Original ArticleUnderstanding the placebo effect from an evolutionary perspective
Introduction
Humphrey (2002, p. 256) defines a placebo as “a treatment which, while not being effective through its direct action on the body, works when and because:
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the patient is aware that the treatment is being given;
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the patient has a certain belief in the treatment, based, for example, on prior experience or on the treatment's reputation;
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the patient's belief leads her to expect that, following the treatment, she is likely to get better;
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the expectation influences her capacity for self-cure, so as to hasten the very result that she expects.”
The resulting improvement in the patient's health is known as the placebo effect, which is well established in medical circles for some conditions (Evans, 2003, Vallance, 2006), though the causes are poorly understood (Benedetti et al., 2003, Olshansky, 2007). Some (e.g., Hróbjartsson & Gøtzsche, 2004) argue that most findings are simply the result of reporting bias, whilst others assert that the effect has both a psychological and physiological basis (e.g., Wager et al., 2004). The magnitude of the effect can be modulated by many factors, such as the colour of pills and the size of doses; injections or surgery tend to produce a stronger effect than pills (Olshansky, 2007). The manner of the physician administering the treatment (e.g., reassuring or formal) can also affect outcomes (Di Blasi, Harkness, Ernst, Georgiou, & Kleijnen, 2001); Walach and Jonas (2004) list 18 ways to enhance healing responses based on the placebo effect.
If the placebo effect is ubiquitous in modern humans, it has presumably persisted for considerable evolutionary time. If individuals are capable of recovering without external aid, why do they rely on an external cue?
Bendesky and Sonabend (2005) argue that “at some point in the history of human evolution, brain development reached a certain level that allowed sick people to understand they could get ‘better’. […] These individuals had probably less prolonged illnesses, […] or else felt better, which would have a similar effect [to] ‘really’ being better.” This line of reasoning does not explain why the placebo effect exists. Just as animals do not need to understand that they must breathe in order to do so, it is not clear why individuals should require an understanding of their illness for their immune system to operate on it.
Many discussions and models of the placebo effect focus on the extent to which the effect occurs consciously (expectancy theory) or subconsciously (through conditioning and psychoimmunological effects). Much of this work has been neatly summarised by Stewart-Williams and Podd (2004), who conclude that these alternatives need not be mutually exclusive. We share this view and prefer to regard the effect in the holistic sense of an individual receiving an external cue, which may trigger a self-generated recovery (or, for that matter, a deterioration). Our aim at this stage is not to identify specific mechanisms in the brain by which the effect occurs, but to understand at a more fundamental level why the effect should have survived the seeming evolutionary pressure against it (i.e., why the effect exists at all) when one would expect that individuals who get better without the need for an external trigger would have a higher fitness.
Humphrey (2002) provides a verbal argument as to why the effect occurs, from the perspective of evolutionary biology. We summarise this argument in Section 2. In subsequent sections, we clarify Humphrey's suggestion using formal models and identify its strengths and weaknesses. This allows us to make predictions about when the effect (or the reverse effect) should occur by drawing out important distinctions about the type of belief that a patient has in a treatment.
Section snippets
Humphrey's concept
Natural selection will tend to favour organisms which are able to manage their resources effectively. As McNamara and Buchanan (2005) hypothesize, “the processes that allow redistribution of physiological resources should distribute resources optimally to maximise fitness.” By drawing a parallel between the internal workings of an organism and the management of resources in a national health service, Humphrey (2002) points out that there are sometimes limitations on the use of resources due to
The importance of environmental cues
In this section, we demonstrate that the operation of the immune system should depend on external cues; we do this by identifying how expectations and cues can mediate between long-term and short-term gains. Our analysis first considers a simple world with only two states and two available actions, before considering a more general situation.
Cues which promise no health benefit
The complexity of the world means that the prioritisation of tasks may not always be perfect. In this section, we identify how prioritisation processes, in conjunction with mental limitations, could result in a placebo effect.
