The Nocebo Effect by Michael H. Bernstein, Charlotte Blease, Cosima Locher, and Walter A. Brown details the investigation into the nocebo effect, the placebo effect’s evil twin. The authors explain the truths behind “the nocebo effect” and its significance in the modern world, while also discussing previous historical applications.
The United Nations described it as a “once-in-a-lifetime pandemic.” As of this writing, almost three years after COVID-19 was first identified, over 600 million people worldwide have been infected with the disease and millions have died from it. The pandemic has resulted in marked changes to our normal lives and the functioning of society. People adapted to wearing face masks, social distancing, lockdowns, and travel restrictions, among other challenges. Vaccination was heralded as a key strategy in combating COVID-19 and allowing societies to return to a new normal. However, even before the pandemic, hesitancy about being vaccinated was common and often fueled by concerns about side effects. The development of several effective vaccines against COVID-19 was met with some concerns about the long-term safety of the vaccines. The COVID-19 pandemic and the global vaccination campaigns provided a perfect environment for the nocebo effect.
The Nocebo Effect From The Vaccine
Like many medical treatments, people receiving the COVID-19 vaccine are susceptible to the nocebo effect due to negative expectations about vaccine side effects. The first telltale signs of nocebo response came from the initial trials testing the efficacy and safety of the newly developed vaccine. In these vaccine trials, one group of participants received the real COVID-19 vaccine, while another group was injected with saline—a substance that does not have any effect on the body and is used as a placebo control. To determine whether the vaccine protected people against the virus, researchers then compared how many participants from the two groups went on to contract COVID-19. Another important aim of the clinical trials was to establish the safety of the vaccine. To do this, the researchers also examined differences in side effect reporting to see if there were any negative symptoms reported at higher rates in the vaccine group compared to the placebo group.
When these studies were published, additional researchers were able to combine the results of many different vaccine trials to produce a more complete picture of how likely side effects were from the COVID-19 vaccine. Three of these bigger studies combining results from smaller experiments were published in January 2022. They looked at the rate of adverse reaction reporting in the placebo groups of COVID-19 vaccine trials. While the rate of side effects was higher in the real vaccine groups, as would be expected, all three reviews found a large overlap in the types of side effects reported by participants who received the actual vaccine and those who received the placebo injection of saline. For example, the review by Dr. Martina Amanzio and colleagues found that while around 55 percent of those receiving the active vaccine reported a general adverse reaction, the most common symptoms being headaches and fatigue, 42 percent of the placebo group also reported these general symptoms. Similarly, the review by Dr. Julia Haas and colleagues reported that after one dose, 46 percent of participants who received the vaccine reported at least one general adverse reaction, and 35 percent of the placebo group also reported a general side effect. This suggests that a large proportion of side effects cannot be attributed to the vaccine. In fact, one review estimated that the nocebo effect could account for 76 percent of the side effects from the COVID-19 vaccine.
In addition to clinical trials, studies conducted during the rollout of the COVID-19 vaccine to the general public also provide evidence for the role of negative expectations in producing side effects. In one study, participants completed a questionnaire measuring various psychological variables prior to receiving the vaccine, such as worry about COVID-19, expectations for experiencing side effects from the vaccine, perceived sensitivity to medicines, and depression. Of all the factors, expecting to experience an adverse reaction was most strongly associated with experiencing side effects later. In a similar study, the more hesitant people felt about having the second vaccine dose, the more side effects they reported after the booster shot six months later. These findings may be due to the nocebo effect, but it might also be that people who genuinely react more to the active ingredient in vaccines feel more hesitant about being vaccinated. However, research has shown that believing you are sensitive to the effects of medicines means you do experience more side effects, even from a placebo tablet.
Researchers have examined the impact of COVID-19 policies on side effect reporting, in particular the move from voluntary vaccination to it being a mandatory requirement for social engagement, as happened in some countries. It is thought that a lack of personal choice could increase vaccine hesitancy and side effect concerns, thereby exacerbating the nocebo effect. This was the case when France introduced a vaccine mandate requiring members of the public to be double vaccinated in order to enter certain public spaces, such as cafes and shops. The proportion of people reporting side effects from the vaccine increased from 34 percent prior to the mandate to 57 percent after it was implemented, suggesting that feeling pressured to be vaccinated can contribute to nocebo effects. Due to our ever-evolving understanding of COVID-19 and the vaccines, some of the trends seen are likely to be a result of the nocebo effect and some may be from other causes.
The Media And The Nocebo Effect
The word “unprecedented” has been frequently used to describe the COVID-19 pandemic. People have found themselves trying to function in an uncertain and ever-changing environment, and the media has played a significant beneficial role with its ability to communicate public health information rapidly to a wide audience. However, the media also mirrors public reaction and anxiety, which has been reflected in dramatic and negative information about the pandemic on news and social media. In discussing COVID-19 vaccination, the media focused heavily on rare side effects, such as blood clots from the AstraZeneca vaccine (which have a 0.0004 percent chance of occurring) or myocarditis from the Pfizer vaccine (0.003 percent chance). Such media coverage increased the public’s worry about vaccine side effects. This attention on side effects can impact people’s negative expectations and exacerbate the nocebo effect from the COVID-19 vaccine, as was the case in New Zealand.
