Placebo Effects: A New Theory

Abstract

Placebo effects have increasingly aroused scientific and public interest for their clinical and research values. However, underlying mechanisms of this mind–body phenomenon are not yet fully understood. In this article, I propose a new model according to which context-based placebo effects source from positive treatment beliefs but are directly caused by benefit expectations. By virtue of mediating belief-expectation transformation, placebo administration triggers, and thus has a pivotal role in, subsequent therapeutic responses.

Keywords

placebo effect belief meaning expectation reward emotion appetitive/aversive motivation route of treatment administration

The provision of medical care is embedded in a unique therapeutic environment that affects a patient’s mind, body, and behavior. Symptom improvements derived from this dramatic environment are generally referred to as placebo effects or placebo responses (Colloca & Benedetti, 2005; Di Blasi et al., 2001; Finniss et al., 2010). Placebo effects are now known to be clinically relevant (Bingel et al., 2011; Kam-Hansen et al., 2014; Rief et al., 2011) and thus can be potentially taken advantage of to improve treatment outcomes and patient benefit (Colloca & Barsky, 2020; Enck et al., 2013; Evers et al., 2018). As a complex neurobiological phenomenon (Geuter et al., 2017; Wager & Atlas, 2015), placebo effects occur across a variety of disorders and conditions, and many cognitive and affective processes have been implicated in those effects, including meaning, expectation, learning (i.e., prior experiences), motivation, reward, and emotion (Benedetti, 2008; Colloca & Miller, 2011a; Price et al., 2008). However, a comprehensive unified model that can well accommodate them is lacking. In the following, I present a theoretical framework with which to unravel behavioral and psychological underpinnings of placebo effects after a clinical intervention.

Treatment Beliefs and Expectations

An important milestone in the efforts to deconstruct placebo effects is the response-expectancy theory put forward by Kirsch in 1985, which maintains that a placebo produces an effect by inducing an expectation of future responses. This theory has been gaining ground over recent years because an accumulating body of evidence supports therapeutic expectations as a principle mechanism in mediation and modulation of effects of a placebo (Benedetti, 2008; Buchel et al., 2014; Colloca & Barsky, 2020; Enck et al., 2008; Finniss et al., 2010; Kirsch et al., 2004, 2014; Price et al., 2008; Stewart-Williams & Podd, 2004). When examining Kirsch’s placebo theory, remember that a patient can expect any benefits from a clinical treatment only if he or she believes that the treatment has therapeutic properties. Without a belief in treatment, there would definitely be nothing to expect, much less that the placebo effects could come about consequently. Given this consideration, it appears reasonable to propose that expectation-mediated placebo effects stem from beliefs regarding treatment potentials. Obviously, when a person believes that a clinical treatment is therapeutically effective, one may also say that this treatment is meaningful to that person. Thus, the present identification of treatment beliefs as the ultimate source of placebo effects underscores a previous meaning model by Moerman (2013), who wrote that placebos are capable of exerting influences on the patient depending on “their powerful abilities to contain and convey meaning” (p. 125), and thus those influences can be attributed to a “meaning response” (Hutchinson & Moerman, 2018; Moerman, 2002, 2011; Moerman & Jonas, 2002).

In fact, effects of placebos can be seen as an expectation-mediated belief response. During the formation of those effects, however, patients’ beliefs about treatment effectiveness do not automatically lead to an outcome expectation. For a given placebo treatment that is believed to have healing properties, the patient absolutely cannot expect to experience any therapeutic benefit before taking it. Or alternatively, for individuals who believe that a placebo is potentially effective, benefit expectations can be induced only in those who have received the treatment. What is behind this idea is the simple fact that any treatment certainly cannot start to work until it has been delivered. Before being administered, a placebo treatment is merely a belief container or conveyor; only after administration can it induce belief-based expectations, which in turn directly set off corresponding responses. In this sense, expectation-mediated placebo effects directly result from the delivery of a meaningful treatment—placebo administration literally serves as the direct trigger of those effects.

