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Research participants randomized to placebo-control conditions often report improved outcomes and can manifest physiologic responses that mirror those of participants who received the bioactive compound. Recent studies show that placebos can have beneficial effects even when the individual is aware that he/she is receiving a placebo, suggesting that the therapeutic context in which a placebo is delivered can be powerful. This context includes environmental and psychosocial factors, such as information disclosure, expectations, conditioning and empathy, embedded within research and clinical encounters that may influence outcomes. In this article, we review these placebo-related factors (PRFs), consider how they may influence the results typically attributed to diet and lifestyle interventions, and offer suggestions on enhancing PRFs in clinical obesity settings.
Participants randomized to placebo-control conditions (e.g., inert pills, sham surgery, health education in lifestyle or weight loss interventions) often report improved outcomes (e.g., pain, fatigue, self-efficacy) and manifest measurable physiological effects (e.g., activation of endogenous opioids) . Indeed, the outcomes of many medications with recognized biological effects (e.g., analgesics, antidepressants) are often indistinguishable from the outcomes of placebos [1, 2]. However, using placebos clinically is considered unethical because patients are led to believe that they are receiving a bioactive treatment. The idea that deception is required for a therapeutic response has been challenged by recent studies indicating that informing participants that they are receiving placebos, when delivered within the context of a clinical research encounter, improves outcomes in several patient groups (e.g., irritable bowel syndrome, clinically depressed) [3–5]. An extensive critical or comprehensive review of literature regarding placebo related factors (PRFs) in diet and lifestyle interventions cannot be provided within the scope of this Perspective Article. Herein, the purpose of this article is to briefly review PRFs, consider how they may influence the results of diet and lifestyle modification trials, and offer suggestions on how enhancing PRFs might increase obesity treatment effects.
It is becoming increasingly clear that placebo responses operate not merely from believing one is ingesting a bioactive compound or undergoing a legitimate medical procedure but also from environmental and psychosocial factors embedded within clinical and research encounters [1, 2] (see Figure 1). These encounters may engage several potential conscious and non-conscious mechanisms, including expectations, conditioning, anxiety reduction, interactions with practitioners/research staff (e.g., emotional support, empathy) and so on. Collectively, PRFs may promote improved outcomes even when participants do not receive a bioactive treatment and regardless of whether they are aware of this [3–5].
A few studies have examined PRFs in the context of diet/lifestyle interventions and have obtained significant effects. Crum and Langer  randomized 84 female hotel room attendants from 7 different hotels to one of two conditions. All participants received educational materials touting the benefits of physical activity. However, only those randomized to an “informed” condition were told that their work as housekeepers satisfied the US Surgeon General’s lifestyle physical activity recommendations. After four weeks, participants in the informed condition reported greater perceived exercise and had greater reductions in weight, BMI, waist-to-hip ratio, and blood pressure.
In another study , participants consumed identical 380-calorie milk shakes. On one occasion, the label said it contained 140 calories (“sensible shake”), and on another, the label said it contained 620 calories (“indulgent shake”). The ‘indulgent’ condition produced a steeper decline in ghrelin (a satiety hormone) and greater self-reported satiety compared to the ‘sensible’ condition. Finally, Chang and Chiou  gave all participants in their study a placebo pill and then randomized them to conditions in which they were told that they had taken either a placebo or weight-loss pill. Those told that they had taken a weight-loss pill ate more during a taste test and preferred larger quantities of sugary drinks compared to those told that they had taken a placebo. The findings suggest that those who believed that they took the weight-loss pill may have perceived that the medication gave them greater “leeway” with regard to intake when offered food during the taste test.
These studies suggest that providing particular information to participants can influence subjective and objective responses and behavioral self-regulation even when that information is inaccurate. Because, within the context of diet and lifestyle modification trials, participants are generally aware of the condition to which they have been randomized (i.e., they know the treatment regimen they have been assigned to, as well as the comparators), it is unknown whether, or to what extent, outcomes may be explained by PRFs. These PRFs include the information provided, expectations created after receiving information, staff responses to questions asked by the participants, study staff’s (conscious or non-conscious) differential enthusiasm for treatment conditions, and so on. Figure 2 offers two hypothetical scenarios of how PRFs could contribute to outcomes typically attributed to the direct effects of treatment. Given that it is difficult, if not impossible, to blind participants to an intervention in diet and lifestyle modification trials, we suggest that when we find differences between the interventions tested, we cannot definitively conclude that the observed effects are solely a function of the intervention per se versus PRFs. As such, isolating the true (direct) effects of the intervention may require study designs that directly manipulate PRFs so that the effects of the intervention, PRFs, and their interactions can be estimated.
Efforts to control or account for PRFs as a potential influence on outcomes in diet and lifestyle modification trials have generally not been employed. However, within the context of pharmaceutical trials, several design features and strategies have been used to minimize the influence of PRFs. These include, but are not limited to, the use of active placebos that will mimic the side effects of experimental treatment, run-in phases, and withdrawal periods . Moreover, standardizing the amount and quality of contact between participants and study staff, as well as ensuring treatment fidelity (by, for example, recording the clinical encounters to ensure consistency) are strategies that may also mitigate PRFs.
However, disclosing information about specific aspects of the trial, even during the consent process, may influence participant expectations and potentially affect outcomes. Developing ways to incorporate and account for expectations and other PRFs is, in our view, a neglected issue in obesity research, as well as in other research contexts where blinding is impossible.
Although we may wish to account for the role of PRFs in diet and lifestyle modification trials, from a clinical perspective, creating conditions that enhance PRFs might improve outcomes. For example, a warm, supportive, and reassuring relationship is a significant predictor of positive outcomes [1, 9]. In addition, conveying information that creates expectations for success, in conjunction with one’s desire to improve, can enhance the therapeutic response [1–5, 9]. Unfortunately, it has been shown that physicians working with patients affected by overweight and obesity tend to demonstrate low levels of emotional rapport that weaken the patient-physician relationship, diminish treatment adherence and decrease the effectiveness of behavioral counseling . However, exploiting PRFs embedded within clinical obesity treatment encounters may significantly enhance the effects of treatment.
In sum, we may wish to account for the potentially powerful influences of PRFs when evaluating effects in diet and lifestyle modification trials. There is a need to isolate PRFs from the intervention effects. Therefore, we suggest that, as testing and imaging techniques become more sophisticated, study designs might begin to include placebo conditions that measure potential genetic, neurobiological and psychophysiological placebo responses, which might serve as biomarkers of the placebo response. Also, strategies to monitor fidelity on an ongoing basis might help to control and minimize the influence of PRFs to better isolate the value of the components in lifestyle modification trials. In contrast, maximizing their influence in the clinic may be desirable to enhance therapeutic outcomes.
FUNDING: This work is supported in part by NIH grants K23DK081607 and 2K24AT004095.