UNDERSTANDING THE PLACEBO AND NOCEBO EFFECTS IN THE CONTEXT OF SPORT: A PSYCHOSOCIAL PERSPECTIVE

Abstract

Research over the past 15 years on the placebo effect has substantiated its contribution to the efficacy of established treatments for a range of clinical conditions and identified its underlying mechanisms. There is also evidence that placebo effects contribute to the performance benefits of many ergogenic aids, and that performance can worsen when dummy treatments are associated with expectations of a harmful outcome (i.e., the nocebo effect). Unfortunately, the bulk of sport research involving placebos and nocebos continues to be hampered by outdated definitions and conceptualizations of the placebo effect and its mechanisms. This has implications not only for research but also application, as nearly 50% of athletes report experiencing a beneficial placebo effect, and a similar proportion of coaches report providing placebos to their athletes. The objective of this paper is to attempt to stimulate research by presenting updated definitions of the placebo and nocebo effects in the context of sport, describing their major mechanisms and, highlighting the importance of the psychosocial setting in the sport setting on placebo effects.

1. INTRODUCTION

1.1. Objectives of the Paper

The objective of this paper is to emphasize the importance of studying placebo and nocebo effects in sport, both in respect to basic science as well as practical application. To achieve this objective, we provide updated definitions of the placebo and nocebo contextualized to sport, provide a model of the psychosocial setting of the placebo effect in sport; describe the primary mechanisms for placebo and nocebo effects and overview research on variables that contribute to interindividual differences in placebo responsivity.

2. HISTORICAL PERSPECTIVE

The term placebo originates from the Latin word “I shall please” (Guijarro, 2015) and was used to describe people hired to mourn at funerals. It was first noted in the medical literature in the late 18^th century (De Craen et al., 1999), and in a medical dictionary published in 1811 defined a placebo as “an epithet given to any medicine adapted more to please than to benefit the patient” (Quincy, 1811). Nearly 150 years later Henry Beecher cited this definition in his classic 1955 publication, “The Powerful Placebo” (Beecher, 1955). Although this work signaled the beginning of the serious investigation of “placebo mechanisms and efficacy” (Ross & Buckalew, 1983), Beecher’s provocative claim that an average of 35% of patients benefitted from placebos was inevitably followed by a backlash. Critics asserted that the positive findings Beecher reported resulted from poor methodology or a consequence of non-specific effects such as regression toward the mean and spontaneous remission (Kienle & Kiene, 1997). Such criticisms were echoed by sport scientists who described the placebo effect as it as a mere motivational incentive or worse, that athletes who used placebos were “in a sense, brainwashed” (Singer, 1975). However, more recent research utilizing brain imaging techniques and novel experimental methodologies (e.g., balanced placebo designs, open trials, conditioning trials) has resulted in a revised perspective on the placebo effect. The results of this work provide convincing evidence that placebos can provide real therapeutic benefits for many clinical conditions by acting through various neurobiological pathways (Beedie et al., 2019), and their actions contribute to the effectiveness of established medications (Amanzio, Palermo & Benedetti, 2016) for many conditions including Parkinson’s disease (de la Fuente-Fernández et al., 2001). Research involving open and closed administration paradigms, in which patients are either aware or not aware they are receiving pain medication, indicate the placebo effect potentiates the benefit of analgesics by 20 to 30% (Benedetti, Carlino & Pollo, 2011), substantiating the contribution the placebo effect makes to proven treatments.

Carefully designed research studies involving placebos in sport settings have also found that they can enhance performance for many athletes, including elite competitors (Beedie & Foad, 2009, Hurst et al., 2019), and that their impact goes beyond one of simply motivating the athlete to make a greater effort. A review of 12 placebo-intervention studies reported that the benefits of placebo effects on sport performance ranged from - 1.9% to 50.7%, with most effects falling between 1% and 5% (Beedie & Foad, 2009). A subsequent meta-analysis of 14 studies found a weighted mean effect size of 0.31 (Bérdi, Köteles, Szabo & Bárdos, 2011). The most recent review (Hurst, Schipof-Godart,et al., 2019) included 32 studies including 1,513 participants, and reported small-moderate effects for placebo treatments (Cohen’s d = 0.36), small-moderate effect for nocebo treatments (d = 0.37), and small-moderate effects when classified as nutritional (d = 0.35) and mechanical (d = 0.47) treatments. The magnitude of these improvements compares closely to the 1-3% percent gains in performance reported for widely-tested ergogenic aids such as Beet root juice (Braakhuis & Hopkins,2015), caffeine (Salinero, Lara & Del Coso, 2019), high intensity training programs (Laursen, 2010), and deceptive avatar pacing (Stone et al., 2012).

