What is the Nocebo Effect?

Most of us are familiar with the placebo effect. The nocebo effect is its evil twin – lesser known but just as important.

The placebo effect refers to when people feel better after taking a pill, potion or other treatment with no plausible mechanism.

The nocebo effect is refers to the flipside: when someone feels worse after a treatment – but not due to its pharmacological properties. This effect has been seen with statins, aspirin, and more, and likely explains some COVID-19 vaccine side effects.

The nocebo effect is not fully understood. Studies suggest that it is driven by expectations, anxiety, hypervigilence, and background symptoms.

The nocebo effect is really important to consider when interpreting clinical trial results. In a 2022 study, Harvard researchers set out to quantify the nocebo effect in COVID vaccine trials. They found that about a third of placebo recipients reported some sort of side effect. Overall, they estimated that nocebo accounted for ~76% of systemic side effects after the first dose and ~52% after the second dose of the real deal.

Nerd note: the study did not include “base rates” of side effects in non-trial contexts. Thus, we don’t know whether fake shots caused a third of people to feel worse or whether the trials captured normal levels of fatigue, headaches, etc. It’s likely a bit of both.

Science in practice

Simply being aware of the nocebo effect is a good place to start. In some cases, it may be wise to focus less on potential negative outcomes, especially when rare. The trick is to find the right balance between exacerbating side effects and staying safe by monitoring them.

For example, when my kids got their COVID shots, I chose not to tell them that the shot may make them feel unwell, because I worried this could be a self-fulfilling prophecy. Instead, I discretely monitored them for the next few days.

The next time you read about a clinical trial, pay attention to both the treatment and placebo groups. If there is no placebo control, be sure to interpret with caution and skepticism.