As far as placebo effects are concerned, belief and expectancy represent distinct psychological entities, although they often overlap. Whereas the former relates to the probability that a placebo possesses a potential benefit, the latter pertains to the possibility of being able to acquire that very benefit, thus having immediate motivational consequences. By mediating the belief-expectation shift, treatment administration has a motivational power and thereby directly triggers placebo responding. People’s beliefs, views, and attitudes concerning a clinical treatment are intrinsic; their generation and maintenance are independent of whether the treatment has been administered. Instead, patients’ expectations toward a clinical treatment are the external manifestation of its internal meaningfulness; they cannot be brought into being before the receipt of the treatment. As a subjective construct, treatment beliefs are “quiet” and “still,” which to date cannot be objectively measured. In comparison, belief-based expectations are dynamic and always fluctuating, which can be detected and evaluated by currently available neuroimaging techniques such as functional MRI and positron emission tomography (see Bingel et al., 2011; de la Fuente-Fernandez et al., 2001; Eippert et al., 2009; Scott et al., 2007; Tinnermann et al., 2017; Wager et al., 2004).

A New Theory

The foregoing analysis highlights a theoretical framework for illuminating how biased perception of a fake (placebo) treatment can lead to real improvements in patients’ symptoms. Placebo effects are rooted in inherent treatment beliefs, but they are the direct and immediate consequence of vigorous benefit expectations born out of those beliefs. Placebo administration has a triggering role in subsequent therapeutic responses by virtue of mediating belief-expectation shift. A placebo treatment cannot have any effects unless two conditions are simultaneously satisfied: (a) the treatment is meaningful, which enables the patient to believe that it has a healing power, and (b) the patient is fully aware that the treatment is being or has been delivered, which makes it possible for him or her to expect a beneficial outcome. According to this reasoning, the strength of placebos is determined by both the degree of the belief in treatment efficacy and the route or method for treatment delivery, which determines how that belief translates into benefit expectations. For a given clinical condition, robust placebo effects can be brought about when and only when a treatment endowed with special meanings and strong beliefs is implemented in an appropriate manner.

Current research has failed to distinguish between beliefs and expectations when describing psychological processes involved in the formation of placebo effects, and those two terms have been frequently juxtaposed and interchangeably used in the literature (see e.g., Ashar et al., 2017; Bingel et al., 2011; Buchel et al., 2014; Schafer et al., 2018, and references therein). A recent study may be helpful in recognizing the boundary line between treatment-related beliefs and expectancies and how they are incorporated into the process of placebo responding. Camerone et al. (2020) evaluated the effect of a placebo treatment on perceived intensity of an electrical stimulation in three groups of healthy participants who were instructed that “an analgesic cream would be applied to reduce painful sensation” and that it “would become effective after 5, 15 or 30 minutes” (p. 44). Generally, across the three placebo groups, subjective pain ratings were found to be significantly reduced only at the preset time point but not earlier (Camerone et al., 2020). Similar results were obtained in a more recent experiment that used more intense, longer-lasting pain (Camerone et al., 2021).

A plausible interpretation of the two experiments above is that before the alleged onset (administration) time, the participant just has a treatment belief but cannot expect to obtain any therapeutic benefits; thus, placebo effects do not occur. Only after the onset time can that belief be transformed into a benefit expectation and can placebo effects in turn be touched off. To my knowledge, this study is the first of its kind to successfully separate treatment beliefs and benefit expectations through varying the information about the onset of ostensible effects of a placebo, although the authors failed to mention that in their work. A similar time course of hyperalgesic effects was also observed in three groups of participants who were given a nocebo cream with the same temporal information (Camerone et al., 2020). This indicates that such a conceptual dissociation between beliefs and expectations is also applicable to detrimental responses to a nocebo treatment. As expectation-mediated belief responses, placebo effects are triggered by a transition from positive beliefs to an expectation of therapeutic benefits, whereas nocebo effects are triggered by a transition from negative beliefs to an expectation of deleterious outcome.

Context-Based Meanings and Beliefs

What makes a clinical intervention meaningful and thereby creates a belief in its effectiveness is undoubtedly the surrounding psychosocial context. Without this overall context, placebo is nothing. Indeed, beneficial responses to placebo have been conceptualized as a “context effect” or “contextual healing” (Di Blasi et al., 2001; Miller & Kaptchuk, 2008), and therefore the study of those responses is “essentially the study of the psychosocial context that surrounds the patient” (Colloca & Benedetti, 2005, p. 545). Although it has a fundamental role in effects of placebo, the psychosocial context does not come into play directly by itself. Only through treatment administration can this potent context be activated, allowing for a transmutation of positive beliefs into benefit expectations, which then directly activate placebo responding. There are many contextual factors that can remarkably influence how a clinical treatment is believed to be an effective therapy.