We assume that there is a link between mental priorities and physical behaviours—specifically the action of the immune system. We have limited mental resources, so it is not surprising that tasks will occasionally be overlooked or incorrectly prioritised. Any prompt which
The reverse of Humphrey's effect
So far, we have considered how placebos can trigger the immune system into action by increasing the expected worth of getting better (be it through paying a lesser cost for fighting the ailment or altering priorities). Without any belief in the cue (i.e., the placebo), such effects would not exist. However, let us now assume that the patients have great confidence that the placebo will cure them.
Rather than increasing the placebo effect, too much belief in the power of a placebo could reverse
The nocebo effect
A nocebo (Latin for “I shall harm”) is a substance which is pharmacologically (medicinally) inactive but which a patient experiences as harmful due to negative expectations (reviewed by Hahn, 1997). Note that some people use the term to mean “all distressing symptoms that accompany placebo administration” (e.g., Barsky, Saintfort, Rogers, & Borus, 2002), whilst others define it in the latter manner but then refer to the placebo (nocebo) effects as occurring through positive (negative)
Evans' suggestion
Jawed vertebrates such as mammals have two types of immune system: innate and acquired. For a summary of these systems and an evolutionary perspective on the mechanisms involved, see Beck and Habicht (1996) and Litman (1996).
The innate (or natural) immune system produces what is known as the acute response. This is a general, fast-acting response because the phagocytic white blood cells (macrophages) of the system are already active in the body prior to infection. The innate system is
Discussion and summary
We have shown that, rather than fight diseases unconditionally, it can be adaptive to wait for (what is perceived to be) a better opportunity. Placebos may act as cues that a better opportunity now exists. The placebo effect may therefore reduce to expectations about when it is worth trying to take action.
We have identified that the placebo effect could be induced in several ways, through modifying perceptions of (a) the external environment, (b) the cost of getting well, or (c) the value of
Supplementary materials
The following are the Supplementary data to this article.
Acknowledgments
This work was supported by the European Research Council (Evomech Advanced Grant 250209 to A.I.H.) and by a University of Bristol Postgraduate Scholarship and EPSRC Doctoral Training Award to P.C.T. We thank Tim Fawcett and the journal reviewers for helpful comments.
References (52)
- et al.
On Schleppfuss' path: the placebo response in human evolution
Medical Hypotheses
(2005) - et al.
When words are painful: unraveling the mechanisms of the nocebo effect
Neuroscience
(2007) - et al.
The placebo effect in Parkinson's disease
Trends in Neurosciences
(2002) - et al.
The basal ganglia and the encoding of value
Suppression of the acute-phase response as a biological mechanism for the placebo effect
Medical Hypotheses
(2005)The nocebo phenomenon: concept, evidence, and implications for public health
Preventive Medicine
(1997)- et al.
Effects of stress on the immune system
Immunology Today
(1990) - et al.
Cortical correlates of false expectations during pain intensity judgments—a possible manifestation of placebo/nocebo cognitions
Brain, Behavior, and Immunity
(2005) - et al.
Classical conditioning and the placebo effect
Pain
(1997) Natural selection and the regulation of defenses—a signal detection analysis of the smoke detector principle
Evolution and Human Behavior
(2005)
Placebo and nocebo in cardiovascular health. Implications for healthcare, research, and the doctor-patient relationship
Journal of the American College of Cardiology
Immunocompetence: a neglected life history trait or a conspicuous red herring?
Trends in Ecology & Evolution
Placebo in emotional processing—induced expectations of anxiety relief activate a generalized modulatory network
Neuron
Inducible defense against pathogens and parasites: optimal choice among multiple options
Journal of Theoretical Biology
Conditioned response models of placebo phenomena: further support
Pain
Behaviorally conditioned immunosuppression
Psychosomatic Medicine
Nonspecific medication side effects and the nocebo phenomenon
Journal of the American Medical Association
Immunity and the invertebrates
Scientific American
The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect
The Journal of Neuroscience
How placebos change the patient's brain
Neuropsychopharmacology
Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses
The Journal of Neuroscience
Assessment of fear of fear in agoraphobics: the body sensations questionnaire and the agoraphobic cognitions questionnaire
Journal of Consulting and Clinical Psychology
Theoretical neuroscience: computational and mathematical modelling of neural systems
Influence of context effects on health outcomes: a systematic review
The Lancet
Placebo; the belief effect
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