On August 30, 2021, the New Zealand government’s Ministry of Health released a statement that a woman had died after receiving the Pfizer COVID-19 vaccine. The death was attributed to the rare side effect myocarditis, an inflammation of the heart wall that is characterized by chest pain, shortness of breath, and an abnormal heartbeat. New Zealand print, television, and radio media platforms discussed this case and encouraged people to be vigilant for cardiac symptoms following vaccination. There were two further deaths in New Zealand from myocarditis, one in December 2021 and another in April 2022, which again received substantial media attention. While myocarditis is a serious side effect of the Pfizer COVID-19 vaccine, it is rare. A study from Israel found that 2.7 people per 100,000 vaccinated experienced myocarditis following the Pfizer vaccine. However, the symptoms of myocarditis, such as chest pain and shortness of breath, are not uncommon in the general population. Population surveys show that in an average week, around 13 percent of people experience breathing problems and 7 percent experience chest pain and 7 percent experience heart palpitations that cannot be attributed to a particular cause. Consequently, media attention on myocarditis and its symptoms might cause people to overestimate its prevalence, resulting in them misattributing everyday symptoms to the vaccine and reporting them as side effects.
In my research as a health psychologist, I have investigated the effect mainstream media coverage can have in exacerbating the nocebo effect. The case of the New Zealand media linking myocarditis to the COVID-19 vaccine seemed to me like a prime situation for the nocebo effect to occur. Using publicly available data on vaccine side effects reported to the New Zealand Centre for Adverse Reaction Monitoring (CARM), I investigated whether the reporting of the three symptoms mentioned in the media (chest discomfort, breathing problems, and altered heart rate) increased following the media coverage. I looked at the reporting rates per 100,000 vaccinations in the seven months prior to the news coverage on myocarditis, and compared this with the reporting rate in the nine months after the first news item in August 2021.
Prior to the media attention on vaccine-induced myocarditis, CARM received an average of 35 reports of chest pain per 100,000 vaccinations. After the media coverage, this increased considerably, to 220 reports. A similar change was seen for breathing problems, which went from 25 to 113 reports, and for heart rhythm symptoms, which increased from 34 to 133 reports. To provide further evidence that it was the media’s focus on these particular side effects that was responsible for this change, I also examined the reporting rate of three control side effects that had not received media attention: musculoskeletal pain, numbness, and fever. The reporting of these side effects did not change that much. For example, musculoskeletal pain went from 41 reports per 100,000 vaccinations before the coverage to 52 reports after.
The symptoms of myocarditis mentioned in the media are also common symptoms of anxiety. It is possible that news stories on deaths attributed to myocarditis provoked concerns about the safety of the vaccine, with the symptoms of chest pain, heart rate, and breathing problems attributed to the vaccine being due to anxiety instead. Prior to the alarmist media coverage, CARM received an average of 15 reports of anxiety per 100,000 vaccinations, which increased to 73 reports following the news items. What’s more, statistical analyses showed that the experience of anxiety was significantly associated with greater attribution of chest pain, breathing problems, and changes in heart rate to the vaccine. This shows that anxiety was responsible for some of the increase in side effects.
In addition to the individual symptoms, the actual cardiac condition myocarditis could be reported to CARM. Prior to the media coverage, myocarditis had an average rate of 0.6 reports per 100,000 vaccinations. After the media coverage described this condition and linked it to the Pfizer COVID-19 vaccine, the reporting rate increased to 11 per 100,000. While 11 as a total number might sound small, it represents an increase of 1,700 percent. This significant increase in myocarditis could be a genuine vaccine response, or it might be due to self-diagnosis. Anyone in New Zealand can submit a medicine adverse reaction report to CARM. Community doctors typically submit around 65 percent of reports, but in the case of the COVID-19 vaccine, they were responsible for only 13 percent. This suggests that a large number of reports of myocarditis came directly from members of the public, who may have interpreted their chest or breathing symptoms as being myocarditis rather than considering other explanations, such as anxiety.
Taken together, these results suggest that a nocebo effect did occur following the media attention on vaccine-induced myocarditis. It is likely that the media coverage, which discussed a death linked to the vaccine and the symptoms of myocarditis, influenced people’s expectations for side effects, prompted greater attention to symptoms, and led to the misattribution of these to the vaccine. These symptoms are frequently experienced in the general population, and it is possible that media attention influenced people’s perceptions and attribution of these common symptoms. This is supported by the fact that the symptoms the media specifically warned about (chest pain, breathing problems, and heart rate changes) saw a sudden increase in reports to CARM, while side effects that did not receive media attention did not see a substantial change in the number of reports. The changes in the cardiac and breathing symptoms could be due to increased anxiety, as concerns about COVID-19 have already been shown to be associated with experiencing a greater number of unexplained physical symptoms.
The Nocebo Effect is the result of the collaboration of a litany of brilliant authors. Micheal H. Bernstein is an experimental psychologist who focuses on harnessing the placebo effect to reduce opioid use among pain patients. Charlotte Blease is a philosopher and interdisciplinary health researcher who writes about the ethics of placebo and nocebo effects. Cosima Locher is a psychologist and researcher dedicated to studying honest placebos. Finally, Walter A. Brown is a Clinical Professor Emeritus of Psychiatry and Human Behavior who has studied the placebo effect for the past 40 years.
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The Nocebo Effect
We are just discovering the power behind The Nocebo Effect, as explored in the groundbreaking work of a dozen top level researchers. Most importantly, researchers have investigated strategies that can be adopted by both clinicians and patients to reduce the nocebo effect.
