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    Path to Science

    Thinking Dictionary

    Nocebo effect

    What it is

    The nocebo effect is the dark twin of the placebo effect. Expecting to feel bad can make you feel bad. Negative expectations can produce real, unpleasant symptoms.¹

    Even the way side effects are explained can play a part.¹ Read a long list of possible side effects, and ordinary aches and pains can start to feel like the medicine's fault. Sometimes they genuinely get worse.

    The Placebo effect entry explains the basics of placebos. This entry looks closely at one careful study of the nocebo effect, and at what it means for you.

    Safety note: Nothing here means you should stop a medicine or ignore a side effect. Some side effects really are caused by the medicine. If you think a medicine is giving you side effects, talk to your doctor.

    Nocebo symptoms are real

    The nocebo effect doesn't mean people are imagining things or faking. The symptoms are real and unpleasant. What studies of the nocebo effect show is something different: sometimes the symptoms aren't being caused by the chemistry of the medicine, but by other things, including what people expect.²

    A careful test: the SAMSON trial

    Statins are common pills that lower cholesterol. Some people stop taking them because of side effects, such as aching muscles. Researchers in the SAMSON trial wanted to know how much of that was caused by the pills themselves.

    They recruited 60 people who had already stopped taking statins because of side effects. Each person took monthly bottles of tablets for a year, in random order:

    • 4 months with a statin,
    • 4 months with a placebo, a dummy tablet with no active ingredient,
    • 4 months with no tablets at all.

    The people taking part didn't know which tablets were real and which were dummies. Every day, they scored their symptoms. Forty-nine of them completed the trial.³˒²

    What they found:

    • With no tablets, the average daily symptom score was 8.0.
    • On statins, it was 16.3.
    • On dummy tablets, it was 15.4.

    There was no significant difference between the statins and the dummy tablets. About 90% of the symptoms that came with taking statins also came with taking dummy tablets.² Six months after the trial, half of the people were back on statins.²

    What it doesn't show: SAMSON was small, and it included only people who had already stopped statins. It doesn't mean that all side effects of all medicines are nocebo effects. It shows something about these symptoms, in this group of people.

    Why it matters

    The nocebo effect explains why someone can feel worse on a medicine without the medicine's chemistry being to blame. That matters, because people sometimes stop useful treatment for that reason. But the answer is not to dismiss anyone's symptoms. It is to find out, carefully, what is really causing them, as SAMSON did.

    It also raises a hard question for doctors: how do you tell patients honestly about possible side effects without making them more likely to feel them? That is still being discussed.¹

    In everyday life

    • Reading the leaflet. Many listed side effects, like headaches, tiredness, or mild nausea, are things people get from time to time anyway. It can be hard to tell whether the medicine caused them.
    • Online reviews of medicines. Stories of side effects are memorable and can shape what you expect to feel.
    • After a scary headline. If you read that something "causes" a symptom, you may notice that symptom more.

    The common trap

    The first trap is thinking that nocebo means faking it. It doesn't. The symptoms are real.

    The second trap is going too far the other way: "If dummy tablets cause the same symptoms, the medicine must be harmless." That was true for these symptoms in this trial. It isn't true in general.

    Some ways out:

    • Talk to your doctor about any side effects, rather than stopping on your own.
    • Ask how we'd know. The fair way to tell whether a medicine causes a symptom is to compare it with a placebo, ideally with blinding, so that nobody knows who got what. See the Blinding entry.
    • Remember that everyday symptoms happen anyway. Not every ache after starting a new pill is caused by the pill.

    Try it

    Look at the list of common side effects in any medicine leaflet. Circle the ones that most people get from time to time anyway, such as headache, tiredness, or mild nausea. For each one, ask: how could anyone tell whether the medicine caused it? (Answer: by comparing with a placebo group, as SAMSON did.)

    Please don't test this on your own medicine. If you have concerns, talk to your doctor or pharmacist.

    Related concepts

    Placebo effect · Blinding · Randomized controlled trial · Regression to the mean · False positives and false negatives

    Sources

    1. Colloca, L., & Miller, F. G. (2011). The nocebo effect and its relevance for clinical practice. Psychosomatic Medicine, 73(7), 598–603. https://doi.org/10.1097/PSY.0b013e3182294a50

    2. Howard, J. P., Wood, F. A., Finegold, J. A., Nowbar, A. N., Thompson, D. M., Arnold, A. D., Rajkumar, C. A., Connolly, S., Cegla, J., Stride, C., Sever, P., Norton, C., Thom, S. A. M., Shun-Shin, M. J., & Francis, D. P. (2021). Side effect patterns in a crossover trial of statin, placebo, and no treatment. Journal of the American College of Cardiology, 78(12), 1210–1222. https://doi.org/10.1016/j.jacc.2021.07.022

    3. Wood, F. A., Howard, J. P., Finegold, J. A., Nowbar, A. N., Thompson, D. M., Arnold, A. D., Rajkumar, C. A., Connolly, S., Cegla, J., Stride, C., Sever, P., Norton, C., Thom, S. A. M., Shun-Shin, M. J., & Francis, D. P. (2020). N-of-1 trial of a statin, placebo, or no treatment to assess side effects [Letter]. New England Journal of Medicine, 383(22), 2182–2184. https://doi.org/10.1056/NEJMc2031173