Treatment characteristics

Effects of placebo pills are significantly influenced by their physical properties, such as color, number, size, and shape (Buckalew & Coffield, 1982; de Craen et al., 1999; Meissner & Linde, 2018; Schapira et al., 1970). Even commercial factors, such as brand name and price, have proven to be important modulators of placebo strength (Branthwaite & Cooper, 1981; Geuter et al., 2013; Meissner & Linde, 2018; Waber et al., 2008). It is obviously not those perceptual features per se that significantly affect the effectiveness of placebo but the actual meanings and beliefs attributed to them. Red placebo pills make better stimulants than blue ones, just because they can induce a higher treatment belief, given that the color red is usually interpreted as “up,” “hot,” and “danger” (Tracey, 2010; Wiech et al., 2008). Likewise, pricing information can alter people’s perception of a treatment: An expensive price value is always interpreted as the equivalence of better effectiveness.

Clinician–patient relationships

The meaningfulness of a clinical intervention is not just associated with its perceptual nature. In daily clinical practice, medical care is provided by the clinician and received by the patient. Thus, clinician–patient relationships represent the most active element of clinical encounters (Ellingsen et al., 2020) and therefore serve a powerful meaning/belief-making function. Early clinical evidence has shown that the quality, style, and content of communications between clinicians and patients are potent factors in placebo outcomes (Benedetti, 2013; Gryll & Katahn, 1978; Oken, 2008; Uhlenhuth et al., 1966; van der Molen & van den Hout, 1988). Alternative therapies (Kaptchuk, 2002b; Kaptchuk & Eisenberg, 1998), such as acupuncture (Kaptchuk, 2002a; Liu, 2007, 2009; Zheng et al., 2014), have pronounced and clinically significant placebo effects in which reciprocal practitioner–patient interactions might have a contributing role. In a prior study that sought to disentangle and quantify component parts of placebo effects of the clinical encounter (Kaptchuk et al., 2008), 262 adults with irritable bowel symptom (IBS) were randomly assigned to three groups: a no-treatment control group (waiting-list group), a second group that received a validated sham acupuncture with a supportive interaction (warmth, attention, and confidence) with the practitioner (augmented group), and a third group that was provided the procedure alone without much interaction with the practitioner (limited group). The results demonstrated a significant difference in symptom relief and quality of life between augmented compared with limited groups. The outcomes of both placebos were superior to those of the waiting-list group.

Learning from prior experience

Prior experience can considerably shape the way that people look at things. When it comes to placebo effects, outcomes of health care accepted previously, personal history of clinician–patient communications, and related information from other sources can greatly affect how people—healthy or sick—view medicine and medical interventions. In fact, prior experience is one of the best—if not the best—means by which a clinical treatment can make meanings and beliefs. Placebo effects have thus been ascribed to a learning phenomenon (Benedetti et al., 2011; Colloca & Miller, 2011b). As a learning procedure most commonly used in laboratory settings, conditioning (repeated associations between treatment cues and suggested therapeutic effects) can greatly enhance placebo responsiveness (Colloca & Miller, 2011b; Enck et al., 2008; Wager & Atlas, 2015) by reinforcing treatment beliefs. I will elaborate on this critical issue in a forthcoming article.

Sociocultural background

Relying on “complex webs of meaning, rich skeins of connected understandings, metaphors, and signs” (Moerman & Jonas, 2002, p. 474), cultures have significant biological consequence by shaping values and beliefs. In fact, culture is the most basic background factor that encompasses all the processes involved in the evolution of meaningfulness of any medical interventions; thus, its big impact on the formation of belief-based placebo effects can never be overemphasized. As a culture-embedded learning process contained in both biomedical and alternative therapies, healing rituals are a good example to show how the sociocultural background can profoundly promote placebo effectiveness through fostering treatment beliefs. Kaptchuk (2011) wrote that they “create a receptive person susceptible to the influences of authoritative culturally sanctioned ‘powers’” (p. 1849). Given that meanings and beliefs are different from culture to culture, a cross-cultural variation in subjective perception of health care interventions and hence placebo responses is likely.

