Mindsets Matter: A New Framework For Harnessing The Placebo Effect in Modern Medicine
Mindsets Matter: A New Framework For Harnessing The Placebo Effect in Modern Medicine
Mindsets Matter: A New Framework For Harnessing The Placebo Effect in Modern Medicine
Contents
1. Introduction 138
2. The Treatment Effect: Drug Plus Placebo Effects 140
3. Psychological Processes Activate Neurobiological Mechanisms 142
3.1 Implicit Learning 143
3.2 Expectancy 144
3.3 Mindsets 146
4. Social and Contextual Factors Inform Psychological Processes 148
4.1 Developmental and Cultural Factors 149
4.2 The Patient–Provider Relationship—Communication, Warmth, and
Competence 150
4.3 Social Influence and Observational Learning 152
4.4 Treatment Type and Characteristics 153
5. Discussion 155
Acknowledgments 156
References 156
Abstract
The clinical utility of the placebo effect has long hinged on physicians deceptively
administering an objective placebo treatment to their patients. However, the power
of the placebo does not reside in the sham treatment itself; rather, it comes from
the psychosocial forces that surround the patient and the treatment. To this end, we
propose a new framework for understanding and leveraging the placebo effect in clin-
ical care. In outlining this framework, we first present the placebo effect as a neurobi-
ological effect that is evoked by psychological processes. Next, we argue that along with
implicit learning and expectation formation, mindsets are a key psychological process
involved in the placebo effect. Finally, we illustrate the critical role of the social environ-
ment and treatment context in shaping these psychological processes. In doing so, we
offer a guide for how the placebo effect can be understood, harnessed, and leveraged in
the practice of modern medicine.
1. INTRODUCTION
Henry Beecher, a World War II army medic, is credited with bringing
about the modern study of the placebo effect. Upon exhausting his supply of
morphine, Beecher continued treating his wounded patients with saline
solution while reassuring them of the pain-relieving power of the infusion.
His observation that patients tended to improve with the sham treatment
and comforting words led to the publication of “The Powerful Placebo,”
which reported on the magnitude of the placebo effect across 15 clinical tri-
als. Beecher’s analysis revealed that over 35% of patients experienced ther-
apeutic benefit from placebo treatments (Beecher, 1955). His finding
intrigued a generation of scientists and laid the groundwork for decades
of subsequent research on the placebo effect.
Since Beecher’s time, the placebo effect has taken on new meaning
depending on the context in which it is studied. In randomized, double-
blind clinical drug trials, new drugs and treatments are compared to a
placebo control. This gold standard for pharmaceutical research and devel-
opment enables researchers to quantify the efficacy of the treatment as it
compares to the effect of the placebo. The ultimate goal of these trials is
to demonstrate the benefit of the active treatment beyond that of the pla-
cebo, and consequently, much of clinical research aims to subtract out or
do away with the placebo effect (Crum, Leibowitz, & Verghese, 2017).
Even when a significant difference between the active treatment and the pla-
cebo is found, any effect of the placebo is later usually forgotten. Despite the
fact that the placebo effect yields clinically significant benefits in clinical trials
for well over half of all medical conditions—including pain, depression,
Parkinson’s disease, anxiety disorders, cardiovascular disorders, and immuno-
logical diseases (de la Fuente-Fernandez & Stoessl, 2002; Goebel, Meykadeh,
Kou, Schedlowski, & Hengge, 2008; Levine, Gordon, Smith, & Fields, 1981;
Petrovic et al., 2005; Pollo, Vighetti, Rainero, & Benedetti, 2003; Shetty,
Friedman, Kieburtz, Marshall, & Oakes, 1999; Walsh, Seidman, Sysko, &
Gould, 2002)—the symbolic effect of randomized placebo-controlled trials
is that placebos are seen either as an adversary that competes with the drug
of interest or as an irrelevant variable to be discounted.
However, a handful of researchers have explored the placebo effect in its
own right. Inspired to understand the strength of and mechanisms behind
Mindsets Matter 139
Fig. 1 The drug effect and the placebo effect contribute to the total effect of treatment.
These components drive the total improvement a patient experiences from a medical
treatment.