3. ATTITUDES OF COACHES AND ATHLETES TOWARDS THE USE OF PLACEBOS IN SPORT

It should not be surprising then, that both coaches and athletes commonly utilize placebo interventions/ergogenic aids to enhance performance. Szabo and Müller (2016) found that in a sample of 96 coaches, 90% were familiar with placebo effects and nearly half (44%) had administered a placebo in the attempt to aid the performance of their athletes. A study of 30 national-level coaches found that 62% reported administering placebos to their athletes, with 10% doing so on a weekly basis (Brooling, Pyne, Fallon, & Fricker, 2008). These findings reveal that not only do the majority of high-level coaches believe in the ability of placebos to improve performance, but that they are willing to deceive their athletes to do so. Unfortunately, there is no published information as to whether they are administering inert substances (e.g., corn powder tablets), nutritional supplements, unsubstantiated PEDs (Beedie et al., 2017) or even off label applications of actual medication, and research is needed to determine the safety and potential ethical consequences of such practices.

Athletes are also aware of the possible performance benefits of placebos. A survey of 79 elite athletes reported that 82% believed that placebos could improve their sport performance (Bérdi, Köteles, Hevesi, Bárdos, & Szabo, 2015). Nearly half (47%) indicated experiencing placebo effects in the past, and these athletes were also more open to using placebos in the future. Sixty-seven percent of the athletes said they would not mind being deceived about a placebo if it was effective. Despite the positive attitudes most of the athletes had toward placebos, they rarely self-administered placebos, consistent with reports that in most cases placebos are provided by the coach (Beedie, 2007). However, the practice of athletes engaging in ritual behaviors or superstitions (e.g., carrying a lucky charm) in attempts to enhance performance could be considered a form of self-administered placebo. In a literature review (Dömötör, Ruíz-Barquín, & Szabo, 2016) contend that much superstitious behaviour in sport is driven by the placebo effect, positing that positive expectancies linked to an object or ritual behaviour increase feelings of control and confidence in an otherwise unpredictable competition. However, little systematic research has been conducted on this possibility.

4. DEFINITIONS

4.1. Placebo, placebo effect, placebo response

The term placebo (or when used in an experimental study, placebo condition) refers to the inert agent or action each which should lack any demonstrated capacity to produce a physical or psychological effect (Kirsch, 1985). The placebo effect describes a favourable outcome, either psychological or physical, that can be attributed to the placebo or the processes (expectation or conditioning) by which placebos act (Hall, Loscalzo, & Kaptchuk, 2015). Importantly, the presence of a placebo is not necessary for a placebo effect to occur because conditioning and expectations are often associated with proven treatments. We previously (Beedie et al. 2018) differentiated the placebo effect from the placebo response, the latter of which also includes changes due to non-specific effects such as regression toward the mean.

Placebos have also been sometimes categorized as either active or passive. Active placebos are typically designed to incorporate key sensory characteristics of the treatment condition such as a perceivable feeling (or side effect), or other evident properties such as taste, smell, shape or colour. Active placebos are often utilized in cases when treatments are associated with obvious side-effects or possess strong sensory characteristics (e.g., the bitter taste of caffeine). The use of an inert, or characterless placebo in such cases would be obvious to test subjects, resulting in what has been called functional unblinding (Alphs, Benedetti, Fleishchhacker & Kane, 2012). It should not be surprising that active placebos often yield stronger results than placebos devoid of sensory characteristics (Miller & Colloca, 2009; Jospe, 1978), given that it is well-established that the efficacy of placebos is influenced by physical characteristics including color, type (e.g., tablet, capsule, injection). Even the presumed expense of a placebo can influence its efficacy (Espay et al., 2015). These characteristics are part of the psychosocial context (Benedetti, 2013) that include not only the physical characteristics of the placebo itself, but also the provider of the placebo (e.g., physician, therapist, coach) and the setting in which the placebo is provided. Figure 1 presents a schematic of the psychosocial context for the athlete in sport modified from a model described by Benedetti (2013).

