When Expecting Side Effects Causes Them
In a trial of people who had quit statins, 90 per cent of the extra symptoms they felt on the drug also appeared on a dummy tablet. What the nocebo effect means.
By The Why We Project · Medical review: [REVIEWER: name to be added]
Key takeaways
- In the SAMSON trial, 60 people who had stopped statins rotated through statin, placebo and no-tablet periods; 49 completed it.
- Average daily symptom scores were 8.0 with no tablet, 15.4 on placebo and 16.3 on the statin.
- Of the extra symptoms felt on the statin compared with no tablet, about 90 per cent also appeared on placebo; half of the 60 later restarted statins.
- Nocebo symptoms are real symptoms; what differs is the cause.
- Do not stop or change a medicine without talking to your doctor or pharmacist.
This article is general information about research on expectations and side effects. It is not medical advice. Do not stop, start or change any medicine because of what you read here; talk to your doctor or pharmacist first. Medical review: [REVIEWER: name to be added].
Ninety per cent. In a trial of people who had given up statins because of side effects, that was the share of the extra symptoms they felt on the drug, over and above months with no tablet, that also appeared when they took an identical-looking dummy tablet. The pills without any drug in them made people feel almost as unwell as the pills with one. How can a tablet with nothing in it cause side effects, and what should anyone do with that knowledge?
What happened when people took nothing at all?
Statins are among the most widely prescribed medicines in the world, used to lower cholesterol and reduce the risk of heart attacks and strokes. Many people who start them report muscle aches and other symptoms, and some stop taking them as a result. A team of researchers set out to test how much of that was caused by the drug.
The trial, known as SAMSON, was first reported by Frances Wood and colleagues as a letter in the New England Journal of Medicine in 2020, with a full account led by James Howard in the Journal of the American College of Cardiology in 2021. Sixty people who had previously stopped statins because of side effects were randomised. Over the trial, each of them rotated through periods taking a statin, periods taking an identical placebo tablet, and periods taking no tablet at all, in a random order, with the statin and placebo tablets impossible to tell apart. Every day they scored their symptoms. Forty-nine completed the trial.
The average symptom scores tell the story on their own.
| What people were taking | Average daily symptom score |
|---|---|
| No tablet | 8.0 |
| Placebo tablet | 15.4 |
| Statin | 16.3 |
Taking a tablet nearly doubled people's symptom scores, whether or not the tablet contained the drug. The difference between the drug and the dummy was small. The researchers expressed this as a nocebo ratio of 0.90: of the extra symptoms people felt on the statin, compared with taking nothing, around 90 per cent were also present when they took placebo.
What happened afterwards is the part with the clearest practical meaning. Half of the sixty participants went back to taking statins afterwards.
This was a small trial, run on people who had already had a bad experience with statins, using one drug at one dose. It does not show that nobody gets side effects from statins. It shows that, for these participants, most of the symptoms they experienced were produced by taking a tablet rather than by the drug inside it.