Mindsets Matter 141
(an immune suppressant) paired with a flavored syrup later displayed drug-
consistent immune responses to the flavored syrup alone (Giang et al., 1996).
How does the nonconscious formation of associative links between
healing symbols and treatment outcomes evoke quantifiable biological
changes in the patient? Implicit learning recruits disease-related processes
in the body to change objective biological markers. This has been demon-
strated in studies of conditioned immune and allergic responses in both
humans and animals. For example, conditioning rats with cyclosporine A,
an immunosuppressive drug, resulted in sympathetic nervous system-mediated
immune suppression even when the drug was absent (Exton et al., 2002). In
humans, pairing the same immunosuppressant drug, cyclosporine A, with a
flavored beverage reduced lymphocyte cell count, cytokine release, and
expression of mRNA when the flavored beverage was later given on its
own (Goebel et al., 2002). Side effects of active treatments also appear to
be conditioned alongside the intended treatment effects. In a study by
Benedetti and colleagues, subjects were given a powerful opioid analgesic
medication that was subsequently replaced with a placebo treatment as part
of a conditioning paradigm. Subjects not only experienced the main effects
of the opioid when given the placebo, but they also exhibited respiratory
depression, a common side effect of opioids (Benedetti, Amanzio, Baldi,
Casadio, & Maggi, 1999).
In the practice of medicine, some benefit is derived from years of asso-
ciating positive outcomes with white coats, pills, and exam rooms. While
this may paint a picture of a patient mindlessly linking stimuli and response
(Wickramasekera, 1980), implicit learning processes often induce positive
responses by reinforcing patient expectations (Rescorla, 1988), as most con-
ditioning paradigms in humans inherently manipulate expectations to some
degree (Benedetti, Pollo, et al., 2003; Montgomery & Kirsch, 1997).
Indeed, implicit learning is not required for placebo effects. Thus, while
implicit learning may work directly, it may also operate by influencing
our conscious expectations.
3.2 Expectancy
Expectations are beliefs about the nature and likelihood of future states. The
expectation of a specific outcome can elicit cognitive, emotional, and
behavioral changes that increase the likelihood of that event occurring
(Kirsch, 1985; Montgomery & Kirsch, 1997). Expectations have been
shown to be one mechanism driving many instances of the placebo effect.
Mindsets Matter 145
3.3 Mindsets
Mindsets are lenses or frames of mind that orient individuals to particular
sets of associations and expectations (Crum, Salovey, & Achor, 2013).
Mindsets help individuals make sense of complex information by offering
them simple schematics about themselves and objects in their world. For
patients, mindsets provide a scaffolding for understanding the broad
nature of illnesses and treatments. While expectations and mindsets are
intimately connected, they are not the same thing. Expectations are spe-
cific beliefs about future events. Mindsets are a more general psychological
construal that orient an individual to a number of mindset-consistent
expectations. For example, the mindset that “cancer is a catastrophe”
may be associated with a number of different expectations such as “the
treatment will be painful and keep me from the things I enjoy” or “I will
not be able to cope with this” that are beyond the more specific expec-
tations of believing a treatment will or will not work. Thus, understanding
broader mindsets is also important for understanding the impact of ill-
nesses and treatments.
Mindsets guide patients’ attentional and motivational processes and affect
both subjective and objective measures of health and well-being (Crum &
Zuckerman, 2007). This has been documented in studies of stress, diet, and
exercise, in which mindsets were found to affect both psychological states
and markers of physical health, including blood pressure, weight loss, cor-
tisol response, and hormone secretion (Crum, Corbin, Brownell, & Salovey,
2011; Crum & Langer, 2007; Crum et al., 2013). Research is beginning to
shed light on mindsets about health and disease and their subsequent impact
on patients, providers, and the health care system (Crum et al., 2017).
Mindsets Matter 147
The interactions that occur in the clinical context and the experience a
patient has with his or her illness and treatment then shape existing mindsets,
reinforcing or altering them. For example, a patient who has the mindset
that their body is capable may preferentially attend to signals that their body
is handling an illness well (Zion, Dweck, & Crum, 2018). They may expect
their body to be able to manage an illness and the side effects of treatment.