FIGURE 1:

THE PSYCHOSOCIAL SETTING IN SPORT (adapted from Benedetti, 2013)

Given this broader understanding and description of the placebo effect, it is unfortunate that in sport science the most widely used definition of the placebo effect remains: “a favorable outcome arising purely from the belief that one has received a beneficial treatment” (Clark et al. 2000). The definition of the placebo effect and identification of placebo mechanisms each has important implications for: 1) design of experiments to identify the magnitude of the placebo effect associated with legitimate treatments; 2) independent tests of the efficacy of placebos and placebo mechanisms and; 3) the broader role of placebo effect in sport (Beedie et al., 2018). In more recent iterations of the definition of the placebo effect, the influence of the psychosocial setting on conditioning and expectations is acknowledged, as for example the: “simulation of an active therapy within a psychosocial context” (Price et al. 2008). In the case of sport this definition may be reframed as: “the simulation of a proven ergogenic effect within a psychosocial context”. We intend the term ergogenic effect to be used in its broadest sense, not only to include substances such as nutritional products or performance enhancing drugs, but also procedures (e.g., physiotherapy), behavior treatments (e.g., relaxation), sport psychology techniques (e.g. imagery) and training programs (e.g., high altitude training).

4.2. The Nocebo Effect

It has also been recognized that the presentation of an inactive medication or therapy with the expectation of a negative outcome (e.g., increased anxiety, fatigue or other symptoms) can often lead to an increase in undesirable symptoms consistent with those described in the instructions. This has been referred to as the nocebo effect (nocebo meaning “I will harm”) (Benedetti et al., 2007). Although limited, sport research has found that nocebo effects can result in diminished performance (Beedie, Coleman & Foad, 2007; Beedie & Foad, 2009; Beedie et al., 2019; Hurst et al., 2019). Notably, the definition of the nocebo effect most commonly used in sport: “subjects in the control group perform worse, because they know they are in the control group” (Bonetti & Hopkins, 2009), differs substantially for the orthodox perspective wherein a nocebo is either: 1) presented with explicit instructions that it will result in harmful consequences such as increased anxiety, pain or fatigue; 2) presented under conditions where the receiver of the nocebo possesses or develops negative expectations that arise from circumstances such as past experience or knowledge or; 3) results from a treatment or medication that is associated with undesirable side effects (iatrogenic effects) (Fassse & Petrie, 2013).

Importantly, while subjects in control groups in sports performance studies should be deprived of the experimental treatment (e.g., creatine, hypoxic tent), they generally undergo a standardized training schedule or program that matches the training load assigned to the subjects in the experimental group. Although being assigned to a control group consisting of standard or unaltered training may diminish the expectation of benefit in an athlete who knows he/she is potentially missing out on a “special treatment”, it is unlikely the athlete would expect an actual decline in performance to occur. A decline in performance (or physical capacity) would, however, be expected when the control condition involved an unplanned reduction or cessation in training (but not a planned rest period or taper), but such an intervention is unlikely unless matched in the experimental condition. Moreover, it is entirely possible that an athlete could develop a negative incidentally-induced expectation in the event he/she grew skeptical of the experimental intervention (“it quit working”) or already possesses an expectation (i.e., habitual expectation) that is negative (it’s bad for me”) because of a bad previous experience (“it made me sick”). Expectations can also be influenced by the social context, including observational learning or information received from others (Colloca & Benedetti, 2009). These examples each reinforce the importance of both carefully controlling the information provided in studies of ergogenic aids in order to minimize the likelihood of generating unintentional study-specific expectations, as well as need for using methods such as questionnaires to identify expectations subjects already possess or may develop during the course of a study (see Lindheimer, Szabo, Raglin & Beedie, 2019).

