Mr A was a 26-year-old male and a participant in the clinical trial of a new antidepressant. After his girlfriend broke up with him, he became lethargic and decided to commit suicide by taking 29 capsules. When he arrived at the emergency department, he stated, ‘Help me, I took all my pills,’ and then collapsed. Mr A had rapid breathing, constant tremor, and the medical examinations showed low blood pressure and a quick heart rate. Everyone was convinced he was going to die. However, after the arrival of the physician of the clinical trial, Mr A was informed that what he thought was a lethal overdose of antidepressant was, in fact, a consumption of harmless placebo capsules. About 15 minutes later, Mr A’s life support functions were entirely normalised.¹ But how is this possible? 

What is the nocebo effect?

The ‘nocebo effect’ was introduced by W.P. Kennedy in 1961 as the opposite of the well-known placebo effect,² which refers to the positive outcome of taking a placebo, an inactive substance. The word nocebo comes from Latin and means ‘I shall harm’,³ referring to its malign effect, mainly due to treatment conditions, when the mind alone can influence the body's functions without any physical intervention.⁴ Taking the nocebo effect into consideration in medical practice is crucial, because just like the placebo effect, its ‘evil twin’ is also a very powerful reaction.

Examples of the nocebo effect

Countless stories in anthropology detail voodoo death when people died believing they had been cursed. Agony, distortion of the body, immense pain and a foaming mouth all accompany the sudden death of the ill-fated victims.⁵

An anecdote originates from the 20th century, from the description of Dr Erich Menninger von Lerchenthal. The students wanted to teach a much-disliked assistant a lesson, and they sprang upon him, threatening that they were going to decapitate him. He got blindfolded, and the students bowed his head onto a chopping board, dropping a wet cloth on his neck. The poor man was so frightened, convinced it was a kiss of a cold steel blade, that he died on the spot.⁵ 

Less drastic examples can also be found in scientific literature. In a study, they examined the side effects of taking gluten and a placebo (rice starch) in patients with non-coeliac gluten sensitivity. The findings show that although gluten triggered worse symptoms, the placebo group also experienced bloating, abdominal pain and a foggy mind.⁶ Similar results were obtained in another research testing lactose intolerance. In this case, the placebo group reported diarrhoea, abdominal pain, vomiting, bowel sounds, and bloating after consuming sugar.⁷

In clinical trials of drugs, participants in the placebo groups often report unpleasant side effects. Such disease trials are:⁴

• Migraine and tension-type headache
• Multiple sclerosis and motor neuron disease 
• Fibromyalgia and neuropathic pain
• Depression
• High cholesterol
• Osteoporosis

What can generate the nocebo effect?

Patient

The nocebo response can be generated by many factors,⁴ and a few of them depend on the patients themselves. For example, personality traits, such as anxiety, can lead to experiencing side effects.⁸ Negative mood and emotions, such as fear, can also increase the nocebo reaction.⁸ A pain study showed that higher stress levels and worry led to nocebo hyperalgesia, which means the participants experienced increased perception of pain.⁹

When someone hears the word ‘painful’, it carries a negative emotional charge (or negative valence factor). This emotional state can lead to fear, anxiety, threat, and the patient sees the world through these lenses. This negative expectation can cause a higher perceived dose of exposure and higher expectations of symptoms.¹⁰

This enhanced fear often leads to catastrophic thinking (or maladaptive cognitive appraisal), when a patient overstresses a symptom, like the feeling of mild dizziness after taking a medication and exaggerates it as a serious side effect. Maladaptive cognitive appraisal can amplify distress, making it harder for the patient to find efficient coping strategies for pain. This mental state can contribute to heightened pain sensitivity and more struggles in daily activities.¹¹

Words and experiences

The most commonly mentioned external factor in generating the nocebo effect is verbal suggestion. Statements from healthcare professionals, such as ‘this will hurt’ or ‘it usually causes a headache’, induce this response in people.⁴ A comprehensive study has proven this correlation, and it also showed that certain individuals are more predisposed to react to these suggestions than others.¹²

Another commonly mentioned indicator of the nocebo effect is a previous negative experience. A patient who experienced pain from a treatment or discomfort after a certain medical examination is most likely to develop the same or even worse reaction the second time.¹³  A sequence of vaccine doses can also create negative reactions: side effects after the first dose are most likely to create similar adverse reactions after the second.¹⁴

