People with depression who benefited from a placebo
showed signature changes in the brain and also
responded better to subsequent medication.
A placebo is a substance, such as a pill or shot,
that doesn’t contain any active medicine. Scientists
typically use placebos as controls in research
studies. This helps them understand how much of a
medicine’s effects are due to the drug itself,
versus how much are due to participants’
expectations or other factors.
People who are given a placebo may report
improvements in symptoms, sometimes even when they
know they’re taking something that doesn’t contain
To better understand the neurochemical mechanisms
underlying the placebo effect, a team led by Dr.
Jon-Kar Zubieta, formerly at the University of
Michigan School of Medicine and now at the
University of Utah, examined such effects in
depression treatment. The study was funded in part
by NIH’s National Institute of Mental Health (NIMH).
Results appeared online on September 30, 2015, in
The scientists enrolled 35 people with major
depression who weren’t taking any medications.
In the first phase of the study, the participants
were randomly assigned to receive placebo pills that
were described as a potentially fast-acting
antidepressant (“active” placebo group) or identical
pills described as a placebo with no antidepressant
effects (“inactive” placebo group).
Each group took the pills for a week, and then after
a few days, the groups switched.
At the end of each week of treatment, the
participants completed a questionnaire about their
They also underwent a PET brain scan to measure the
activity of µ-opioid receptors, which are known to
be involved in emotion, stress, social rewards, and
During the scan, the active placebo group received
intravenous doses of saline with the understanding
that it might activate brain systems involved in
mood improvement. This was done to monitor the acute
effects of an active placebo on brain function.
The inactive placebo group received no infusions
during the scan.
In the second phase of the study, all participants
were treated for 10 weeks with antidepressants
(usually selective serotonin reuptake inhibitors),
and their depression symptoms were monitored.
At the end of the study, each person was fully
briefed on the study design and use of placebos.
The researchers found that the participants reported
significant decreases in depression symptoms when
they took the active placebo, compared to when they
took the inactive placebo.
These reductions were linked to increased µ-opioid
receptor brain activity in regions of the brain
associated with emotion and stress regulation.
Notably, the increased µ-opioid activity induced by
the active placebo was also associated with
significantly better responses to the subsequent
“These results suggest that some people are more
responsive to the intention to treat their
depression, and may do better if psychotherapies or
cognitive therapies that enhance the
clinician-patient relationship are incorporated into
their care as well as antidepressant medications,”
Zubieta says. “We need to find out how to enhance
the natural resiliency that some people appear to
For more information
Association Between Placebo-Activated Neural Systems
and Antidepressant Responses: Neurochemistry of
Placebo Effects in Major Depression.