When It Really Is All in Your Head: Placebo and Nocebo Effects on Health

How we experience the world is shaped by our expectations. This is especially true in health, where people can feel better simply because they anticipate improvement (the “placebo effect”), or feel worse when they expect harm (the “nocebo effect”). “Nocebo” is Latin for “I will harm,” and it describes ill effects caused by the suggestion or belief that something is dangerous.

The Framingham Heart Study illustrated this vividly: women who believed they were prone to heart disease were nearly four times more likely to die than women with the same risk factors who did not have that belief (1). An even more extreme version is “voodoo death,” in which the belief of being cursed triggers fear, stress, and sympathetic overload, sometimes leading to sudden cardiac death.

Placebo and Nocebo Effects Are Real

Placebo and nocebo effects are real and grounded in psychology and neurobiology. Believing something will help or harm you and then having it shape your outcome does not mean you are “crazy.” It is how our brains and bodies are wired, and it makes evolutionary sense. What bothers me as a clinician is how often patients with nocebo effects are dismissed, while doctors happily take credit when patients benefit from placebo effects.

Indeed, 25% to 50% of the effect of medications on symptoms is due to placebo. For example, in many pain trials, patients receiving placebo report improvements of 20-30% on standard pain scales, while those on active drugs improve by 40-60%. In other words, about half of the observed benefit comes from expectation and belief, not from the drug itself (2). As one of my mentors used to say, “The best doctors have the best placebos” — not because they handed out sugar pills, but because they instilled confidence and positive expectations.

How Placebo and Nocebo Effects Work

Several psychological mechanisms explain these effects (3):

· Conditioning: pairing pill-taking with a side effect can make even the sight of a pill bottle trigger symptoms. A classic example is anticipatory nausea in patients on their way to chemotherapy.

· Verbal suggestion: what a clinician says can seed expectations. Telling a patient, “Call me if you get muscle aches, because it could lead to kidney damage” virtually ensures more reports of pain.

· Observational learning: seeing or hearing about how others react to treatment can amplify one’s own symptoms, even when the stimulus is weak.

These pathways have neurobiological underpinnings. Anticipatory anxiety activates neurochemical systems that heighten pain transmission and trigger stress responses. Brain imaging confirms that expectation changes activity in pain and reward centers. These effects are not imaginary — they are biologically real.

What Statins Can Teach Us About Expectations in Medicine

The nocebo effect is highly relevant in clinical medicine, particularly with statin therapy. Muscle aches are one of the most common reasons patients stop these safe and effective medications, yet true statin-induced muscle injury is very uncommon (estimated at <1 in 2,000). Before the mid-2000s, such complaints were unusual. Their sudden rise coincided with the growth of the internet, where negative stories about statins became widespread.

The landmark ASCOT trial shed light on this (4). In its blinded phase, patients randomized to atorvastatin 10 mg or placebo reported muscle symptoms at almost identical rates of about 2% per year. But once the trial was unblinded, muscle complaints were 41% higher in those who knew they were on statins. In another trial of patients who had stopped multiple statins due to muscle aches, 78% were able to tolerate atorvastatin 20 mg when they did not know whether they were taking it or placebo (5) . Clearly, expectations were playing a major role.

Proof of the Nocebo Effect with Statins

The strongest evidence for a nocebo effect with statins comes from two recent trials. The SAMSON trial enrolled 60 patients who had stopped statins due to muscle symptoms (6,7). Each month, they were randomly assigned to one of three identical pill bottles: one was empty, one had placebo tablets, and one had identically matching atorvastatin 10 mg tablets, so they did not know if they were taking stain or placebo. Every day they rated their symptoms on a smartphone app. The results are striking, and the numbers are easy to understand. After a year, the average symptom scores were 8.0 on no pill, 15.4 on placebo, and 16.3 on statin. This meant 90% of the symptoms blamed on statins were also seen on placebo. Nearly half were present even in the absence of any pill — the aches and pains of daily life. Furthermore, participants could not tell whether they were on a statin by when or how quickly symptoms began or ended. Interestingly, when shown their own results, only about half were willing to restart statins.