Route of Administration: Invasive Placebos Versus Placebo Pills

As outlined above, treatment administration triggers a shift from positive beliefs to benefit expectations. Thus, the route of administration could have a potential role in determining subsequent placebo responses, which is consistent with research findings showing that the magnitude of placebo effects differs markedly between treatment modalities (Kaptchuk et al., 2000; Meissner & Linde, 2018). This cannot be better demonstrated, perhaps, than in enhanced placebo effects with an invasive procedure. In a clinical study that directly compared an invasive placebo and an oral placebo in 270 patients with chronic arm pain (Kaptchuk et al., 2006), a validated sham-acupuncture procedure was substantially more effective than an inert pill after 6 weeks of treatment. In line with these results, systematic reviews have revealed enhanced placebo responses with sophisticated and invasive interventions, such as acupuncture, injection, and surgical procedures, compared with oral medications (Bannuru et al., 2015; de Craen et al., 2000; Hrobjartsson & Gotzsche, 2010; Linde et al., 2007; Meissner et al., 2013).

For ethical reasons, clinical studies of surgery seldom include a sham control group (Horng & Miller, 2002). Despite this, some randomized controlled trials (RCTs) of surgical interventions have dramatically demonstrated the degree to which self-reported symptom improvements after an invasive procedure can be due to placebo effects by showing that a real procedure was no better than its sham control—that is, patients undergoing actual and simulated operations experienced equal and clinically meaningful benefits in subjective measures such as pain and function—whereas uncontrolled observational studies have supported procedural success (Flum, 2006). Procedures and conditions studied include, just to list a few, arthroscopic surgery for osteoarthritis of the knee, degenerative meniscal tears, and shoulder pain (Beard et al., 2018; Moseley et al., 2002; Sihvonen et al., 2013); vertebroplasty for osteoporotic compression fractures (Buchbinder et al., 2009; Kallmes et al., 2009); percutaneous coronary intervention and bilateral internal mammary ligation for angina (Al-Lamee et al., 2018; Cobb et al., 1959; Dimond et al., 1960); and transplantation of fetal dopaminergic cells for severe Parkinson’s disease (Freed et al., 2001). Comparable results were reported by large high-quality RCTs of acupuncture in which no outcome difference was observed in patients receiving real and sham procedures; however, both groups were significantly better than no-treatment or standard-care control groups (Brinkhaus et al., 2006; Cherkin et al., 2009; Haake et al., 2007; Linde et al., 2005; Melchart et al., 2005; Witt et al., 2005). Given powerful placebo effects associated with acupuncture (Kaptchuk et al., 2020), sham-needling procedure has been used as a tool to study placebo effects both experimentally and clinically (Kaptchuk et al., 2006, 2008; Kong et al., 2006; Wechsler et al., 2011).

To account for the superiority of invasive over noninvasive placebos, Moerman and Jonas (2002) suggested that invasive procedures are particularly good at “inducing a profound meaning response in modern medical practice” because they “usually have compelling rational explanations, which drug treatments often do not, . . . especially for people in a culture rich in machines and tools” (p. 473). However, this explanation alone may not be sufficient. Noninvasive treatments can be especially meaningful and believable as well, and an invasive treatment does not always have to be more appealing and persuasive under any circumstances. Actually, what essentially distinguishes invasive from noninvasive placebos is the route or method by which they are delivered. Thus, arguably, patients’ experience when undergoing a perceived invasive procedure should be one crucial component of pronounced placebo responses following it.

Compared with oral pills, therapeutic outcomes of an invasive intervention can be achieved only at the cost of suffering actual and perceived unpleasantness caused by its administration. When a patient is receiving an invasive procedure (whether it be real or sham) that is therapeutically meaningful and thus is believed to have potential benefits, the experienced invasiveness renders those benefits rewarding, thus having an appetitive motivational power. No sooner has the procedure begun than the patient is immediately motivated to gain as many therapeutic rewards as possible out of the aversiveness being experienced. Considering this, patients’ experience during the performance of an invasive placebo can be characterized as a process that mediates the transformation from treatment beliefs into a reward expectation and thereby directly stimulates therapeutic responses. In addition, this particular administration route, in itself, can greatly contribute to subsequent placebo responsiveness. During the course of administration of an invasive procedure, its perceived invasiveness as an appetitive motivational drive can progressively elevate belief-based reward expectations to an extremely high level (negative reinforcement), and therefore potent placebo effects are consequently formed.

