supportive care. These results were closely tied to the patients’
expectations of how well the pills would work (British Journal of
Wager says this, too, makes sense according to the
neuroscience of placebo effects, noting that depression is a
motivational disorder as much as a mood disorder. “Patients
can’t get out of bed — they can’t muster up the energy. The
disorders that show the most reliable placebo effects are those
in which the brain’s motivational circuitry, including the
prefrontal cortex and striatum, plays an important role.”
Beliefs and expectations are a potent mix, Wager says, and
future neuroimaging research must try to tease out how much
of a placebo response is due to conscious expectations versus
an unconscious learning from prior experiences. Expectations
can be influenced by verbal instructions, nonverbal cues about
care, and other elements of the treatment context, whereas
unconscious learning requires prior experiences of success (or
failure) with a treatment, such as experiencing pain relief after
taking a pill. In one study of people with migraines, placebos
elicited a response without any verbal cue to effectiveness.
Slavenka Kam-Hansen, MD, and colleagues openly labeled
placebo pills for some patients, who reported as much pain relief
as those who also got a placebo but had been told they’d received
a real medication (Science Translational Medicine, 2014).
Scientists are also exploring who might respond best to placebos.
Research suggests that children appear to be particularly
receptive to the placebo effect. Peter Krummenacher, PhD,
of the University of Basel in Switzerland, tested 6- to 9-year-
olds with a placebo or control treatment. The placebo was a
“topical analgesic” that the children were told might affect how
they sensed applied heat. Their placebo response was 5. 6 times
greater than adults in a similar study (The Journal of Pain, 2014).
“Conditioning and learning play a crucial role, especially in
infants, before we can use the power of language,” says Luana
Colloca, MD, PhD, an associate professor at the University of
Maryland, Baltimore. “Suggestibility may be higher in children,
and they also have less negative experience and experience of dis-
ease. And learning mechanisms are powerful at that stage of life.”
Studies also suggest that people who respond more to
rewarding stimuli show larger placebo effects, Atlas says. One of
the most thorough studies on placebo and personality markers,
conducted by John Kelley, PhD, and colleagues at Harvard
Medical School, found that patients with irritable bowel
syndrome (IBS) who responded best to placebo acupuncture
tended to be female, agreeable and extroverts who were open
to new experiences, but only in a subgroup of participants who
had augmented encounters with a health practitioner — warm,
communicative and empathic — when receiving the placebo
(Psychosomatic Medicine, 2009).
Since then, a meta-analysis by Kelley and colleagues of 13
studies showed that the quality of clinician-patient relationships
in terms of measures like empathy, communication and better
attention to nonverbal signals, played a small but significant role
in health outcomes for various conditions (PLOS ONE, 2014).
The findings suggest that a focus on human relationships
should always be at the forefront of treatment, Kelley says,
adding, “I’m very interested in the degree to which [physicians]
who have good outcomes are practicing an intuitive form
of psychotherapy. They’re listening to the patients, helping
the patients believe a treatment works. Although this is often
referred to as a placebo effect, it’s really a relationship effect.”
Other research suggests that social influences determine who
responds to placebos. Colloca and colleagues found that study
participants who watched others benefit from a pain medicine
that was actually a placebo had about the same response to it as
participants who were exposed to the pain relief. Participants
who responded most were also rated as more likely to empathize
with other people overall (European Journal of Pain, 2014).
A better knowledge among clinicians of how to create
placebo responses using verbal prompts and how to maximize
interactions with patients can boost treatment effectiveness,
Colloca says. “If you are aware of placebo mechanisms, you are
more careful about your communication style, the time you
spend with your patient, the words you choose.”
Columbia’s Rutherford says setting expectations may
be particularly helpful when it comes to antidepressant
medications. While there is debate about how much of their
effect for mild depression is due to the placebo response,
he advises psychologists to maximize all potential effects by
helping patients already on or interested in medication to
believe the pills will work.
“Providing supportive care and eliciting a positive
expectancy of improvement — obviously within the bounds
of truthfulness — seem to be a very powerful treatment for
mild depression,” he says. “Whether you use a benign pill or
• Atlas, L. Y., & Wager, T. D. (2014). A meta-analysis
of brain mechanisms of placebo analgesia: Consistent
findings and unanswered questions. Handbook of
Experimental Pharmacology, 225, 37–69.
• Benedetti, F., Carlino, E., & Pollo, A.
(2011). How placebos change the patient’s
brain. Neuropsychopharmacology, 36( 1), 339–354.
• Colloca, L., Klinger, R., Flor, H., & Bingel, U. (2013).
Placebo analgesia: Psychological and neurobiological
mechanisms. Pain, 154( 4), 511–514.
• Rutherford, B. R., Wall, M. M., Glass, A., & Stewart, J.
W. (2014). The role of patient expectancy in placebo and
nocebo effects in antidepressant trials. Journal of Clinical
Psychiatry, 75( 10), 1040–1046.