The use of performance-enhancing drugs and substances is common in sports (1,2). Athletes frequently will use legal and illegal supplements if they feel it will enhance their performance. The benefit of these drugs may not be due solely to some physiological effect at the cellular level. The change may be caused by an array of psychological factors, one of which is the placebo effect (a positive outcome resulting from the belief that a beneficial treatment has been received). This is when an athlete notes some improvement in performance after receiving an inert (non-active) substance; it might legitimately be described as a placebo effect. Such effects have been observed anecdotally and experimentally.
Placebos can be classified in two groups: inert and active. Inert placebos are those substances that are devoid of physiological action. Active placebos are substances that have some physiological actions, but the action is not specific to the condition for which they are administered. Placebos can have positive and negative effects (the nocebo effect is a negative outcome resulting from the belief that a harmful treatment has been received). Nocebo effects are observed when patients report that they are getting worse or that they are experiencing an unpleasant side effect (participants in placebo studies often complain of a wide range of side effects, from impotence to nausea).
PLACEBO AND THE BRAIN
Placebo treatment may exert an analgesic effect on at least three stages of pain processing, by 1) influencing pre-stimulus expectation of pain relief, 2) modifying pain perception, and 3) distorting post-stimulus pain rating. The effect upon one stage can affect the other two stages. Importantly, contribution from any or all of the three stages may vary by situation and individual. The literature suggest that multiple brain regions, including the anterior cingulate cortex, anterior insula, prefrontal cortex, and periaqueductal grey, play a pivotal role in these processes (3).
Brain imagery techniques lend support to the theory that placebo effect may occur at a location other than the cellular level. Nine people were exposed to a standardized, brief, non-harmful, painful experience. They received either no treatment or an injection of either placebo or analgesic. Subsequent positron emission tomography (PET) scans indicated activation of the rostral anterior cingulate cortex for both treatments, although the injected analgesic did provide more pain relief (4).
Nemoto et al. (5) examined changes in regional cerebral blood flow (rCBF) under three different conditions (resting, hot, and painful) using H(15)2O and PET scan in 10 subjects. In five subjects, placebo administration significantly decreased their pain-intensity scores, and rCBF in the medial prefrontal cortex (MPFC), posterior parietal cortex (PPC), and inferior parietal lobe (IPL) increased after placebo administration, compared with before placebo administration under the painful condition. Even more noteworthy is the increase in rCBF in the MPFC, PPC, and IPL under the resting condition after placebo administration compared with before placebo administration. However, there was no rCBF change under the rest condition in those who did not respond to placebo under painful stimuli. These results suggest that placebo analgesia has its effect under the resting condition, and MPFC, IPL, and PPC may have an important role in placebo analgesia (5).
Athletes believe that placebos are beneficial. Beedie (6) sent an electronic survey to 48 competitive, international, and professional athletes. Thirty athletes returned the surveys. The majority (97%) of respondents believe that the placebo effect can exert an influence upon sports performance. A significant number of respondents (73%) had experienced a placebo effect. These effects can be divided into several categories: explicit placebo effects, inadvertent false beliefs, and ritual or reverse placebo effects. Ten respondents (33%) in the study offered explanations as to the nature of the placebo effect. These explanations fall into several categories, including deliberate changes in competitive strategy, belief and expectancy, marketing, and faith in a third party.
Beedie et al. (7) administered three doses of placebo disguised as caffeine to six cyclists in a repeated measures design. Significant improvements in performance were observed. The authors evaluated pre-trial questionnaires and post-study interviews and report that five of the six participants believed they had experienced a placebo effect in one or more of the three experimental trials. The remaining participant indicated that he did not believe he had experienced any placebo effect. The authors suggest that further research should be structured to elucidate placebo effect not to simply control for it (6). McClung et al. (8) used a double disassociation design that compared sodium bicarbonate and placebo additives given to athletes completing a series of 1000-m time trials. Results showed that believing one had taken the sodium bicarbonate resulted in times almost as fast as times associated with consuming the drug itself. In contrast, taking the sodium bicarbonate without knowledge yielded no significant performance increment. The expectancy effects of using a supplement in high-performance sport can be very significant (8). This should be considered when looking at research and in clinical practice.
A study by Beedie et al. (9) examines placebo and nocebo effects associated with the administration of a hypothetical ergogenic aid to athletes. Forty-two team-sport athletes were randomly assigned to two groups. Baseline 3x30-m sprint trials were performed, after which they were administered identical placebos which were described to them as an ergogenic aid. The first group was provided with positive information about the likely effects on performance of the substance. The second group was provided with negative information about the same substance. The 3x30-m sprint trials were repeated. The mean speed for the first group did not differ significantly between baseline and experimental trials. There was a significant linear trend of greater speed with successive experimental trials, suggesting that positive belief exerted a positive effect on performance. The negative information group however ran 1.57% slower, suggesting that negative belief exerted a negative effect on performance. These data suggest that subjects' belief in the efficacy of a placebo treatment might significantly influence findings in experimental research (9).
