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Table of Contents
Year : 2021  |  Volume : 35  |  Issue : 4  |  Page : 157-159

Nocebo effects from COVID-19 and vaccination Hesitancy: The question of to be or not to be vaccinated

Department of Psychiatry, Psychotherapy and Counseling Center; Department of Medical Research, Clinical Trial Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation; Department of Medicine, Tzu Chi University, Hualien, Taiwan

Date of Submission30-Jul-2021
Date of Decision27-Aug-2021
Date of Acceptance28-Aug-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
M.D., Ph.D Chaucer Chiao-Hsiang Lin
No. 1, Lane 11, Dong An Street, Sou Fong Township, Hualien County 97451
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/TPSY.TPSY_33_21

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How to cite this article:
Lin CC. Nocebo effects from COVID-19 and vaccination Hesitancy: The question of to be or not to be vaccinated. Taiwan J Psychiatry 2021;35:157-9

How to cite this URL:
Lin CC. Nocebo effects from COVID-19 and vaccination Hesitancy: The question of to be or not to be vaccinated. Taiwan J Psychiatry [serial online] 2021 [cited 2023 Jan 31];35:157-9. Available from: http://www.e-tjp.org/text.asp?2021/35/4/157/332962

At the time of writing this editorial, people around the world have been combating the COVID-19 pandemic with multiple efforts. The most effective measures to control the COVID-19 infection are receiving vaccinations, wearing mask, and keeping social distance. Meanwhile, hesitancy and even protests exist across countries against the need of receiving vaccinations. Receiving vaccination may be regarded as an unnatural intervention with concerns about interfering personal freedom through public policy. Such hesitancy to receive vaccination may also be caused due to vaccine attributes (working mechanism, efficacy, and side effect profiles), proposed policy interventions, and misinformation on public vaccination preferences, etc. [1].

Some people experience different levels of adverse events ranging from mild or common fever, headache, injection site pain, to rare and severe blood clot, anaphylactic shock, and even death after receiving various COVID-19 vaccines of different mechanisms. The news about vaccine side effects, especially the dramatic and negative descriptions given by the media, lead to much public concerns whether to receive or which vaccine to receive, causing vaccine hesitancy and obviously hampering the progress of mass vaccination program [2].

Nocebo effect, a less noticed opposite corresponding phenomenon or an “evil twin” of the more familiar placebo effect, is negative response experiencing more adverse events and/or less treatment effects in clinical care or trials [3]. In this editorial, I intend to raise awareness of nocebo effect in recent COVID-19 vaccination and related vaccination hesitancy.

  Nocebo Effects as a Component of Adverse Events Top

All available COVID-19 vaccines use different strategies to carry parts of the virus to the immune system. The adverse events may be the responses of the immune system to the vaccines [4]. But different levels of adverse events have been reported in COVID-19 vaccine trials, in trial participants of the treatment arms and those of placebo ones [5]. In randomized control trials for pain and psychiatric disorders, nocebo effects may contribute to the reporting of adverse events in 19% of adults and 26% of old adult persons taking placebos and stopping therapies due to adverse events in up to 25% of patients in placebo arms [6]. A systematic review and meta-analysis studied adverse events in placebo groups in 143 placebo-controlled trials of selective serotonin reuptake inhibitor and tricyclic antidepressant for depression [7] and so did another similar study on 58 placebo-control trials for second-generation (atypical) antipsychotic drugs for schizophrenic spectrum disorders [8]. The investigators reported that adverse events in placebo groups are similar to those in the matched groups receiving real drugs. They also concluded that nocebo effects of drugs for depression and drugs for psychosis (as defined in the neuroscice-based nomenclature system at www.NbN.ECNP.org) are not simply nonspecific clinical symptoms. A research on psychotherapy for patients with chronic primary pain and depression [9] has indicated that nonimprovement or even worsened symptoms are related nocebo effects.

In the real world of the COVID-19 pandemic, various negative feelings, especially fear, are possibly to be emotional reactions causing more discomfort and anxiety, causing individuals to have nocebo phenomena when and/or after receiving vaccines. For some vaccinated individuals, the knowledge itself that they have been vaccinated are sufficient to have adverse events, possibly leading to vaccine hesitancy and even refusal of receiving vaccination [2].

  Possible Mechanisms of Nocebo Effects Top

Mechanisms proposed for causing nocebo effects include patients' negative expectations, learning and classical conditioning, public incorrect information, procedures of adverse events data collected, and neurobiological factors [3],[10],[11].