When a placebo is being delivered under the guise of an invasive procedure, its perceived invasiveness always drives a reward expectation that is positive in nature, regardless of contextual and individual specificities. By contrast, when a placebo is provided in the form of a pharmacological pill, most often the patient just expects the experienced symptom to be alleviated (an expectation that is less negative in nature) because there is a lack of appetitive motivational drive. Placebo responses under this condition are an effect that would take place when, just as argued by Brody (2018), “the meaning of the illness experience for the patient is altered in a positive direction” (p. 353). Note that a reward expectation might also be generated with the application of a noninvasive treatment in some limited exceptions—for instance, when the patient has a personality trait that predisposes him or her toward perceiving expected symptom relief as rewarding or when the patient is experiencing a severe disease and thus has a higher level of desire or need for improvement. Even so, generally speaking, the capacity of a noninvasive placebo to produce reward expectations is inferior to that of an invasive placebo with respect to both their likelihood of occurrence and the level of intensity. Together, from the standpoint of motivational processes, the patient has fundamentally different experiences during the implementation of invasive and noninvasive interventions. In the first case, positive (reward) expectations drive an appetitive motivation, whereas in the second case, lowered negative expectations lead to a less aversive motivation.

Invasive procedures such as injection, acupuncture, and surgery are rarely alternatives in clinical practice; however, patients undergoing those procedures have similar experiences in terms of appetitive motivation (or a reward expectation) driven by procedures’ perceived invasiveness. That is the reason why, in most cases, invasive procedures are associated with enhanced placebo effects. Current evidence supports a strong relationship between induced activities in dopaminergic brain reward regions during the implementation of a perceived invasive procedure and behavioral placebo outcomes. In two experiments by the same group of investigators, Scott et al. (2007, 2008) first convinced healthy subjects of the effectiveness of placebo by giving clinical-trial-type instructions through which an environment analogous to that of typical placebo-controlled drug trials (no preconditioning, no deception, either a real or sham drug could be administered) was established. After that, during the 20-min period before actual pain challenges, a placebo treatment (1 ml of 0.9% isotonic saline) was delivered intravenously every 4 min, and the subject was made aware of the treatment administration through a computer-generated human voice recording, followed by a second-by-second count of the infusion timing. Featuring a perceived invasive nature, repeated treatment sessions, prolonged duration of administration, and purposely intensified warning cue, this especially enhanced method for placebo delivery can greatly augment subsequent analgesic effects by boosting the process through which treatment beliefs are turned into a reward expectation. The authors found that high and low placebo responses were tracked by the activation of the mesolimbic dopamine system (Scott et al., 2007, 2008) and the endogenous opioid system (Scott et al., 2008) within the nucleus accumbens as measured by functional molecular imaging. Note that both neurotransmitter systems were activated in advance of pain when the placebo treatment was being delivered (Scott et al., 2007, 2008), and the activation of nucleus accumbens dopamine neurotransmission was demonstrated to be associated with the magnitude of μ-opioid responses in placebo-responsive regions (Scott et al., 2008).

Further evidence comes from a study using positron emission tomography, conducted in patients with chronic knee pain, in which imaging data were collected during the performance of an invasive acupuncture procedure (Pariente et al., 2005). Both real and covert sham needle stimulation (with the same reward expectations), compared with overt sham stimulation (with no expectation), induced brain activations in the dorsolateral prefrontal cortex, the anterior cingulate cortex, and the midbrain periaqueductal gray (PAG). Those brain areas have together been linked to reward expectation (Schultz, 2002), and changes in the function of this well-defined descending pathway involved in the processing of sensory stimuli are suggested to be driven primarily by altered motivational state (Fields, 2004).

