A patient’s genetic makeup may
explain the “placebo effect,” in which people perceive that a
fake treatment makes them feel better, according to a study that
may help researchers design better clinical trials.
Patients with a certain variation on a gene linked to
release of dopamine, a brain chemical that affects emotions and
sensations of pleasure and pain, were more likely to respond to
a placebo version of acupuncture than patients with a different
variation, a study in the journal PLoS One found.
The findings may be useful for designing clinical trials,
understanding why a placebo effect exists or trying to control
it, researchers said. A stronger than expected response to
placebo can make even a potentially effective drug appear to
work less well, said Ted Kaptchuk, associate professor of
medicine at Harvard Medical School and an author of the study.
“A clinical trial has one purpose: to show a difference in
drug and placebo,” Kaptchuk, who is also director of the
Program in Placebo Studies & the Therapeutic Encounter at Beth
Israel Deaconess Medical Center in Boston, said in a telephone
interview. “If the placebo effect is very big, that makes
things very difficult. It’s the Holy Grail in drug development -
- how we can predict and control placebo response is critical.
This may be an opening to that question.”
The research released yesterday, funded by the National
Institutes of Health, was done in patients with irritable bowel
syndrome who enrolled in an acupuncture trial that evaluated
their self-reported change in areas like abdominal pain over
The patients were separated into three groups: one that
received no treatment, called the “wait list” group; one that
received fake acupuncture with little interaction with the
caregiver, called the “limited” group; and one that received
fake acupuncture with an enhanced interaction with the provider,
called the “augmented” group.
The “validated sham acupuncture,” as the study called it,
was done similarly to real acupuncture, except the needles were
placed over non-acupuncture points, Kaptchuk said. Patients were
able to receive real acupuncture after the three weeks of the
placebo study, he said.
A genetic analysis based on blood samples separated
patients by variations on the COMT gene, or catechol-O-
methyltransferase, known to be related to dopamine release. The
researchers focused on COMT variations because the gene had been
shown in earlier studies to have a potential association to
Patients with a variation referred to as met/met, for their
two copies of the methionine allele, were shown to be more
likely to respond to the placebo treatments, the study found.
Those with a variation called val/val, for two copies of the
valine allele, responded the least. Patients with one copy of
each fell in the middle.
The study was unique in that it included a “wait list”
arm, in which patients didn’t receive placebo or treatment. That
enabled researchers to compare the two placebo groups with a
The patients who saw the most improvement, those in the
met/met group, responded more when they received care in the
“augmented” placebo arm, reinforcing the importance of doctor-
patient interaction, the authors wrote. They didn’t respond more
than other patients in the “wait list” group, indicating
met/met “is a predictor of the placebo effect, not just
improvement in general,” the researchers wrote.
Their response is thought to be tied to the availability of
dopamine in their prefrontal cortex. Dopamine has been linked to
reward and “confirmation bias,” or the adherence to a first
impression, Kaptchuk said.
“People with met/met look for evidence to confirm their
first impression or intuition that something will work versus
people with val/val, who if the evidence switches they’ll switch
more easily,” he said. As met/met people start getting better,
“they start seeing more ways of getting better.”
If the results are replicated in future studies, they may
enable designers of clinical trials to screen patients’
genotypes and use that data to minimize placebo effects, said
Kathryn Hall, the study’s lead author and a fellow in
integrative medicine at Beth Israel Deaconess.
The implications are most applicable to studies in which
patients report their pain, fatigue, nausea, anxiety or
depression, Kaptchuk said. Outcomes such as tumor shrinkage
among patients on placebo aren’t as well understood, Hall said.
The study’s findings are likely to ignite research within
existing databases of clinical trial results that showed strong
placebo responses, Hall said.
“It’s really interesting to now think that there’s this
potentially fundamental difference between people,” Hall said
in a telephone interview. “And it involves not just the placebo
or the physical pill, but also involves this interaction that
you have with your caregiver. It’s really important to think
about the ways in which we’re similar and different, and design
or develop medicines that are going to help us all heal.”
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