September 13 2021 Hana El Semmary
Healthcare & Pharmaceuticals

Placebo and Nocebo effects in Healthcare


COVID-19 Vaccines and the Nocebo Effect

A long-awaited silver lining emerged in December 2020, when the first vaccine against COVID-19, Comirnaty (most known as the BioNTech-Pfizer vaccine) received emergency approval by the WHO. Ever since opinions have been split whilst opponents and proponents advocated their viewpoint on the efficacy, safety, need,s and most of all risks of the vaccine. 

One has most definitely heard of the most common side effects accompanying the COVID-19 vaccinations, including headaches, fever, body aches, nausea, and general tiredness. However, with countries ramping up vaccinations worldwide and a higher number of individuals receiving their doses and while herd immunity is within closer reach, though rare, dangerous side effects have started emerging within the vaccinated global population. 

The news tumbled when the viral-vector-based vaccines, also known as the Oxford-AstraZeneca and Johnson & Johnson vaccine, were associated with rare, but dangerous and possibly fatal blood clots, especially for younger individuals. Countries were fast to react, with some completely banning vaccinations with the viral-vector based vaccines, while focusing on the vaccines with the new mRNA technology (BioNTech/Pfizer and Moderna) or following another approach, by encouraging the vaccination of the 60+ population with the AstraZeneca and Johnson & Johnson vaccines. 

With these side effects emerging, resistance and hesitancy regarding the vaccines have also seen exponential growth worldwide.  For example, the following phenomenon occurred in vaccination centers in the US: cases of “fainting, excessive sweating, nausea, and vomiting” were reported in vaccination centers across the country, after individuals received their dose of the Johnson and Johnson vaccine. With further investigation into the reason behind and the actual cause of the mentioned side effects, federal health authorities such as the CDC noted that for most individuals, fainting, nausea, etc. were indeed anxiety-induced events.

Hence, the question remains as to why individuals experienced such occurrences after receiving the new COVID-19 vaccine. The answer may lie in the worldwide known phenomena of the Placebo and Nocebo effects.


What is a Placebo or Nocebo Effect?

The previously mentioned (indirect) effects of the COVID-19 vaccine on individuals, causing dizziness, fainting, nausea, etc. is a clear example of an altered Nocebo effect. Literature defines the classic Nocebo effect 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”. 

For example, as proven by previous experiments, patients were given a pill as treatment for a certain condition (for example fatigue or depression) and are told to expect side effects such as nausea, drowsiness, or pain. Although some individuals are merely given a sugar pill, individual cases still reported such side effects.  Hence, although the COVID-19 vaccine is a substance with a clear medical effect, patients and individuals receiving their dose perceived a worsening of their wellbeing, most likely due to anxiety, uncertainty, and perhaps not having established enough trust with the new vaccine. 

On the other hand, the Placebo effect is the exact opposite of the Nocebo effect. Defined as “a substance without medical effects, which benefits the health status because of the patient’s belief that the substance is effective”. Classically, similarly to the Nocebo effect with negative outcomes, the Placebo effect sees patients experiencing a clear improvement of symptoms faced before starting the therapy and general advancement of wellbeing. 

In conclusion, whether interlinked with positive or negative health effects or experiences for individuals, both effects are the result of psychological and physical reactions to non-active ingredients and most often transpire due to expectations, conditioning, idea framing, and individual psychological state.  


Clinical Management and Reversing (or Fortifying) of Both Effects

The question remains as to how both effects can be clinically managed, or if they should. As highlighted, the cause of both effects is highly individual-based and is still to be further analyzed and researched in the literature, as a gap remains for this parameter. Recent research and experiments, especially regarding the Nocebo effect, highlight the importance of managing patient expectations, providing a comprehensive overview of the treatment plan, clearly discussing possible side effects as well as double-checking with each patient on an individual level if all parameters associated with the treatment are understood and accepted.

Additionally, the method of “counterconditioning” has also been proved to be highly effective in the case of Nocebo effects. By “turning previously negative learned associations into positive associations”, for example by highlighting positive expectations more profoundly than negative side effects, Nocebo effects can be drastically reduced and even converted into a (sometimes) useful Placebo effect.

Therefore, regarding the profitability, advantages, and disadvantages of each effect, although both depend on non-active ingredients in pharmaceuticals, treatments, vaccines, etc. and the body and mind’s reaction thereof, literature provides information on the pros and cons of each effect and hence portrays the boon and bane of the effects respectively. 

Firstly, in regards to possible positive outcomes of the Nocebo effect, as mentioned, the literature and experiments so far do not highlight any advantages of the effect on patient outcomes. It is quite the contrary, as patients report reversed, negative side effects or experience side effects that are not usual as a reaction to treatment, due to predispositions, anxiety, etc. treatment regimens are not effective to the required level and extent and could also possibly be less beneficial to harmful for patients. It is not always possible to reduce, yet alone prevent Nocebo effects, however, they should try to be derated as far as possible by downscaling possible negative side effects to positive treatment outcomes, effective communication between doctor and patient, etc. 

Secondly, for Placebo effects, the literature suggests that to a certain extent, the effect could be beneficial for patients, but should be carefully examined and executed, following a “Minimize, Maximize and Personalize” approach. Research suggests that during clinical trials, the Placebo effect should be, as far as possible, minimized to correctly evaluate the efficacy and success rates of a drug still in the investigational period. However, once a drug is marketed, maximizing Placebo effects could be very helpful as improved patient outcomes and positive treatment results are expected to be higher, even if coupled with the phenomenon of Placebo. Lastly, in all cases, evaluating and including patient parameters such as their personality, past medical history, treatment experience, and hence “personalizing” the patient experience could also help exponentially grow positive therapeutic outcomes.

In sum, both effects are highly prevalent among patients globally, especially during the COVID-19 pandemic. As proven, individuals can cease to experience negative outcomes due to vaccinations, which are most likely merely anxiety induced and have no correlation to the actual active ingredients of the vaccinations. On the other hand, individuals also experiencing Placebo effects by self-medicating or relying on home treatments (such as homoeopathy) and advocating online the efficacy of the treatment for COVID-19, while experts reviews prove these treatment regimens as ineffective, merely a Placebo and planning possible bans and warnings on the self-medications for COVID-19 patients. 

Going forward, physicians and patients must be aware and educated on the impact of Nocebo and Placebo phenomena to be able to evaluate, minimize or maximize effects accordingly. Most importantly in regards to both effects, ethics, especially in clinical trials of drugs and vaccines need to be highly taken into consideration and put as a priority, in general, but especially during the COVID-19 pandemic to ensure fairness, positive patient outcomes and public health safety. 


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