Experienced Pleasant Aversiveness

An invasive intervention is an aversive experience; however, at the same time, it brings forth therapeutic benefits. Thus, when a perceived invasive procedure is being performed, the patient is in reality experiencing a “pleasant aversiveness” (Liu, 2017) that always drives a reward expectation and hence strong placebo effects after the procedure. Note that the experience of pleasant aversiveness is not unique to the patients who are exposed to an ongoing invasive procedure. Side (adverse) effects secondary to therapeutic benefits of medications are obviously an aversive experience that often causes unnecessary worry, impairs treatment adherence, or even precipitates undesirable outcomes. In the setting of RCTs, however, drug-related side effects can be conferred with a positive meaning because they are often taken by patients as a sign that they have received a real potent treatment and are thus more likely to benefit from it. So, the perception of side effects can be described as an experience of pleasant aversiveness that can greatly heighten placebo responsiveness. This provides an explanation for an RCT of different analgesic agents for postherpetic neuralgia in which the presence (or absence), the number, and the maximal severity of side effects were significantly correlated with reported pain relief (Max et al., 1988). Likewise, in a meta-analysis of RCTs for IBS, higher incidence of side effects predicted larger subjective symptom improvements (Shah et al., 2014). The same is true for antidepressant clinical trials finding that an “active” placebo, which is ineffective for the condition being studied but mimics drug-related side effects, is better than an “inert” placebo that does not exhibit those effects (Moncrieff et al., 2004).

Laboratory investigation reveals that behavioral and neural responses to noxious stimuli can be greatly attenuated when an aversive experience is perceived as pleasant. In a study (Benedetti et al., 2013), two groups of healthy volunteers were exposed to ischemic arm pain after manipulated verbal information. One group was honestly informed about the aversive nature of the task. Conversely, a second group was told that the ischemia would have positive effects on muscle cells, which led to an experience of pleasant aversiveness because the meaning of pain was changed from negative to positive. The authors found that pain tolerance in the second group was significantly increased compared with the first group. In another study by Leknes and colleagues (2013), an identical moderate painful stimulus was applied in opposing motivational states: (a) a relative-relief context in which the moderate pain represented the best outcome, and the only alternative outcome was intense pain, and (b) a control context in which the moderate pain represented the worst outcome. When presented in the relative-relief context, the normally aversive, moderate pain is encoded as a preferred reward—that is, the subject is experiencing a pleasant aversiveness—whereby the ongoing stimulation drives a motivation to secure the reward, which is the experienced pain itself. During the context manipulation, skin conductance and neural activity in some key pain-processing regions were observed to be significantly decreased, along with an increased functional connectivity between the reward and valuation circuitry (the medial orbitofrontal and ventromedial dorsolateral prefrontal cortex) and the periaqueductal gray, relative to the control stimulus (Leknes et al., 2013). These findings conceivably point to the suggestion that experiencing a pleasant aversiveness, which drives a reward expectation (or an appetitive motivation), can suppress the perception of sensory stimuli via the activation of brainstem structures. This same mechanism is likely to subserve robust placebo effects on pain as well as other aversive sensory experiences.

A Motivational Account of Placebo and Nocebo Effects

Illness experience inherently drives an aversive motivation. A placebo/nocebo treatment may take effect by altering the motivational context in which somatic symptoms are being perceived and experienced. Althoogh nocebo effects occur in response to a more aversive motivation, effects of placebo are the direct result of either a less aversive motivation or an appetitive motivation. Altered motivations are always accompanied by changes in emotional state; thus, emotions are likely to have a role in motivationally driven placebo/nocebo responses. This confirms and extends a prior desire-expectation emotion model of placebo effects (Price et al., 2008). Figure 1 depicts how the magnitude of placebo effects varies as a function of motivational and emotional processes during treatment.

Fig. 1.

Schematic illustration of the correlation between expectations about treatment, changes in motivational and emotional state, and the magnitude of placebo effects. Aversive and appetitive motivations are at the opposite ends of the same behavioral spectrum. When a clinical intervention is being implemented, it induces either a decreased aversive motivation (a less negative to neutral expectation) or an appetitive motivation (a positive reward expectation) depending on the behavioral context surrounding the patient. Weak to strong placebo effects are generated when belief-based treatment expectations shift from less negative through neutral to positive.