Not only personal experiences but also observing others' negative reactions affects the response to a treatment. Imagine you are in a dentist's office waiting for your filling when the previous patient walks out, holding their cheek in pain. Witnessing such suffering can create increased pain experience (or side effects) in the observer.¹⁵ 

The impact of other people's side effects can also work on a larger scale, called mass psychogenic modelling. This phenomenon refers to a spread of a disease or side effects through a population in the absence of a physical cause, poison or contagion agent. Wind turbine syndrome is most likely one of the examples of mass psychogenic modelling.⁴ Research shows that people who live near wind turbine farms often report side effects such as sleep disturbance, headache, tinnitus, nausea, dizziness, or vibration in the body. Multiple governmental institutions and organisations tried to find an explanation for these adverse effects unsuccessfully. Research shows that the symptoms are most likely connected to negative information, creating anxiety and fear.^16,17 

Informing about the negative consequences of a medical or pharmaceutical treatment is legally mandatory. We are all familiar with the sentence from drug information leaflets that ‘like all medicines, this medicine can cause side effects’. Although unavoidable, warnings can also elicit a nocebo response. If someone is informed about a possible side effect of a medication, such as a headache, that person is more likely to experience it. Patients who were informed of potential gastrointestinal symptoms during an experiment experienced a sixfold increase in these types of symptoms compared with others.¹⁸

Changes in drug characteristics

For more than 30 years, Eltroxin, a thyroid hormone replacement, had been on the market in New Zealand without any problem. In 2007, the company decided to move the manufacture of this drug from Canada to Germany. Although the active ingredient (thyroxine) was still made in Austria, the tablet’s inert ingredients changed in terms of colour, size, markings, taste and tongue dissolution rate. Once the new tablets were introduced, the reported side effects rate drastically increased, from 14 reports in 30 years to more than 1400 in 18 months. Research finds no other explanation than simply the different characteristics between the old and new drugs could create a nocebo effect.¹⁹

Microenvironment

We all have the experience of walking into a GP’s office or, in more serious cases, a hospital. The walls, the tiles, nurses and doctors in scrubs, and the distinctive smell of antiseptic agents are characteristics of this environment. Studies show that these cues can induce a nocebo effect and worsen the side effects of treatments.⁴ Anticipatory nausea and vomiting (ANV) is a common condition among patients who receive chemotherapy. Around 25% of people around the fourth treatment cycle start to develop these symptoms, which can be merely induced by the smell of chemotherapy.²⁰

White coat syndrome, or white coat hypertension, is a widely known phenomenon. It is characterised by the observation that in medical settings, such as a doctor’s office, the blood pressure is elevated, while outside, such as at home, it is normal. This symptom is probably induced by anxiety, stress and fear and can be triggered by the medical environment. It is important to note that in the absence of the recognition of white coat hypertension, it can lead to unnecessary treatment or overdosed medications.²¹

Strategies to reduce the nocebo effect

The nocebo effect plays a crucial role in medical care and clinical trials because suggested side effects can decrease compliance, lead to treatment discontinuation, and prompt higher dosages for efficiency.²² Thus, eliminating this negative response is essential. Studies found that the following strategies can reduce the nocebo effect:²³

• Providing enhanced treatment information
  • Information on the nocebo effect itself
  • Extensive and comprehensive information about the treatment
• Optimising patient-clinician communication
  • Emphasising positive results
  • Authorised concealment of side effects
  • Creating a trusting and friendly consultation environment
  • Education on communication for healthcare professionals
• Screening for patients with possible nocebo reactions
  • Screening tools, such as questionnaires about fear of side effects, insufficient knowledge about the disease and treatments
  • Personalised interventions to prevent/reduce the nocebo effect

Summary

The nocebo effect is the evil twin of the placebo effect, when the mind of a person can induce side effects in the body. From voodoo death to allergens, multiple examples exist in the literature about this harmful reaction. The nocebo response can originate from the patient’s anxiety, fear, and mental state. But it can also be influenced by verbal suggestions, negative emotions, experiences, or drug information leaflets. Study shows that changes in a drug's outlook can also generate stronger side effects. Providing enhanced information, optimising communication and screening for patients with possible nocebo reactions can be successful strategies to eliminate the nocebo response.