The Nocebo Effect: Placebo's Evil Twin
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THE NOCEBO EFFECT: PLACEBO'S EVIL TWIN
By Brian Reid
Special to The Washington Post
Tuesday, April 30, 2002
Ten years ago, researchers stumbled onto a striking finding: Women who
believed that they were prone to heart disease were nearly four times as
likely to die as women with similar risk factors who didn't hold such
The higher risk of death, in other words, had nothing to with the usual
heart disease culprits -- age, blood pressure, cholesterol, weight. Instead,
it tracked closely with belief. Think sick, be sick.
That study is a classic in the annals of research on the "nocebo"
phenomenon, the evil twin of the placebo effect. While the placebo effect
refers to health benefits produced by a treatment that should have no
effect, patients experiencing the nocebo effect experience the opposite.
They presume the worst, health-wise, and that's just what they get.
"They're convinced that something is going to go wrong, and it's a
self-fulfilling prophecy," said Arthur Barsky, a psychiatrist at Boston's
Brigham and Women's Hospital who published an article earlier this year in
the Journal of the American Medical Association beseeching his peers to pay
closer attention to the nocebo effect. "From a clinical point of view, this
is by no means peripheral or irrelevant."
Barsky's target is drug side effects, which cost the U.S. health system more
than $76 billion a year, according to a 1995 University of Arizona study. If
even a small percentage of those costs are caused by patient expectations of
harm, addressing the nocebo effect could save a nifty sum.
But convincing doctors that their patients' problems may be more than
biochemical is no simple trick. The nocebo effect is difficult to study, and
medical training leads doctors to seek a bodily cause for physical ills.
"Nocebos often cause a physical effect, but it's not a physically produced
effect," said Irving Kirsch, a psychologist at the University of Connecticut
in Storrs who studies the ways that expectations influence what people
experience. "What's the cause? In many cases it's an unanswered question."
Looking for Trouble
The word nocebo, Latin for "I will harm," doesn't represent a new idea --
just one that hasn't caught on widely among clinicians and scientists. More
than four decades after researchers coined the term, only a few medical
journal articles mention it. Outside the medical community, being "scared to
death" or "worried sick" are expressions that have long been part of the
popular lexicon, noted epidemiologist Robert Hahn from the Centers for
Disease Control and Prevention in Atlanta.
Is such language just hyperbole? Not to those who accept, for example, the
idea of voodoo death -- a hex so powerful that the victim of the curse dies
of fright. While many in the scientific community may regard voodoo with
skepticism, the idea that gut reactions may have biological consequences
can't be simply dismissed.
"Surgeons are wary of people who are convinced that they will die," said
Herbert Benson, a Harvard professor and the president Mind/Body Medical
Institute in Boston. "There are examples of studies done on people
undergoing surgery who almost want to die to re-contact a loved one. Close
to 100 percent of people under those circumstances die."
But the nocebo effect can lead to more subtle outcomes as well.
Fifteen years ago, researchers at three medical centers undertook a study of
aspirin and another blood thinner in heart patients and came up with an
unexpected result that said little about the heart and much about the brain.
At two locations, patients were warned of possible gastrointestinal
problems, one of the most common side effects of repeated use of aspirin. At
the other location, patients received no such caution.
When researchers reviewed the data, they found a striking result: Those
warned about the gastrointestinal problems were almost three times as likely
to have the side effect. Though the evidence of actual stomach damage such
as ulcers was the same for all three groups, those with the most information
about the prospect of minor problems were the most likely to experience the
Despite the smattering of doctors' anecdotal reports and a few modest
clinical studies, research on the phenomenon has not been robust, mostly for
ethical reasons: Doctors ought not to induce illness in patients who are not
Changing ethical standards have made it difficult to even repeat some of the
classic nocebo experiments. In one century-old effort, conducted long before
anyone thought up the word nocebo, doctors set an allergy sufferer wheezing
by showing an artificial rose, proving that at least some aspect of the
allergic response is stimulated by visual cues. In a study from the early
1980s, 34 college students were told an electric current would be passed
through their heads, and the researchers warned that the experience could
cause a headache. Though not a single volt of current was used, more than
two-thirds of the students reported headaches.
But resistance to in-depth study of the nocebo effect rests on more than
ethical reservations, said the CDC's Hahn. Belief, he said, does not have a
strong place in the anatomy-centered world of modern medicine.
"The fact is that phenomena that essentially come down to what people
believe are conceptually difficult in our medical system," Hahn said.
"Health is thought to be a biological phenomenon. More psychosomatic
elements are hard to deal with."
Science is wearing away at the wall between mind and body. With the aid of
high-tech imaging devices, neurologists are getting better at taking
pictures of the brain in action. In one blinded study last year, researchers
found that patients with Parkinson's disease given a placebo released a
brain chemical called dopamine, just as the brain exposed to an active drug
That flood of brain chemicals, it appears, has everything to do with what
the mind expects. In most cases, like the Parkinson's study, the outcome is
positive -- the placebo effect in action. But for some patients --
depressed, wary of medication or worried about drug side effects -- getting
a prescription filled is an angst-ridden experience. And such patients
appear even more likely to exhibit those side effects.
Barsky has even sketched out a profile of the kind of patient likely to
experience the nocebo effect -- worse side effects and poorer outcomes -- on
a given drug. When Barsky sees a patient with a history of vague,
difficult-to-diagnose complaints who is sure that whatever therapy is
prescribed will do little to battle the problem, he says, those low
expectations are inevitably met. The treatments usually fail.
"Whether you trust your doctor or not probably makes a huge difference in
whether you report side effects, but there's almost no data on that," Barsky
said. He hopes to include information about a person's psychology in an
upcoming placebo-controlled clinical trial to see if patients with a
particular outlook on life fare better or worse than other subjects.
Far more esoteric factors may also shape both the placebo and nocebo
response. A Dutch study, for example, found that most people considered red
and orange pills to be stimulating, with blue and green-colored pills more
likely to have a depressant effect.
"One of the most important things about a pill is [its] color," said Daniel
Moerman, an anthropologist at the University of Michigan-Dearborn who has
studied the placebo and nocebo effects across different cultures. "That
seems to be fairly widespread."
But the mind is a funny thing, and generic responses to color go just so far
in explaining the placebo or nocebo response. Consider this: In Italy,
Moerman says, blue placebos made excellent sleeping pills for women but had
the opposite effect on men.
The apparent reason? "The Italian national football team's color is
azzurri," he said. "Blue."
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