meta-analysis of randomized, placebo-controlled COVID-19 vaccine trials, researchers at Beth Israel Deaconess Medical Center (BIDMC) compared the rates of adverse events reported by participants who received the vaccines to the rates of adverse events reported by those who received a placebo injection containing no vaccine. While the scientists found significantly more trial participants who received the vaccine reported adverse events, nearly a third of participants who received the placebo also reported at least one adverse event, with headache and fatigue being the most common. The team’s findings are published in JAMA Network Open.

“Adverse events after placebo treatment are common in randomized controlled trials,” said lead author Julia W. Haas, PhD, an investigator in the Program in Placebo Studies at BIDMC. “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.”

Haas and colleagues analyzed data from 12 clinical trials of COVID-19 vaccines. The 12 trials included adverse effects reports from 22,578 placebo recipients and 22,802 vaccine recipients. After the first injection, more than 35 percent of placebo recipients experienced systemic adverse events – symptoms affecting the entire body, such as fever – with headache and fatigue most common at 19.6 percent and 16.7 percent, respectively. Sixteen percent of placebo recipients reported at least one local event, such as pain at site of injection, redness, or swelling.

In comparison after the first injection, 46 percent of vaccine recipients experienced at least one systemic adverse event and two-thirds of them reported at least one local event. While this group received a pharmacologically active treatment, at least some of their adverse events are attributable to the placebo – or in this case, nocebo – effect, as well given that many of these effects also occurred in the placebo group. Haas and colleagues’ analysis suggested that nocebo accounted for 76 percent of all adverse events in the vaccine group and nearly a quarter of all local effects reported.

After the second dose, adverse events among the placebo group dipped to 32 percent reporting any systemic events and 12 percent reporting any local effects. In contrast, participants who received the vaccine reported more side effects, with 61 percent reporting systemic adverse events and 73 percent reporting local adverse events. The researchers calculated that nocebo accounted for nearly 52 percent of the side effects reported after the second dose. While the reason for this relative decline in nocebo effects cannot be confirmed, the researchers believe that the higher rate of adverse events in the vaccine group the first time may have led participants 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,” said senior author Ted J. Kaptchuk, director of the Program in Placebo Studies and the Therapeutic Encounter at BIDMC and professor of medicine at Harvard Medical School. “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.”

Kaptchuk and colleagues are known for a large and growing body of evidence showing that full disclosure of placebo treatment, what he calls “open label placebo,” can actually improve common chronic conditions without any nocebo effects. While some researchers believe that informing patients about adverse effects may cause harm, Kaptchuk believes it is ethically necessary to fully inform participants about the vaccines’ potential adverse reactions.

“Medicine is based on trust,” said Kaptchuk. “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.”

Reference: “Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials” by Julia W. Haas, PhD; Friederike L. Bender, MS; Sarah Ballou, PhD; John M. Kelley, PhD; Marcel Wilhelm, PhD; Franklin G. Miller, PhD; Winfried Rief, PhD and Ted J. Kaptchuk, 18 January 2022, JAMA Network Open.
DOI: 10.1001/jamanetworkopen.2021.43955

Co-authors included Sarah Ballou, PhD, and John Kelly, PhD of BIDMC; Friederike L. Bender, MS, Marcel Wilhelm, PhD, and Winfried Rief, PhD of Philipps University Marburg; and Franklin G. Miller PhD, of Weill Cornell Medical College.

This work was supported in part by a postdoctoral fellowship by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD) to Haas.

Beth Israel Deaconess Medical CenterCOVID-19PlaceboPopularPublic HealthVaccine
Comments ( 17 )
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  • hungryhippoz

    So is it 2/3 or 1/3?

    • George M

      It’s written poorly, but it’s 2/3rds. They looked at reactions from the vaccinated and unvaccinated, noting that a certain percentage of the unvaccinated (nocebo) experienced side-effects. Therefore, a similar percentage of those who actually got vaccinated and reported side-effects may also be from nocebo.

  • Dr Robert Atkins

    Misleading headline. The data tells us nothing other than what has been known regarding any drug. This facts given in this article indicates most side effects are in fact – real.

    • George M

      “This facts given in this article indicates most side effects are in fact – real.”

      Actually, it doesn’t. The data reported said that over half (“nearly 52 percent”) of the reported side effects from those who got vaccinated (61% and 73%) were nocebo. That means that they concluded that less than half were real and not nocebo; i.e., less than most.