If a patient expects to experience a relieved symptom (less negative expectations) when administered a placebo (Fig. 1), the aversive motivation tends to be lessened, as does the related anxiety. Prior studies have supported the involvement of anxiety reduction in the development of placebo effects (Flaten et al., 2011; Meyer et al., 2015; Petrovic et al., 2005; Vase et al., 2005). Conversely, when expecting a worsening of symptoms (heightened negative expectations), which begets an increase in aversive motivation, the patient will feel more threatened and thus become more anxious (Benedetti et al., 2006, 2007). Under this condition, as Benedetti and colleagues (Colloca et al., 2008) showed, anxiogenic verbal suggestions were capable of turning innocuous stimuli into pain and low-intensity painful stimuli into high-intensity pain (nocebo effects). Emotions are associated not only with aversive motivations (negative affect) but also with appetitive motivations (positive affect; Lang et al., 1992; Villemure & Bushnell, 2002). When expecting/anticipating a rewarding benefit (positive expectations), which drives an appetitive motivation (Fig. 1), a patient may get considerably anxious as well because he or she urgently wants to get that benefit. This suggests that increased anxiety may also participate in placebo responding, which is compatible with early behavioral studies that found that individuals are more likely to demonstrate a placebo effect when they are feeling anxious than when they are not feeling anxious (Geers et al., 2006; Medvedev et al., 1984; Shapiro et al., 1973) and that high pain-anxiety volunteers demonstrate greater responses to both placebo and nocebo interventions (Staats et al., 2001).

Nowhere is this more apparent than in the implementation of an invasive procedure for which the perceived invasiveness not only drives a reward expectation but also, more often than not, causes some extent of anxiety that significantly correlates with the intensity level of that expectation. As a negative reinforcer and a key indicator of the reward expectation during procedure administration, the induced anxiety could substantially contribute to, and hence reliably predict, subsequent placebo responsiveness. A good example is acupuncture, an ancient Chinese therapy, which is especially good at producing placebo effects (Kaptchuk, 2002a; Liu, 2009; Zheng et al., 2014). Depending on the insertion of fine needles into specific parts of the body for therapeutic purposes, acupuncture is, at any rate, an invasive procedure. Although the actual invasiveness of acupuncture is minimal compared with other invasive procedures such as injection and surgery, its perceived invasiveness could still have such a great impact on patients’ minds that considerable anxiety can be caused when they experiencing the needling procedure. This might be responsible for a variety of so-called side effects of acupuncture that take place immediately before or during needle administration (i.e., needle insertion and manipulation), including severe nausea, actual fainting, severe dizziness, heavy sweating, and vomiting (Liu, 2009; MacPherson et al., 2001). Future studies can use sham acupuncture as a model to test the correlation between experienced anxiety during the performance of a perceived invasive procedure and resultant placebo responses after the procedure.

Open-Label Placebo

It is generally believed that for a placebo treatment to be effective, its true nature must be withdrawn from the patient. This is because the awareness or knowledge that a treatment contains nothing active but sugar or starch will render the treatment meaningless, and thus placebo effects can by no means be evoked. Contrary to this conventional wisdom, however, the results of a series of small randomized trials show that open-label placebo pills can produce significant therapeutic effects in patients with, for example, menopausal hot flushes (Pan et al., 2020), postsurgical pain (Flowers et al., 2021), episodic migraine attacks (Kam-Hansen et al., 2014), cancer-related fatigue (Hoenemeyer et al., 2018), chronic low-back pain (Carvalho et al., 2016), IBS (Kaptchuk et al., 2010; Lembo et al., 2021), allergic rhinitis (Schaefer et al., 2018), and major depressive disorder (Kelley et al., 2012). But can one infer from those trials that effects of placebo can be mediated in the absence of conscious beliefs and expectations? The answer may be no.