Worries about the actual effects of medicines and belief that medicines cause harm can lead to patients' negative anticipations of an adverse event. Negative anticipation is from specific communications such as the list of adverse events in the informed consent in clinical trials and the ways of communication from prescribing physicians. Experiences during the clinical trials or care from the therapeutic milieu such as physical environments and the attitude of staff can also impact on patients' anticipations about the treatment they receive and thus how they feel. Negative expectations may trigger anticipatory anxiety and predispose the patients, especially those with worse baseline symptoms [8] to have more adverse events [3]. A review on affect and emotions in placebo and nocebo effects [12] has shown that affective states and nocebo effects influence each other through a reciprocal dynamic existing between a treatment event, affect, and nocebo effects.

Summaries of studies [13],[14] have proposed that learning and classical conditioning play rôle in nocebo effects. The situations, where neutral stimuli have previously been associated with adverse events, may evoke similar side effects without receiving an active drug in subsequent procedures. With the learning and classical conditioning mechanism in action, patients who have experienced adverse events during previous treatments, are associated with a higher likelihood of experiencing adverse events in later trials or care setting.

Theory of social modeling [15],[16] suggests that behaviors may be learned through observing the action of others. Public information can mislead people to believe that they have been exposed to something hazardous to cause increased symptoms and to foster nocebo effects. We are overwhelmed with exposures to media coverage and discussion on information and stories of people having adverse events on television, newspaper, social media, Internet forums, and opinions from friends and families during the COVID-19 pandemic. Those sensory overloads lead to our more concerns that an intervention can cause harm [3],[16].

Studies of neurobiological factors for nocebo effects, especially in the field of nocebo hyperalgesia, indicate that the effects may be mediated through the neuropeptide cholecystokinin and associated with increased activity of the hypothalamic–pituitary–adrenal axis in healthy persons [10]. Genetic influences on nocebo effects are linked to activating the cannabinoid receptors and increased prostaglandins synthesis as well as to deactivating D2-D3 dopamine and μ receptors [10].

  Managing Nocebo Effects in Clinical Care and Clinical Trials Top

While we may like to maximize placebo effects in clinical care and minimize them in clinical trials, we should aim at minimizing nocebo effect in both clinical care and trial setting [17]. To minimize the nocebo effects in clinical care in preventing patients from suffering unneeded perceived discomforts that cause nonadherence and even stopthe drug, the clinicians should do the following [18],[19]:

  • To be familiar with the mechanisms of nocebo effect themselves
  • To communicate nocebo effect concept to patients as possible reasons of treatment experiences
  • To collect information about patients' expectations about treatment outcomes and
  • To talk about their previous negative experiences with treatments as a part of the medical history and discuss with them
  • To inform patients with realistic possible side effects of the intervention and frame them in ways to reduce a discrepancy between what is expected and what actually occurs
  • To streamline therapeutic milieu such as clinic environment, procedures, and operations of medical staff to reduce possible negative associations with treatment given.

An expert consensus [17] has recognized the importance of informing patients about nocebo effects and given suggestions to train health professionals in patient-clinician communication to minimize nocebo effects. As for the patients in clinical care setting and participants in the treatment arm of clinical trials, the information of side effects and their nature given to trial participants in the placebo arm may influence the types and severity of reported adverse events. To minimize nocebo effects in clinical trials, the clinical investigators need to explain the benefit–risk profile, information about side effects of the intervention under the study in informed consents with standardized language and framing strategies [3]. Since mistaken beliefs, worrisome expectations, and previous negative medication experiences can produce nocebo effects, exploring them with trial participants can help lessen the effects. The potential solution of “contextualized informed consent” and “authorized concealment” that participants in clinical trials are asked whether they would like to be informed of the nonspecific side effects of a treatment has been proposed and under debate [9],[18]. Tools and procedures applied to manage the tension resulting from the nocebo effects should balance ethical principle of nonmaleficence and respect for patients' autonomy [20].

Clinical trial investigators can help lessen study participants' concerns about side effects through the communication method of obtaining answers from trial participants what previous bothersome or dangerous adverse events they experienced and worried about? If they are currently experiencing benign adverse events, what significance they presume and do they expect the adverse events to worsen over time [20]? At the data collection stage, review of studies on randomized, double-blind, placebo-controlled trials determining efficacy of drugs for psychosis [21] stresses the need to develop standardized procedures for collecting information about adverse events. Similar standardized questions and structured checklists should be used to collect data on adverse events not only for participants remain in both treatment and placebo group but also for those drop out from trials [3].

  Conclusion Top

Nocebo effects are relevant to outcomes of clinical care and clinical trials for all types of medical intervention, be it drug, surgery, device, procedure, psychotherapy, or vaccines as in the current COVID-19 pandemic. Better understanding and managing nocebo effects can help better deal with adverse events and related issues experienced and resulting in having concerns in general clinical care and clinical trials, including the vaccination hesitancy in the COVID-19 pandemic.