Critically, these expectations can often be self-fulfilling and an understand-
ing and compassionate physician can help reinforce these adaptive mindsets
(Howe, Goyer, & Crum, 2017).
Fig. 2 The relationship between the components of the placebo effect. Social and con-
textual factors inform psychological processes, which in turn activate biological
mechanisms.
Mindsets Matter 149
It is not just the way treatments are described that can influence patients’
mindsets. When doctors intentionally or inadvertently assign meaning to
conditions or symptoms, it can shape how the patient experiences them.
Cancer pain, for example, is often perceived as more unpleasant than post-
operative pain. While cancer pain carries with it associations of sickness and
death, postsurgical pain is often associated with a recovery processes (Ferrell,
Dean, Grant, & Coluzzi, 1995; Smith, Gracely, & Safer, 1998). By assigning
positive or negative meaning to pain, medical providers are activating
preexisting mindsets. This can influence pain tolerance and modulate
endogenous opioid and cannabinoid systems in the brain (Zubieta &
Stohler, 2009).
Although there is never one correct way to communicate with a patient
or an ideal model of the patient–provider relationship, certain characteristics
appear to be universally important. Indeed, decades of social psychological
research suggest that two qualities are of paramount importance: warmth
and competence. When a patient meets a physician, he or she rapidly assesses
the benevolence of the physician’s intentions (warmth) and their ability to
carry out these intentions (competence) (Fiske, Cuddy, & Glick, 2007).
Warmth denotes a physician’s understanding of the patient as a whole
person, with a life, values, and goals outside of the health care context, while
competence denotes a physician’s understanding of medicine (i.e., the dis-
ease, prognosis, and treatment). Patient assessments of physician warmth and
competence shape patient expectations about treatment, impact mindsets
about illness, and modulate the magnitude of the placebo effect. In a recent
study, an allergic reaction was induced in participants via a histamine skin
prick. A placebo cream was administered with either positive (i.e., this
cream will reduce your symptoms) or negative (i.e., this cream will exacer-
bate your symptoms) expectations under different conditions of provider
warmth and competence. Expectations had a larger impact on the efficacy
of the placebo cream when it was administered by a warm and competent
provider and negated the effects when administered by a cold and incom-
petent provider (Howe et al., 2017). The social context in which the treat-
ment was administered—seen here as the interaction with a provider who
varied in warmth and competence—moderated the impact of patients’
expectations on their allergic response.
The strength and quality of the patient–provider relationship is further
shaped by empathy and trust. Physicians signal their warmth through their
empathy, or ability to understand a patient’s unique situation. Empathy is
expressed explicitly through verbal information and implicitly through
152 Sean R. Zion and Alia J. Crum
nonverbal cues like head and body position (Harrigan & Rosenthal, 1983).
Displays of warmth and competence not only foster trusting patient–
provider relationships, but they also help patients engage in adaptive psycho-
logical processes. For instance, physician empathy is significantly associated
with reductions in patient anxiety and distress in addition to better clinical
outcomes (Derksen, Bensing, & Lagro-Janssen, 2013). In a large retrospec-
tive study of over 20,000 diabetic patients, the patients of more empathetic
physicians had significantly fewer metabolic complications (Del Canale
et al., 2012). Practitioner characteristics such as empathy also affect biolog-
ical markers of disease. In another study, patients who sought care for
symptoms of the common cold were randomly assigned to either a standard
interaction with a physician or an enhanced, empathetic interaction. Patients
in the enhanced condition rated their physicians as more empathetic,
reported lower severity of cold symptoms, and had a greater change in
interleukin-8 (IL-8) and neutrophil counts 48 h after the interaction
(Rakel et al., 2011).
(de Craen, Roos, Leonard de Vries, & Kleijnen, 1996). Shape and form also
play a role according to a study in which patients perceived capsules to be
stronger and more effective than tablets (Buckalew & Coffield, 1982).
