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The nocebo effect

Dr Sundararajan Rajagopal,
Consultant Psychiatrist
South London & Maudsley NHS Foundation Trust
Adamson Centre for Mental Health
St. Thomas' Hospital
London SE1 7EH

The nocebo effect

The wide range of responses that placebos elicit is a subject that has intrigued researchers for many years. A placebo, in general, is an inert substance that has no inherent pharmacological activity. It looks, smells and tastes like the active drug with which it is being compared. The term 'nocebo effect' refers to the negative consequences arising from the administration of a placebo. The same placebo can result in both a significant placebo effect such as improvement, and a prominent nocebo effect such as a major adverse reaction. If a placebo causes mainly nocebo effects, it would be called a nocebo; in research studies an artificial procedure inducing an aversive symptom (e.g. causing arm pain by increasing blood pressure using a tourniquet) is also known as a nocebo. Walter Kennedy introduced the concept of 'nocebo reaction' in 1961, a few years after Henry Beecher published his landmark paper on the placebo effect.1,2 Kennedy attributed it to a "quality inherent in the patient, not the remedy". While the better studied placebo effect has itself still not been fully explained, the nocebo effect is even poorly understood.

The main psychological mechanisms for the nocebo effect, as for the placebo effect, seem to be the related factors of subconscious conditioning and conscious expectations. Patients who have had previous experience of prominent side-effects with an active drug may be conditioned to experience similar side-effects subsequently even when they are only given a placebo. Patients may also anticipate adverse effects if they are influenced by the knowledge of the list of potential side-effects described by researchers before entering a placebo-controlled trial, and also by the memory of past side-effects suffered by oneself or others. Obviously, conditioning and expectations would be prominent during placebo therapy only if the patient is blind to the fact that they are now receiving an inert treatment.

Biological factors also appear to play a role. Nocebo hyperalgesia, an increase in pain from administration of a non-nociceptive substance, has been shown to be mediated by cholecystokinin, and to be abolished by the cholecystokinin-antagonist proglumide.3 Another study, in which arm pain was induced in healthy volunteers, suggested that nocebo hyperalgesia was associated with hypothalamic pituitary adrenal (HPA) axis hyperactivity; proglumide antagonised the hyperalgesia but not the HPA axis hyperactivity.4 In a different experiment, volunteers had arm pain induced and then were given an injection (saline) with some being told that it was a pain relieving and others advised that it was a pain increasing (nocebo) substance5; cortisol levels increased in both groups but was greater in the nocebo group, suggesting that expectation of pain increase was an added factor.

While the majority of studies on placebo and nocebo effects show results consistent with patient expectations, it has also been suggested that negative expectations may paradoxically have a protective effect. In one study, motion sickness was induced by an optokinetic drum, prior to which volunteers were given inert pills, some with the message that the pill was anti-nauseous and those in the nocebo group being informed that it would make nausea worse.6 Contrary to expectations, the latter group developed significantly fewer symptoms.

A review of more than a hundred phase I double-blind, placebo-controlled trials found an overall rate of spontaneously reported side-effects in those receiving placebo of 19%, with higher rates following repeated dosing and in the elderly7; the commonest adverse events were headache, drowsiness and asthenia. A history of adverse reactions to drugs is likely to increase the rate of nocebo effects in future; in a trial of 600 patients with such a past history, 27% developed side-effects, with a significantly higher occurrence in females.8 Another study of phase I healthy volunteers showed that those with Type A personality traits were almost thrice as likely to report side-effects after placebo administration as subjects with Type B personality features.9 A review of antidepressant trials found a slightly higher rate of nocebo effects in females.10

Placebo and nocebo effects are not just restricted to inert substances, but are ubiquitous phenomena that follow active treatments too. Hence, not all symptoms that develop after taking an active drug are necessarily due to the drug. When surveyed, a significant proportion of the general population report a range of physical symptoms,11 that are similar to the common non-specific side-effects of drugs. Therefore, the nocebo effect recorded systematically during a placebo-controlled trial is likely to also include pre-existing and spontaneously occurring symptoms that are independent of the placebo. In the same way, these trials may also be overestimating the frequency of non-specific side-effects of the active drugs being compared with placebos.

Just as a proportion of the positive outcomes of a successful drug may be explained by the placebo effect, so may a proportion of the negative consequences by the nocebo effect. In clinical practice, it is vital for the physician to not immediately attribute all the side-effects, especially the non-specific ones, following drug administration to the drug; it is important to consider the possible role of a drug-unrelated nocebo effect. Although the concepts of placebo and nocebo effects have been in modern medicine for about half a century, our knowledge of these fascinating fields is still far from complete, and so they certainly warrant, and also offer scope for, further research.

Competing interests: None.


1. Kennedy WP. The nocebo reaction. Med Exp Int J Exp Med 1961;95:203-5.
2. Beecher HK. The powerful placebo. J Am Med Assoc 1955;159:1602-6.
3. Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 1997;71:135-40.
4. Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci 2006;26:12014-22.
5. Johansen O, Brox J, Flaten MA. Placebo and Nocebo responses, cortisol, and circulating beta-endorphin. Psychosom Med 2003;65:786-90.
6. Levine ME, Stern RM, Koch KL. The effects of manipulating expectations through placebo and nocebo administration on gastric tachyarrhythmia and motion-induced nausea. Psychosom Med 2006;68:478-86.
7. Rosenzweig P, Brohier S, Zipfel A. The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies. Clin Pharmacol Ther 1993;54:578-83.
8. Liccardi G, Senna G, Russo M, Bonadonna P, Crivellaro M, Dama A, et al. Evaluation of the nocebo effect during oral challenge in patients with adverse drug reactions. J Investig Allergol Clin Immunol 2004;14:104-7.
9. Drici MD, Raybaud F, De Lunardo C, Iacono P, Gustovic P. Influence of the behaviour pattern on the nocebo response of healthy volunteers. Br J Clin Pharmacol 1995;39:204-6.
10. Casper RC, Tollefson GD, Nilsson ME. No gender differences in placebo responses of patients with major depressive disorder. Biol Psychiatry 2001;49:158-60.
11. Rief W, Hessel A, Braehler E. Somatization symptoms and hypochondriacal features in the general population. Psychosom Med 2001;63:595-602.


Copyright Priory Lodge Education Limited 2007

First Published September 2007

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