The StatinWISE trial confirmed this (8). Two hundred patients went through blinded periods alternating between atorvastatin 20 mg and placebo. Muscle symptoms were reported by 62% of patients in both groups, with no difference in intensity or discontinuation rates. Even after seeing the data, one-third still refused to restart therapy. Together, these studies show that negative expectations can create real symptoms, strong enough to stop people from taking medications that prevent heart attacks and strokes.

Placebo Effects Beyond Statins

Placebo effects are not limited to pills (2). Sham heart surgery can improve angina symptoms and improve treadmill performance in people with heart disease. Patients often perceive branded drugs as more effective than generics and superficial cues such as pill color and dosing frequency influence outcomes.

What Patients and Clinicians Can Do With This Knowledge

The fact is that all medications are associated with side effects. Sometimes those side effects are directly caused by the drug, but often they arise from the very act of taking a pill and linking it to a symptom.

My most important strategy for avoiding nocebo effects in my practice is what I call “verbal pre-treatment.” This means preventing nocebo effects before they arise by framing treatment positively and honestly - in other words, using positive expectation as a therapeutic tool. I tell patients the honest truth: “This medicine is safe and prevents heart disease.” I emphasize that the vast majority of patients tolerate statins well, and the only place I routinely see problems is on the internet. For rosuvastatin, I share that I take it myself.

I also align expectations by normalizing symptoms. Everyone experiences aches and discomforts, but not all symptoms are caused by medications or even by what we think triggered them. Humans are natural cause-and-effect machines that evolved to explain unpleasant experiences, but sometimes we get it wrong. For highly sensitive patients, I sometimes record their baseline aches in the medical record so we can compare later. I explain that localized symptoms cannot be caused by statins, since the drug circulates throughout the body. Most importantly, I reassure them that any side effects are reversible and that I will not abandon them or think they are “crazy” if they complain.

When symptoms do occur, I empathize and reassure. What I do not do is repeatedly start, stop, or adjust statin regimens. That approach reinforces false associations, as seen in SAMSON, where symptoms disappeared rapidly even after stopping placebo. Constant adjustments create the illusion of causality and replace uncertainty with false certainty. That cycle is not good medicine.

Of course, true statin side effects do occur and there are warning signs to look out for, such as muscle weakness and tenderness to touch. A good clinician uses the patient’s history, examination, and blood tests to determine next steps.

Conclusions

Placebo and nocebo effects remind us that expectations may just be in the head, but they are real and shape physiology, symptoms, and outcomes. For clinicians, the challenge is to avoid seeding harm through careless framing while leveraging the healing power of positive expectations. For patients, the lesson is equally important: how we think about treatments can be as powerful as the treatments themselves.

Expectations don’t just change how we feel; they can be the difference between rejecting and embracing therapies that save lives. In that sense, belief itself becomes a form of medicine.

If expectations can shape how we feel, what happens when expectations about nutrition don’t pan out? *Next up: something fishy about fish oils. Once hailed as heart-protective, the supplements haven’t lived up to their reputation…

References:

1. Eaker ED, et al. Myocardial Infarction and Coronary Death among Women: Psychosocial Predictors from a 20-Year Follow-up of Women in the Framingham Study. Am J Epidemiol 1992;135:854-64.

2. Olshansky BO. Placebo and Nocebo in Cardiovascular Health: Implications for Healthcare, Research, and the Doctor-Patient Relationship. J Am Coll Cardiol 2007;49:415–21.

3. Colloca L, et al. Placebo and Nocebo Effects. N Engl J Med 2020;382:554-61.

4. Gupta A, et al. Adverse Events Associated with Unblinded, But Not with Blinded, Statin Therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): A Randomised Double-Blind Placebo-Controlled Trial and its Non-Randomised Non-Blind Extension Phase. Lancet 2017; 389:2473-2481

5. Moriarty P, et al. Efficacy and Safety of Alirocumab Vs Ezetimibe in Statin-Intolerant Patients, with a Statin Rechallenge Arm: The ODYSSEY ALTERNATIVE Randomized Trial. J Clin Lipidol 2015; 9:758-769.

6. Wood FA, et al. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. N Engl J Med 2020; 383:2182-2184.

7. Howard JP, et al. Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment. J Am Coll Cardiol 2021; 78:1210-1222.

8. Herrett E, et al. Statin Treatment and Muscle Symptoms: Series of Randomised, Placebo Controlled n-of-1 Trials. BMJ 2021;372:n135.