Summary by Paul Bridgman, 22 February 2022


Side effects from taking statin tablets are driven by the act of taking tablets, rather than whether the tablets contain a statin. So says Prof Darrel Francis of Imperial College in the report of the SAMSON Trial.(1)


In a three-armed cross-over trial of active tablets placebo and no tablets, the SAMSON Study showed that it is the act of taking the tablets which causes the side effects. This is what is termed a “nocebo effect”. A placebo effect is a beneficial effect produced by a placebo or drug treatment which cannot be attributed to the properties of the treatment itself. A nocebo effect is a similar effect that is negative or noxious, such as myalgia or muscle cramps with statins.


In the SAMSON Study, there were 60 participants with self-reported statin intolerance. They were randomised into a 12 month protocol. For each month the patients would be given a bottle containing either atorvastatin 20mg, matching placebo, or no tablet. Months were allocated in random order and the study was double-blind.


The planned statistical analysis was complicated because the investigators incorrectly assumed that every individual participant would have substantially more symptoms whilst taking active drug than not. As patients exited the study it became clear that a number of patients had significantly less symptoms on active drug than at other times. Supplementary analyses were therefore performed. From these Francis reports that stopping medications was no more frequent with statin therapy than with placebo (p = 0.17), and that subsequent symptom relief was similar between statin and placebo. The nocebo ratio was 0.9.


The study results are concordant with several randomised controlled studies in which side effect rate from placebo was very similar to that with statin. An implication of the SAMSON Study is that it is wrong to interpret rapid symptom-decline with stopping tablets as evidence that statin was the cause. The data also argues against the use of a second therapeutic challenge with statins as a means of scientifically proving the association with the tablets and side effects is cause and effect due to the statin. In clinical practice an informal experiment of a second trial of taking active drug, which patients and clinicians often use to test causation, may paradoxically confirm a non-existent association.


What does this mean for management of our statin-intolerant patients? These are real side effects. The data increases our certainty as to their cause and informs discussion with patients around what are very troublesome symptoms.



  1. James P. Howard (et al). 2021 Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment. Journal of American College of Cardiology.