Study suggests 'nocebo effect,' not jabs, could be behind two-thirds of mild COVID-19 vaccine reactions

A new study that did a systematic review of COVID-19 vaccine trials suggests that the negative version of the placebo effect may be behind mild COVID-19 vaccine side-effects like headache and fatigue, and not the vaccines themselves.

The study, published in the JAMA Open Network on Tuesday, examined 12 COVID-19 vaccine trials in the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases that were published up until July 14, 2021.

The researchers behind the study say that according to a global survey from January 2021, 47 per cent of respondents were worried about adverse effects (AEs) from a COVID-19 vaccine, which may feed into vaccine hesitancy.

However, the study found that the “nocebo” effect accounted for approximately 76 per cent of all common AEs after the first dose of COVID-19 vaccine and close to 52 per cent after the second dose.

The nocebo effect refers to when a person experiences unpleasant side-effects after taking a placebo, and is thought to stem from negative expectations associated with taking the treatment.

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The researchers suggest that a large portion of common side-effects to COVID-19 vaccines like headaches, fatigue and pain in the arm are not from the vaccine, but from factors like anxiety and wrongly attributing various ailments with getting inoculated.

The findings suggest that approximately two-thirds of common side-effects that are reported in COVID-19 vaccine trials were prompted by the nocebo effect, especially headache and fatigue, which are often listed as common reactions after inoculation.

The study examined the AEs reported in the 12 trials, which included data on the participants who received a placebo (salt solution) instead of the vaccine. The study did not examine severe side-effects like myocarditis or blood clots.

Thirty-five per cent of the participants in the placebo cohorts reported side-effects like headaches and short-term fatigue, and 16 per cent reported arm pain, swelling or redness at the injection site.

Participants who received the real vaccine in the trials experienced more side-effects, with approximately 46 per cent reporting headache and fatigue and 66 per cent reporting at least one localized side effect such as arm pain, swelling or redness at the injection site.

The findings suggest that after the first vaccine dose, nocebo responses accounted for 76 per cent of “systemic” side-effects like headache and fatigue, and 24 per cent of localized AEs.

However, after the second dose, 32 per cent of the placebo cohorts reported systemic side-effects and 12 per cent reported localized AEs, compared with 61 per cent of the vaccine recipients reporting systemic side-effects and 73 per cent reporting localized AEs.

The study states that compared with the first-dose findings, the larger difference in adverse effects between the placebo groups and vaccine groups in the trials was found after the second dose.

However, ratios between adverse effect proportions in the placebo and vaccine cohorts of the trials indicated that nocebo responses accounted for 52 per cent of systemic side-effects and 16 per cent of localized AEs after the second dose.

The researchers posit that listing the common side-effects on COVID-19 vaccination leaflets may increase nocebo effects related to anxiety and expectations from the recipients, and say that an increase in transparent communication about nocebo responses may be helpful to the public.