A final potential complication is that while iatrogenic (unpleasant) side effects of medication often result in nocebo effects, there is the potential for paradoxical responses in the case of sport. Several ergogenic aids taste unpleasant or are associated with negative side effects such as creatine and bicarbonate loading. The athlete community is well-aware of this and so the more unpalatable aspects of ergogenic aids may be perceived as evidence of their efficacy (i.e., a positive expectation). In fact, there is evidence that bitter tasting drinks can directly improve performance by increasing corticomotor excitability (Gam et al., 2016)

Given the previous issues and concerns, it is proposed that the definition of a nocebo in the context of sport or physical activity be reconceptualized as;

“an inert ergogenic effect that is administered with the suggestion of a negative impact on athletic performance.”

5. MODES OF ACTION OF PLACEBO AND NOCEBO EFFECTS

5.1. Conditioning

Classical conditioning occurs when an unconditioned stimulus (the active treatment) is paired or associated with a conditioned stimulus. In the case of treatments in sport, such unconditioned stimuli could involve properties of the active treatment such as its mode of administration (e.g., capsule or injection), even its color or smell. Following a sufficient number of pairings between the unconditioned stimulus and a therapeutic outcome (i.e. the conditioned response), the conditioned response could result after the presentation of the conditioned stimulus alone (i.e., a placebo that possesses the properties shared by the unconditioned stimulus). Conditioning-mediated placebo effects are generally regarded to occur below the level of awareness and involve involuntary bodily changes that are not perceived (i.e., they are unconscious). However, there is not complete agreement about the issue of imperception among placebo researchers, and there is some evidence that conditioning can become supraliminal and change expectations (Kirsch, 1990), and it also has been proposed that some expectations are non-conscious. Accordingly, some researchers (Stewart-Williams & Podd, 2004) categorize conditioning as either explicit, resulting in conscious expectations or implicit non-conscious conditioning that does not generate expectations (Stweart-Williams & Podd, 2004).

Conditioning procedures have been used both in the case of placebos in clinical therapy, such as placebo-controlled dose reduction (Doering & Reif, 2012) and in studies involving the influence of placebos on physical performance. For example, in a study by Benedetti and colleagues (Benedetti, Pollo & Colloca, 2007) had individuals undergo several trials of pharmacological conditioning in which they were given morphine before experiencing a painful stimulus. They found that the conditioned subjects experienced greater analgesia from placebo-morphine than subjects received morphine without previously undergoing the preconditioning procedure. Another method of placebo conditioning is deceptive conditioning, a procedure in which the intensity of a stimulus (e.g., pain intensity) is surreptitiously reduced in trials where the subjects are given a placebo, and there is evidence that this procedure can also enhance physical performance (Carlino, Benedetti & Pollo, 2014).

5.2. Expectation

Expectations have been described as predictions about future events (Kirsch, 1999). They can be formed by numerous factors including suggestion, observational learning, conditioning and common factors in therapy such as the doctor-patient relationship. The terms belief and expectation are often used interchangeably in placebo research, but they also have been studied as distinct and even sometimes incongruent concepts (Main et al., 2010). Some researchers contend that there are several categories of beliefs, only one of which involves expectations (DeGood & Tait, 2010).

Kirsch (1999; 2018) has further distinguished between two categories of expectation. Stimulus expectancies were defined as “as anticipations of external events”, whereas response expectancies are “predictions of nonvolitional responses”. Applied to a sport setting, stimulus expectation would refer to the expected intensity of a training practice (i.e., stimulus), whereas the expectation that the practice will feel less intense (despite no change in the actual practice intensity) would be a response expectancy. Response expectancies are more likely to result in larger placebo effects, particularly when there is greater ambiguity about the stimulus (in this example, ambiguity about exactly how intense the practice session will be). This is important because either the stimulus or response expectancy can be experimentally manipulated in studies involving physical exercise, each of which can influence the strength of a placebo effect (see Lindheimer et al., 2019).

While the terms expectation and expectancy have often been used interchangeably, others have distinguished them. For example, Corsi and Colloca (2017) define expectancy as: “psychophysical predictions that can be present without full awareness” (p.,3, Corsi & Colloca, 2017), and use the term expectation to refer to specific, verbalized and measurable constructs” (p.3., Corsi & Colloca, 2017). In the following sections we will defer this definition of expectation.