      In contrast, participants who received the vaccine reported more side effects, with 61 percent reporting systemic adverse events and 73 percent reporting local adverse events. The researchers calculated that nocebo accounted for nearly 52 percent of the side effects reported after the second dose.

  • SC

    “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.”

    This is overly optimistic. There is no way that any messaging about the ‘nocebo effect’ will break through the disinformation bubble that cause it in the first place.

  • Adam

    Why does nocebo side effects include pain and redness at the injection site? You jabbed your body with a metal object. Pain and redness could simply be caused by that and is not a nocebo effect, it’s a direct effect.

  • Dani

    While main stream media condemns using ivermectin the most populated area in India simply declared they’re actually COVID free after promoting this safe tested medicine. In addition to this, Ivermectin attaches covid spike proteins and stops them from binding to ACE2 receptors. I recommend everyone to have ivermectin for emergency situations https://truthpharmacy.com

  • Bruce Kee

    Tragically flawed. Note after the second dose of vaccine 73% report local Adverse Events that they attribute as nocebo for 52% of the events. So 35% adverse effects…like stroke,myocardial events and fatigue. (Why the 6 ft. Man drowned in a lake averaging 3 feet.)

  • Ducksworth

    Hey, you got a red mark and swelling from an injection? Oh, that’s a NOCEBO effect. Brilliant, Doctor Obvious. We already knew that. Why don’t you explain the people dying instead?

    That’s the real issue here, all those very real effects that are being reported. Heart issues, blood clots, strokes, rashes, menstrual disruptions, strange illnesses, and that pesky death thing. Even if only 33% of the reactions reported fall into this category, then that’s still a problem.

  • Wbrab

    Was my mom’s week of puking a placebo effect? She was just imagining she was puking her guts out and had a headache? How about my brother’s Diarrhea? Was that placebo?

  • Wbrab

    “Hey, you got a red mark and swelling from an injection? Oh, that’s a NOCEBO effect. Brilliant, Doctor Obvious. We already knew that. Why don’t you explain the people dying instead?”

    How preposterous. There were obviously genuine flu-like reactions in some of the people who’ve had the vaccine. But 225 million people are vaccinated and 4.53 BILLION people have been vaccinated around the world. The only refrigerated morgues left are full of people too stupid to get vaccinated. Period.

  • Longjohn119

    I have to disagree with this study’s basic conclusion

    The reason 2/3 are experiencing Side Effects is NOT because of the Placebo Effect per se but because of Right Wing Propaganda surrounding the vaccine. Right Wing Propaganda has drummed into everyone’s subconscious that the vaccines are bad for you because that’s just how Propaganda is designed to work

  • Jason

    How dishonest and myopic. No one gives a crap about headache and fatigue shortly after getting the vaccine. The concern is with serious and/or long lasting health effects, that is no way can be explained by placebo or ‘nocebo’ effects.

    By doing studies like this, targeted to avoid looking at the real issues, you are undermining trust and faith in science, researchers and doctors. You are intentionally avoiding the real issues and it will be seen by most as attempting to hide from potentially real problems. Unless they are complete idiots, which itself would be a bad sign, they understand this, and yet do it anyway.

  • The Duke of New York

    Headache is one thing, but show me how you can have psychosomatic Bell’s Palsy or a heart attack

  • Cedric

    Experts interviewed by ABC News said that if more people knew that experiencing side effects from the COVID-19 vaccines is not as common as they think, more people may be encouraged to get vaccinated. That it’s why is so important to write about placebo and how it is involved in all this vaccination story. More info about how this effect can affect your mind, you will find in a book by Randy Baker – net-bossorg/the-power-of-the-placebo-effect-by-randy-baker

  • XXXXXXXXXXXX

    So funny how this “study” just suddenly comes out. What a bogus bunch of BS. What is it, are we all the guinea pigs participating in a “vaccine trial” study without our knowledge? It’s a known fact that a certain percentage of the so-called vaccines being administered world-wide are merely placebos. The real “vaccines” are killing people. That’s no placebo effect. Filthy liars.

  • Joe

    Last findings lead us to suggest that informing the public about the potential for nocebo responses (net-bossorg/the-power-of-the-placebo-effect-by-randy-baker) could help reduce worries about Covid-19 vaccination, which might decrease vaccination hesitancy.