Why The Placebo Effect
Varies From Person To Person
Why do some people experience a "placebo effect"
that makes them feel better when they receive a sham treatment
they believe to be real -- while other people don't respond at
all to the same thing, or even feel worse?
A new study from the University of Michigan Health System may help
Using two different types of brain scans, U-M researchers have
found that the extent to which a person responds to a placebo
treatment is closely linked to how active a certain area of their
brain becomes when they're anticipating something beneficial.
Specifically, the research finds strong links between an individual's
response to a placebo "painkiller", and the activity
of the neurotransmitter known as dopamine in the area of the brain
known as the nucleus accumbens. That's a small region at the center
of the brain that's involved in our ability to experience pleasure
and reward, and even to become addicted to the "high"
caused by illicit drugs.
The new research, published in the July 19 issue of the journal
Neuron, builds on research previously published by the same U-M
team in 2005. That study was the first to show that just thinking
a placebo "medicine" will relieve pain is enough to
prompt the brain to release its own natural painkillers, called
endorphins, and that this corresponds with a reduction in how
much pain a person feels.
"Receptors for both endorphins and dopamine are clustered
heavily in the nucleus accumbens. So, taken together, our studies
delve directly into the mechanisms that underlie the placebo effect,"
says senior author and U-M neuroscientist, psychiatrist and brain-imaging
specialist Jon-Kar Zubieta, M.D., Ph.D. "This is a phenomenon
that has great importance for how new therapies are studied, because
many patients respond just as well to placebo as they do to an
active treatment. Our results also suggest that placebo response
may be part of a larger brain-resiliency mechanism."
For the current study, Zubieta and his colleagues -- led by neuroscience
graduate student David J. Scott -- combined information from two
types of brain scan to come to their conclusions. They performed
PET (positron emission tomography) scans on the brains of 14 healthy
volunteers, and fMRI (functional magnetic resonance imaging) scans
on those 14, and on 16 other healthy volunteers.
The PET scans focused on brain dopamine, looking at its activity
as volunteers were told to expect, and then received, a painful
injection of saline solution in their jaw muscle. They were then
told to expect, and then received, an injection that they were
told could either be a painkiller or a placebo. (Both were in
fact placebos.) The fMRI scans looked at volunteers' brains while
they played a game. Before each round, they learned that a correct
answer would win or lose an amount of money, up to $5.
The PET scans were made using 11C-raclopride, which combines
a drug that binds preferentially to dopamine receptors with a
short-lived radioactive form of carbon that can be "seen"
on PET scans. Throughout the PET scanning session, volunteers
were asked to rate their level of pain on a numerical scale, and
to describe any emotions they were experiencing.
Before the painful injection began, but after the volunteers
had been told it was coming, they were also asked to guess how
much pain relief they'd get from the "painkiller" if
they received it. Half the volunteers were women, all in the same
stage of their monthly cycle to avoid differences in hormonal
state that might affect tolerance of pain -- another topic that
Zubieta's team has studied.
The PET scans and pain ratings revealed that as a group, the
volunteers experienced significant pain relief from the placebo.
But when researchers looked at each individual's results, they
found that only half of the volunteers reported less pain when
they received the "painkiller" placebo.
These placebo responders, as they were dubbed, had significantly
more dopamine activity in their left nucleus accumbens than the
other volunteers, beginning when they were told the painkiller
medicine was about to begin flowing into their jaws. It also turned
out that these individuals had also all anticipated the "painkiller"
would give good pain relief before they even received it.
Meanwhile, of the seven individuals who didn't experience the
placebo effect, four actually reported feeling more pain when
the "painkiller" was delivered -- a phenomenon that
has been dubbed the "nocebo" effect and has been observed
in other situations.
Just to make sure that the volunteers' pain ratings weren't affected
by the fact that they always received painful injections followed
by placebo "painkiller", the researchers put a separate
group of 18 male volunteers through the same experience twice,
but no placebo was actually given, and actual PET scans were not
done. Their pain and emotion ratings were significantly different
from those of volunteers who received placebo.
"The results of these functional molecular imaging studies
indicate that dopamine activity is activated in response to a
placebo in a manner that's proportional to the amount of benefit
that the individual anticipates," says Zubieta, who is the
Phil F. Jenkins Professor of Depression in the U-M Medical School's
Department of Psychiatry and a member of U-M's Molecular and Behavioral
Neuroscience Institute, Depression Center and Department of Radiology.
The fMRI scans, which were performed on different days from the
PET scans, revealed additional information about how individual
expectations correlated with their placebo response. Each volunteer
had an fMRI scan that looked at blood oxygenation throughout their
brain, which allows researchers to spot areas where neurons (brain
cells) are especially active as the individual performs a task
or plays a game. In this case, the task was a very simple gambling
game, in which subjects were scanned while expecting varying levels
of a monetary reward or no reward.
As in the PET scans, the nucleus accumbens was a hotbed of activity
as the volunteers were told how much money they could win or lose
in the next round; as they waited for the round; and as they pressed
the button and learned if they had succeeded in winning or avoiding
Then, the researchers compared the PET and fMRI scans for the
volunteers who had had both types of scan. They also compared
the ratings of anticipated placebo effect, the analgesia induced
by the placebo during the pain studies, and the emotional changes
associated with it. They found that those who expected a placebo
to help them and got greater benefit from it (more analgesia,
better emotional state) were also those who had the most activity
in their nucleus accumbens during the anticipation of receiving
a reward in the fMRI money game.