The nocebo effect: Can we think ourselves unwell?

 Almost everyone has heard of the placebo effect — when people experience beneficial effects from an inert drug. But few are aware of its flip side, the “nocebo effect.” Here, individuals taking a drug, whether placebo or not, experience unwanted, negative effects. Medical News Today spoke to experts in the field to investigate the basis of the nocebo effect and find out what might be done to minimize its impact on treatments and trials.

All drug trials must have a control group. People in this group receive an inert substance, also known as a placebo — a “fake” drug that does not contain an active ingredient.

If the trial is testing a specific pill, the control group will receive a pill that looks identical but does not contain an active ingredient. If testing a vaccine, the control group will receive a placebo injection.

However, there is a curious phenomenon whereby people taking placebos sometimes notice changes consistent with what they expect to happen.

Therefore, many will notice an improvement in symptoms — the so-called placebo effect. Others, however, will notice side effects that might be expected from the drug being trialed, and they may be unpleasant.

The term derives from the Latin word “nocere,” meaning “to harm,” and was first used to describe adverse effects caused by a placebo.

One study defined the nocebo effect as “unpleasant or adverse outcomes triggered by the treatment context, beyond any inherent pharmacological effects of the treatment itself.”

So the mere act of taking a tablet or having an injection might cause side effects, which are not due to any drug it contains. And it can happen to those on prescribed medication, not just in trials.

Cause of the nocebo effect

If the medication itself is not responsible for the side effects, why do they happen? The need for medical professionals to gain informed consentTrusted Source might go some way to explaining the nocebo effect.

People undergoing medical treatment must give informed consent for that treatment. To gain informed consent from a patient or trial participant, physicians have to explain the risks and benefits of the treatment in detail, including possible side effects. 

Older researchTrusted Source has suggested that when participants in a trial are told about side effects, they are likely to experience them whether they are taking the active drug or not.

So, can negative expectations produce negative outcomes? According to Chambers, this could be the case: “While it’s such a complex mix of things […] on the basic level, it’s having negative side effects because you have been told there might be negative side effects.”

Dr. Fabrizio Benedetti, professor of neuroscience at the University of Turin Medical School, Italy, who has published widely on the nocebo effect, agreed, noting that “[m]any adverse events may be attributable to nocebo effects and not so much to the drug itself.”

A recent studyTrusted Source of COVID-19 vaccination trials illustrates this. Researchers who analyzed data from 12 trials found that 35% of people given placebo injections experienced systemic effects — effects experienced in areas of the body other than the treatment site, such as headache and fatigue — following the first dose. 

This was compared with 46% of those given the real vaccine. Therefore, the authors of this study suggest that some 76% of adverse effects reported by those given the real vaccine were nocebo effects. In other words, they were not caused by the vaccine but by participants’ expectations.

Dr. Benedetti was unsurprised by these findings: “It has long been known that nocebo effects occur in many conditions, such as pain and Parkinson’s disease. Therefore, it is not surprising that they also take place in COVID-19 vaccination. If you expect a negative outcome, you can get it.”

Physical or mental causes?

These symptoms experienced are undoubtedly real, so if they are not due to active treatment, what might be the cause? Experts have attributed the nocebo effect to both psychological and neurobiological causesTrusted Source.

Dr. David A. Merrill, adult and geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, explained:

The psychology may be that negative expectations are fulfilled. If a patient hears that a treatment may cause drowsiness, and then feels drowsy, they will blame that sleepiness on the treatment.

In addition, people who have negative expectations of side effects may be more aware of symptoms and, therefore, more likely to report them.

And studiesTrusted Source have found that those who experience anxiety and depression may also be more likely to experience the nocebo effect.

Conditioning and past experience

Another explanation may lie in conditioning. The color of tablets is a case in point. A 1996 studyTrusted Source found that people associate red, yellow, or orange tablets with stimulant effects and blue or green tablets with sedative effects.

The researchers gave otherwise identical blue tablets to one group and pink to the other. The group taking the blue tablets reported more drowsiness.

And those who have experienced adverse drug effects in the past are more likely to report them after a new treatment.

One part of the nocebo effect that is a result of neurobiology is nocebo hyperalgesiaTrusted Source, where the expectation of pain increases the pain experienced.

When a person anticipates pain, they release cholecystokininTrusted Source, which allows pain transmission. If that anticipation and anxiety can be reduced, the pain will also be reduced.

Dr. Merrill explained how this happens: “Sensations can be amplified by our brain in feedback loops triggered by fear, which results in amplification of pain and other symptoms. This does not mean the pain is not real, but rather that the pain is primarily signaling fear rather than damage.”

Effect on treatment

The real risk with the nocebo effect is when it affects treatments or drug trials. If a person attributes negative side effects to an effective treatment, they might stop that treatment, losing the benefits along with the side effects. Over-reporting of side effects in a drug trial may mean that the drug does not get licensed.

This can have a real impact on health outcomes, as Lee Chambers outlined: “You don’t want someone to discontinue something that’s beneficial because of these negative effects that they feel they are having because of it. It [the nocebo effect] can increase those reported side effects… and lead to negative health outcomes.”

Some studiesTrusted Source have suggested that reducing information about side effects might reduce the nocebo effect, but there are ethical problems. When asked whether he thought withholding such information could be justified, Dr. Benedetti was clear:

Source: Medical News Today