Cost may serve as a mediator between the social valuation of an object
and the impact that object has on the individual. Numerous studies have
found that beliefs about the characteristics of consumer goods—unrelated
to their objective characteristics—shape how they are perceived (Lee,
Frederick, & Ariely, 2006). Knowing the price of a bottle of wine, for
instance, influences how pleasant that wine is perceived to be and affects
blood oxygen levels in the medial orbitofrontal cortex, a region of the brain
that is involved in expectation and reward (Kringelbach, 2005; Plassmann
et al., 2008). Price has also been found to moderate the efficacy of treatments
in clinical populations. In a double-blind study, patients with Parkinson’s
disease were randomized to receive an injection of saline that was described
as either an inexpensive or an expensive “novel injectable dopamine
agonist” (Espay et al., 2015). Patients responded to both placebo treatments,
but those who received the expensive placebo exhibited greater benefit.
If given an expensive treatment first, patients exhibited a twofold increase
in motor function over the cheaper placebo. These changes in motor func-
tion were associated with corresponding changes in activation of the left
putamen, a major target for dopaminergic projections that govern motor
activation in Parkinson’s disease.
Similar effects have been found in patients’ strong preferences for brand
name rather than generic drugs. Although generic drugs and their brand
name counterparts contain the same type and dose of medication, patients
perceive generic drugs to be less effective and experience more side effects
when taking them. Generic drugs are also viewed as less trustworthy, less
powerful, and many patients do not feel they are appropriate for serious
medical conditions (Figueiras et al., 2010; Himmel et al., 2005). In a related
study, university students were given placebos and told they would be
taking a new beta-blocker (an antihypertensive medication) to reduce per-
formance anxiety. Subjects were randomized to remain taking the original
“medication” or to switch to either a different brand or a generic condition.
Those who remained on the same placebo treatment exhibited a greater
reduction in blood pressure and anxiety compared to those who changed
treatments. The switch to a generic beta-blocker yielded the lowest efficacy
and the greatest number of adverse events (Faasse, Cundy, Gamble, &
Petrie, 2013).
Mindsets Matter 155
5. DISCUSSION
In this chapter, we have argued that the power of the placebo effect is
not separate from but a critical component of medical treatment. In other
words, the total effect of any treatment is the combined effect of the phar-
maceutical agent and the psychosocial components that make up the placebo
effect. These components include the psychological processes and social/
contextual factors that drive neurobiological changes and influence subjec-
tive and objective treatment outcomes. They can powerfully shape the
impact of an active treatment and should not be discounted in the practice
of medicine where they can be harnessed to improve patient care.
The power of the placebo to boost active treatments is not novel to many
clinicians who witness its effects in their own patients on a daily basis.
However, for decades, the notion of the placebo effect was synonymous
with deceiving patients by prescribing an inert treatment, a practice that
is at odds with the core principles of the profession. So how can the placebo
effect be ethically harnessed in the practice of medicine? First, we encourage
a wider dissemination of knowledge about the nature of the placebo effect as
a psychological process with disease-specific neurobiological effects that are
shaped by the social environment and treatment context. This process then
can be harnessed to improve patient care and treatment outcomes in a
relatively simple and cost-efficient way.
Second, we suggest being aware of each patient’s individual psycholog-
ical characteristics and tendencies, with a specific focus on their mindsets and
expectations. How does each patient think about themselves and the world?
Recognizing patients who may hold maladaptive mindsets and observing
how these mindsets shape their expectations and subsequent health, disease,
and treatment is one way to harness the power of the placebo effect in the
clinical encounter. Taking an active role in understanding how and why
patients have the mindsets they have about health and healing could allow
physicians to nondeceptively leverage the same forces that underlie placebo
effects in the clinical encounter.
Finally, we encourage physicians to recognize that how they interact
with their patients shapes the social environment and treatment context,
which in turn influences patient health outcomes. Does the patient trust
that the provider has his or her best intentions in mind? Does the patient
feel like he or she is understood as a whole person, not just as a body with
156 Sean R. Zion and Alia J. Crum
ACKNOWLEDGMENTS
We wish to acknowledge and thank the Stanford Mind & Body Lab, Kari Leibowitz, and
Isaac Handley-Miner for their feedback and comments on the manuscript.
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160 Sean R. Zion and Alia J. Crum
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