In a study that examined the influence of both conditioning and expectation, Carlino et al. (2014) tested the effects of placebo caffeine on muscular endurance task (number of repetitions of leg extensions at 60% of maximum) using both deceptive non-pharmacological conditioning and experimentally-manipulated expectation. The researchers manipulated the strength of their verbal suggestions with instructions that the probability of receiving caffeinated coffee would be 0%, 25%, 50% or 100% depending on the trial. Deceptive conditioning was achieved by first having subjects undergo an exercise endurance test of leg extensions at 60% of 1-repetition maximum to fatigue. In a second trial the subjects consumed what they were told was caffeinated coffee. They then completed another leg extension test with the resistance surreptitiously lowered to 45% maximum, which resulted in significantly improved performance. It was found that verbal suggestions alone elicited a significant improvement under conditions in which the subjects thought there was a 50%, or 100% chance they had received caffeinated coffee, but not when the chance was only 25%. When the subjects were told the chance of receiving caffeinated coffee was 0%, there was no improvement. In trials in which verbal suggestions were previously reinforced by conditioning, improvements occurred in all three conditions (i.e., 25%, 50%, 75%). However, the magnitude of performance improvement was not associated with the strength of the verbal suggestions, and this differs from clinical research in which the effectiveness of placebo analgesia increased with the strength of the verbal suggestions provided (Pollo et al., 2001). This study not only provides a unique experimental design to concurrently examine the influence of conditioning and expectation, but it also reveals the unique contribution that conditioning can make in establishing a placebo response for an ergogenic aid.

Manipulated expectation can also influence placebo and nocebo responses in unanticipated ways. For example, Levine and colleagues (2006) examined the effect of inert pills subjects were told would reduce symptoms of nausea (i.e., placebo) or worsen symptoms (i.e., nocebo) during an unpleasant procedure designed to induce nausea. A third control group were told they were receiving an inert placebo pill. Gastric tachyarrhythmia, an objective measure of abnormal stomach activity, was assessed as were ratings of nausea using a validated questionnaire. Contrary to their hypothesis (i.e., experimenter expectation), it was found that the negative expectation (i.e., nocebo) condition reduced nausea and gastric dysrhythmia, whereas the positive-expectation placebo condition was ineffective and no better than the control condition. The authors concluded that the subjects modified their expectations after experiencing unpleasant symptoms during the procedure, an example of experimental expectations we describe elsewhere as incidentally-induced expectations (Lindheimer et al. 2019). Based on this finding they made the intriguing suggestion that providing patients objective information about discomfort likely to be experienced during medical procedures could mitigate the intensity of the symptoms they experience, a procedure that could have potential application in sport.

An additional means by which judgements about expectations can alter responses to either actual or placebo treatments has been linked to expectation bias, a meta-cognitive process described as the degree to which people believe expectations (e.g., caffeine improves sport performance) bias actual experiences (e.g., how much less fatigued caffeine makes people feel). Individuals who believe that expectations bias their own experience are likely to try to correct for the influence of the expectation. This correction involves reducing the magnitude of their perceived rating (e.g., “I don’t feel much less fatigued”), but it is possible to negate (e.g., “I don’t feel any less fatigued”) or even reverse their response and over-correct (e.g., “I feel even more fatigued”) for their bias. In a placebo study examining expectation bias, Handley et al. (2011) exposed subjects scoring differently to expectation bias to a painful cold-pressor test. Prior to two tests, an inert cream was applied to the tested hand with instructions that it was either hand cream or a powerful analgesic. In both conditions it was found that the more subjects believed in expectation biases about a pain stimulus, the less consistent their pain ratings were with the experimental hypothesis (i.e., that pain would be intense in the control condition or reduced in the analgesic condition). Specifically, subjects scoring high in expectation bias attempted to correct their pain ratings by rating pain lower in the control and higher in the placebo condition than those with low expectation bias. These results indicate that beliefs about expectations can alter the response to a placebo, and that expectation bias can be a useful variable for explaining some of the individual differences typically observed in placebo studies.