Generally, across those clinical trials conducted in the context of a supportive patient–practitioner relationship, the patients were informed that they would receive a placebo treatment that contained no active medications; at the same time, however, they were told things like “placebo effects are powerful” and that “the body can automatically respond to taking placebo pills” (Carvalho et al., 2016; Hoenemeyer et al., 2018; Kaptchuk et al., 2010; Pan et al., 2020; Schaefer et al., 2018). Although those verbal instructions were purposely designed for the removal of disbelief caused by negative connotations of placebo through “an accurate description of what is known about placebo effects” (Kaptchuk et al., 2010, p. 6), they most likely created an uncertain belief that ranged from neutral to positive. After receiving those instructions, the patients were in fact facing a situation like that encountered by patients in double-blinded drug trials after they have been randomly assigned into either the treatment group or the sham control group. In two recent clinical trials in patients with IBS and menopausal hot flushes (Lembo et al., 2021; Pan et al., 2020), openly prescribed placebos elicited significant benefits similar to those of placebos given under double-blind uncertainty. In short, the demonstrated effects of open-label placebo might be attributed to false beliefs resulting from the briefing about placebo effects before treatment administration (Colloca & Howick, 2018; Miller & Colloca, 2009). Placebo effects are more a conscious than unconscious psychobiological phenomenon.

As a prerequisite for a placebo to work, treatment beliefs can be a reliable predictor of the magnitude of placebo effects, which are directly determined by belief-based benefit expectations. However, this may not always be the case, especially when a placebo is delivered in a substantially enhanced context but the patient does not have a strong belief in its effectiveness. That is precisely what really happens in the clinical trials under discussion: The patients were first given vague information about placebo effects and were then required to “take the placebos faithfully” (see Kaptchuk et al., 2010; Kelley et al., 2012; Pan et al., 2020; Schaefer et al., 2018). That requirement can greatly enhance the administration process and hence foster belief-expectation transformation by achieving a better patient engagement. Under this condition, it is very likely that some transient and dramatic changes can be induced in the patient during the administration period such that low positive beliefs, or even neutral beliefs, are encoded into high-benefit expectations, thereby evoking strong placebo effects. This may explain the finding that manipulating the level of information did not influence the magnitude of placebo responses (Schaefer et al., 2018) and that reported hope and expectations (they are actually treatment beliefs in the present placebo theory) after random assignments were not associated with placebo responsiveness (Pan et al., 2020).

Placebo Effects Without Treatment Application

Although in this article I focus primarily on contextually driven placebo responses to the administration of a clinical treatment, note that the psychosocial context alone can directly elicit therapeutic effects before treatment application or in the absence of discrete treatment interventions at all, possibly through allowing the patient to reappraise the symptom being experienced so that it becomes more controllable and less unpleasant (Tracey, 2010; Wiech et al., 2008), resulting in a reduction in aversive motivation. There has been evidence that the context of usual clinical encounters is an independent factor that potently affects health outcomes (Kaplan et al., 1989; Ong et al., 1995; Stewart, 1995) and that merely possessing a placebo treatment (without actually using it) could create significant benefits (Wai-Lan Yeung et al., 2020; Yeung & Geers, 2021). Some experts have argued that the placebo effect in clinical care can be promoted by reinforcing the therapeutic context through improving communications between the clinician and the patient, with no need to resort to placebo treatments (Brody, 1982; Hrobjartsson, 2008), which are thought to be ethically problematic for inherently involving concealment or deception (Miller & Colloca, 2009). Although this argument is true in any case, note that an enhancement of clinician–patient interactions without the application of a treatment intervention may not be able to produce stable and significant placebo effects because, on most occasions, it merely induces a less negative to neutral expectation (an expectation of reduced symptom severity) rather than a positive/reward expectation.

Concluding Remarks

Placebo effects are prominent in many conditions and paradigms. It seems unlikely that there are separate and specific mechanisms involved in each instance (Schafer et al., 2018). In this article, I proposed that effects of placebo are codetermined by treatment beliefs and how those beliefs are converted into benefit expectations and motivations but are unrelated to the symptom being experienced. Various long-standing, well-established approaches to placebo effects, such as the meaning-response theory (Brody, 1980, 2018; Moerman, 2002; Moerman & Jonas, 2002) and the response-expectancy theory (Kirsch, 1985), are not mutually exclusive, but they address different phases or aspects of the same psychological process underlying those effects.

Footnotes

Transparency

Action Editor: Kenneth J. Sher

Editor: Kenneth J. Sher

Author Contributions

T. Liu is the sole author of this article and is responsible for its content.

ORCID iD

Tao Liu

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