Two studies with deceptive design looking at anabolic steroids demonstrate that athletes who falsely believed they had been administered anabolic steroids performed better than their baseline or when compared with controls (10,11). When participants in these studies believed they would obtain a benefit, based on positive reinforcement or participant belief, their performance improved. This illustrates the bias that can be introduced into a study on ergogenic aids. This bias should be considered in the design of research studies using placebos.
COLOR, COST, INJECTION
When Beecher (12) published his paper "The Powerful Placebo," in 1955, he analyzed 26 studies and found that an average of 32% of patients responded to placebo. Since then, it has been found that the response rates to placebos vary greatly and are frequently higher than the one third commonly quoted. In fact, for relief of pain, the placebo response may be as high as 70% (13). There appear to be multiple factors that influence the effects of placebo. The color of a drug, price of the pill, injection versus oral medication, and knowledge of administration all seem to affect the effect of the placebo. These factors influence the outcome of research on the effect of medications.
Pill color influences an athlete's response. Colors like red, yellow, or orange pills are associated with a stimulant effect, whereas blue or green pills are related to a calming effect (14). A study looking at preferred color and shape of tablets found white tablets are accepted best, and brown and purple are least accepted for medication effect for the identical medication (15). Further research contributing to a better understanding of the effect of colored medication is certainly warranted.
The cost of a medication appears to have an effect upon its ability to relieve pain. A study that used two identical placebo pills randomized participants to two groups. The first group was told their medication was a "high-priced" pill, at $2.50 per pill, and the second group was told their medication was a $0.10 pill (16). No expectations were relayed to the participants. They found that the participants in the first group perceived more pain relief from the higher-priced pill. This might explain the popularity of COX-2 inhibitors versus other non-steroidal anti-inflammatory drugs (NSAID), although no difference is found in pain relief in experimental studies (17).
The use of injection versus pills can have a strong placebo effect. Injections work better than pills, and visible injections of analgesics work far better than hidden injections (18). Subjects who were given oral ibuprofen with placebo injection had onset of pain relief earlier than oral ibuprofen alone (19,20). It is no surprise that ketorolac injection anecdotally is found to be more beneficial than oral medication prior to athletic events, although studies found equal pain relief (20).
ELUCIDATING THE PLACEBO EFFECT IN EXPERIMENTAL RESEARCH
In a Cochrane review of placebos, no evidence was found for a generally large effect size for placebo interventions. A possible small effect upon patient-reported continuous outcomes, like pain, could not be distinguished clearly from bias in studies (21). It is warranted to look at how the placebo effect might be elucidated. The Table illustrates the potential outcomes of an experimental intervention study. When an experimental intervention results in improved performance over the placebo condition (Table, rows 1, 5, and 7), the efficacy of the intervention can be demonstrated using both two- and three-condition designs. The use of the two-condition design precludes evaluation of whether the performance results in the placebo condition were equal to baseline (Table, row 5), more effective than baseline (Table, row 7), or less effective than baseline (Table, row 9). The justification for the use of a placebo control is the assumption that a placebo effect is associated with the experimental intervention and there is an associated improved performance over baseline. This assumption may not be true; if the placebo has a negative performance (i.e., nocebo) effect to baseline because of some inherent bias in the study design, but the experimental condition is equal to baseline (Table, row 8), it suggests that even if an experimental intervention is found to be significantly more effective than a placebo control, it might in fact be no more effective than true baseline.
Beedie (4) suggests that, depending upon the aims or hypotheses of the study, designing a study to elucidate the placebo effect might not be necessary. However, he argues that if a true reflection of the mechanisms underlying an effect is to be derived, a two-condition design might be insufficient. That is, if no significant differences are observed between experimental and placebo conditions (Table, rows 2, 4, and 6) in a well-controlled study, the only conclusion that can be drawn is that the intervention was unsuccessful. However, given the same outcome, using the three-condition design it is possible to ascertain whether placebo and experimental conditions did not differ from true baseline (Table, row 4), in which case the intervention was indeed ineffective, or whether both placebo and experimental conditions resulted in similarly improved performances over baseline (Table row 6), suggesting that the intervention was successful but that it has a significant psychological component. This would produce a somewhat different conclusion than "on the basis that there was no significant difference between the intervention and the placebo control, it was deemed unsuccessful." The two-condition design will mask any placebo effects and it does not reflect the true mechanisms underlying enhanced performance. More studies using a three-condition design will help elucidate the placebo effect and the true effect of supplements in sports.
Athletes believe that the placebo effect exists and they have benefited from the effect. These effects may not occur at the cellular level, but the belief in the supplement or drug triggers changes in the regional blood flow of the brain similar to the medication. Many factors affect these beliefs, including the placebo's color, cost, and method of delivery. Research design should incorporate methods to identify placebo effect; this would aid clinicians in the treatment of athletes.
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