Side Effect Patterns in Statin, Placebo, and No Treatment

Quick Takes

  • A placebo is a substance without medical effects, which benefits the health status because of the belief that the substance is effective. The nocebo is defined as a substance without medical effects, but which worsens the health status of the person taking it by the negative beliefs and expectations of the patient.
  • In persons who abandon statins because of symptoms, the most common is the nocebo effect.
  • Of those who abandon statin therapy because of side effects, about 50% will restart when shown they have the nocebo effect. The N of 1 placebo-controlled study of statins should be considered for statin-intolerant patients.

Study Questions:

Are there differences in daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins?


The SAMSON (Self-Assessment Method for Statin Side-effects Or Nocebo) trial, conducted in 17 referral centers in the United Kingdom, enrolled participants with statin side effects within 2 weeks sufficiently severe enough to have abandoned statin therapy. Many had tried several statins. Participants received 12 1-month medication bottles, four containing atorvastatin 20 mg, four placebo, and four empty. Daily symptom intensity was measured for each using an app (scale 1-100). Nocebo effect was measured by a “nocebo” ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. Exclusion criteria included concomitant use of fibrates or “dangerous side effects.” Study required two visits, no blood tests, and other contact by telephone or smartphone.


Of the 284 potentially eligible, a total of 60 participants were randomized and 49 completed the 12-month protocol, and 59 responded to the 6-month post-trial follow-up. Mean age was 65.5 (8.6) years, 58% were male, mean body mass index was 29 (6.7) kg/m2, and 77% were treated for primary prevention. All had abandoned statins after trying a median of two statins, with median previous statin duration 1.06 years (interquartile range, 0.13-3.30 years). The most common symptom for abandonment prior to enrollment was “muscle ache” in 60%, fatigue or tired in 15%, and cramps in 10%. Mean symptom score was 8.0 (95% confidence interval [CI], 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI, 13.0-19.6; p < 0.001), but also in placebo months (15.4; 95% CI, 12.1-18.7; p < 0.001), with no difference between the two (p = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (odds ratio [OR], 1.02; 95% CI, 0.98-1.06; p = 0.28) nor extent of symptom relief on stopping (OR, 1.01; 95% CI, 0.98-1.05; p = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (p = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins.


The majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo.


Considering the cost benefit of generic statins for both primary and secondary atherosclerotic cardiovascular disease prevention, the findings support being able to do an N of 1 study for patients who have typical or atypical symptoms from statins. With approval from the patient, insurers should consider reimbursement for a trial.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Prevention, Nonstatins, Novel Agents, Statins

Keywords: Atorvastatin, Body Mass Index, Fatigue, Fibric Acids, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Muscle Cramp, Myalgia, Nocebo Effect, Primary Prevention, Secondary Prevention, Smartphone

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