Individual differences to placebo effects have also been hypothesized to be related to traditional psychological traits, but research has generally failed to identify the placebo-prone personality. As noted by Geers and colleagues “…the relationship between placebo effect and individual-difference variables such as suggestibility, introversion, intelligence, and self-esteem, have, thus far, been found to be unreliable.” (p. 122, Geers et al., 2005). Problems with this research include the use of invalid personality measures, basic methodological flaws (e.g., non-random treatment assignment), or employing experimental designs not intended to probe for individual differences such as randomized controlled trials (RCT) (Geers et al., 2005). In the RCT design, subjects are informed they have a 50-50 chance (i.e., a conditional expectation) of receiving an active treatment or inert placebo, whereas researchers intending to examine the placebo effect typically utilize deceptive-placebo conditions (e.g., balanced-placebo design) intended to maximize response to placebos.

In a study examining individual responses to a placebo, Geers et al. (2005) found that differences in the trait of optimism-pessimism modulated the response to a negative-placebo expectation (i.e., nocebo) when subjects were given a pill with deceptive expectations (i.e., the pill would result in unpleasant feelings). Specifically, pessimists were more like to report negative symptoms in the deceptive-expectation condition than optimists. However, under a conditional-expectation (i.e., the pill would either make them feel unpleasant or it was an inactive substance) differences between optimists and pessimists were not observed.

Acute emotional differences in subjects have also been found to influence the response to placebos. Zubeita et al. (2005) had healthy subjects undergo trials of a pain challenge (hypertonic saline injection) alone or with a placebo analgesic. Consistent, with earlier research it was found that the placebo was less effective for individuals scoring higher in negative mood, presumably because negative emotions interfere with endogenous opioid system activation. However, individuals with more positive moods also exhibited less placebo activation. The authors speculated that for individuals experiencing more positive emotions during the pain stimulus, the motivation for activating the endogenous opioid system was reduced because the pain was “not as bad as expected.” More research is needed to confirm these findings, but their results suggest that the relative need for pain relief could influence the placebo response independently from expectation.

The findings reported in the previous section suggest that in the context of placebos, conditioning and expectation both influence and interact in complex ways to influence the strength of placebo effects or the occurrence of negative (i.e., nocebo) effects. This work also highlights circumstances in which experimental expectations are not related to the strength or even the direction of the effect, because of the influence of other psychological factors including belief in expectations, need, psychological traits or states. These findings have implications for increasing our understanding of how psychological factors may influence individual differences in placebo to ergogenic aids. They also highlight the importance of assessing expectancies in research examining the efficacy of ergogenic aids, which is a manipulation check rarely employed in sport research.

6. GENERAL SUMMARY

Long maligned as little more than a motivational incentive, recent research has provided compelling evidence in support of the placebo and nocebo effects as discrete neurobiological processes. This research convincingly demonstrates that, far from being consequences of so-called non-specific effects or enhanced motivation, placebo and nocebo effects are the result of the modulation of the same neurobiological pathways by which clinical treatments and ergogenic aids (in the case of placebos) and arguably side effects in the case of nocebos, operate.

Among the reasons why this is important in sport is the widespread use of placebos and dubious ergogenic aids by coaches and athletes. Research on the placebo effect has also broadened our understanding of the role the psychosocial setting plays in the mechanisms of conditioning and expectation, and the complex ways these mechanisms interact to influence placebo and nocebo effects. This work has also provided insights into identifying psychological factors that influence both expectation and the interindividual differences in placebo responsivity. All the previous examples reinforce not only the necessity but benefits of incorporating placebo conditions in sport research, while also measuring expectation and other relevant psychological variables. Aside from the obvious applications for research examining putative ergogenic aids or training programs, consideration of the placebo effect could benefit research on other topics of sport research such as athletic pacing, as expectation has been found to influence both pacing strategy and performance.

HIGHLIGHTS:

1. Placebos and nocebos can significantly influence sport performance.

2. The placebo effect contributes to the benefits associated with many ergogenic aids.

3. Widely cited definitions of the placebo and nocebo effect in sport are not consistent with contemporary understanding of these phenomena.

4. Studying placebo and nocebo effects in sport science is well justified in the attempt to determine their potential contribution to ergogenic aids and as phenomena in their own right.