  Acknowledgment Top

Viewpoints expressed are author's personal opinions and are unnecessarily reflecting on those of any related affiliations or organizations.

  Financial Support and Sponsorship Top


  Conflicts of Interest Top

The author has no conflicts of interests to declare in writing this editorial.

  References Top

Kreps S, Dasgupta N, Brownstein JS, et al.: Public attitudes toward COVID-19 vaccination: the role of vaccine attributes, incentives, and misinformation. NPJ Vaccines 2021; 6: 73.  Back to cited text no. 1
Amanzio M, Cipriani GE, Bartoli M: How do nocebo effects in placebo groups of randomized controlled trials provide a possible explicative framework for the COVID-19 pandemic? Expert Rev Clin Pharmacol 2021; 14: 439-44.  Back to cited text no. 2
Colloca L, Barsky AJ: Placebo and nocebo effects. N Engl J Med 2020; 382: 554-61.  Back to cited text no. 3
Sprent J, King C: COVID-19 vaccine side effects: the positives about feeling bad. Sci Immunol 2021; 6: eabj9256.  Back to cited text no. 4
Kaur RJ, Dutta S, Bhardwaj P, et al.: Adverse events reported from COVID-19 vaccine trials: a systematic review. Indian J Clin Biochem 2021; 36: 1-13.  Back to cited text no. 5
Rief W, Avorn J, Barsky AJ: Medication-attributed adverse effects in placebo groups: implications for assessment of adverse effects. Arch Intern Med 2006; 166: 155-60.  Back to cited text no. 6
Rief W, Nestoriuc Y, von Lilienfeld-Toal A, et al.: Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis. Drug Saf 2009; 32: 1041-56.  Back to cited text no. 7
Palermo S, Giovannelli F, Bartoli M, et al.: Are patients with schizophrenia spectrum disorders more prone to manifest nocebo-like-effects? a meta-analysis of adverse events in placebo groups of double-blind antipsychotic trials. Front Pharmacol 2019; 10: 502.  Back to cited text no. 8
Locher C, Koechlin H, Gaab J, et al.: The other side of the coin: nocebo effects and psychotherapy. Front Psychiatry 2019; 10: 555.  Back to cited text no. 9
Frisaldi E, Shaibani A, Benedetti F: Understanding the mechanisms of placebo and nocebo effects. Swiss Med Wkly 2020; 150: w20340.  Back to cited text no. 10
Faasse K, Petrie KJ: The nocebo effect: patient expectations and medication side effects. Postgrad Med J 2013; 89: 540-6.  Back to cited text no. 11
Geers AL, Faasse K, Guevarra DA, et al.: Affect and emotions in placebo and nocebo effects: what do we know so far? Soc Personal Psychol Compass 2021; 15: e12575.  Back to cited text no. 12
Bajcar EA, Adamczyk WM, Wiercioch-Kuzianik K, et al.: Nocebo hyperalgesia can be induced by classical conditioning without involvement of expectancy. PLoS One 2020; 15: e0232108.  Back to cited text no. 13
Bräscher AK, Kleinböhl D, Hölzl R, et al.: Differential classical conditioning of the nocebo effect: increasing heat-pain perception without verbal suggestions. Front Psychol 2017; 8: 2163.  Back to cited text no. 14
Faasse K, Helfer SG, Barnes K, et al.: Experimental assessment of nocebo effects and nocebo side effects: definitions, study design, and implications for psychiatry and beyond. Front Psychiatry 2019; 10: 396.  Back to cited text no. 15
Faasse K, Parkes B, Kearney J, et al.: The influence of social modeling, gender, and empathy on treatment side effects. Ann Behav Med 2018; 52: 560-70.  Back to cited text no. 16
Evers AW, Colloca L, Blease C, et al.: Implications of placebo and nocebo effects for clinical practice: expert consensus. Psychother Psychosom 2018; 87: 204-10.  Back to cited text no. 17
Nestoriuc Y, Pan Y, Kinitz T, et al.: Informing about the nocebo effect affects patients' need for information about antidepressants – an experimental online study. Front Psychiatry 2021; 12: 587122.  Back to cited text no. 18
Petrie KJ, Rief W: Psychobiological mechanisms of placebo and nocebo effects: pathways to improve treatments and reduce side effects. Annu Rev Psychol 2019; 70: 599-625.  Back to cited text no. 19
Gelfand S: The nocebo effect and informed consent-taking autonomy seriously. Camb Q Healthc Ethics 2020; 29: 223-35.  Back to cited text no. 20
Amanzio M: Nocebo effects and psychotropic drug action. Expert Rev Clin Pharmacol 2015; 8: 159-61.  Back to cited text no. 21


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