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For years, Ted Kaptchuk performed
acupuncture at a tiny clinic in Cambridge,
a few miles from his current
office, at the Harvard Medical School.
He opened for business in 1976, on a
street so packed with alternative healers
that it was commonly referred to as
“quack row.” Kaptchuk had just returned
from Asia, where, as an exiled alumnus
of the turbulent sixties, he had spent four
years honing his craft. “There were lots
of alternatives on that street in those
days, but no practitioners of Chinese
medicine,” Kaptchuk, who is sixty-four
and still lives in the neighborhood, told
me recently as we sipped (Chinese) tea
in the study of his house. “The area is a
little too L. L. Bean for my taste now,”
ANNALS OF SCIENCE
THE POWER OF NOTHING
Could studying the placebo effect change the way we think about medicine?
BY MICHAEL SPECTER
he said. “It was a different place then.”
Not long after Kaptchuk arrived in
Boston, he treated an Armenian woman
for chronic bronchitis. A few weeks later,
she showed up in his office with her husband,
who had a Persian rug slung over
his shoulder. He nodded to Kaptchuk and
said, “This is for you.” Kaptchuk accepted
the rug, which he still owns, but had no
idea what he had done to earn it. “Oh,
doctor, you have been so wonderful,” the
woman told him. “You cured me. I was
about to have an operation on my ovaries
and the pain went away the day you saw
me.” Kaptchuk never spoke to the woman
again, but he has been unable to get her
out of his mind. “There was no fucking
way needles or herbs did anything for that
Scientists are now seriously investigating—and debating—our response to sugar pills.
woman’s ovaries,” he told me, still looking
mystified, thirty-five years later. “It had to
be some kind of placebo, but I had never
given the idea of a placebo effect much attention.
I had great respect for shamans—
and I still do. I have always believed there
is an important component of medicine
that involves suggestion, ritual, and belief—all
ideas that make scientists scream.
Still, I asked myself, Could I have cured
her? How? I mean, what could possibly
have been the mechanism?”
At the time, few serious scientists
would have entertained such questions,
let alone allowed words like “ritual” and
“belief ” to seep into a conversation about
medicine. Placebos had a bad name,
which is not surprising, since they have
been used primarily to deceive people. In
clinical trials, if a drug and a sugar pill
produce similar results, the drug has generally
been considered worthless. But the
definition of medical treatment is changing,
and so are attitudes about placebos.
This year, Harvard created an institute
dedicated wholly to their study, the Program
in Placebo Studies and the Therapeutic
Encounter. It is based at the Beth
Israel Deaconess Medical Center and
Kaptchuk was named its director. He
has already recruited leading researchers
from around the world, in disciplines as
diverse as neuroanatomy and semiotics.
The program was formed to explore an
idea that even twenty years ago would
have seemed preposterous: that placebos—given
deliberately—might be deployed
in clinical practice. As medicine.
Kaptchuk has no shortage of critics.
They acknowledge the power of the
mind to influence health but question
the rigor of studies suggesting that placebos
could possibly prove as valuable as
drugs. Indeed, the idea of dispensing
sugar pills is jarring even to those who,
like Kaptchuk, are enthusiastic about it.
After all, placebos have almost always
been defined as exactly what medicine
is not. “I realized long ago that at least
some people respond even to the suggestion
of treatment,” Kaptchuk said.
“We know that. We have for centuries.
But unless we figured out how that process
worked, and unless we did it with
data that other researchers would consider
valid, nobody would pay attention
to a word we said.”
The research has been propelled in
large measure by the emerging discipline
ANDERS WENNGREN
30 THE NEW YORKER, DECEMBER 12, 2011
of neuroimaging—which, like a live satellite
feed from inside the human body,
permits scientists to track precisely how
a person reacts to a drug (or a placebo) as
soon as he takes it. An injection of saline,
for example, that has been described as a
drug not only will reduce symptoms of
Parkinson’s disease but can help a patient
produce more of the dopamine that
the disease destroys. Results like those
have provided scientists with chemical
evidence of something they had long
suspected: simply believing in a treatment
can be as effective as the treatment
itself. In several recent studies, placebos
have performed as well as drugs that
Americans spend millions of dollars on
each year.
Transforming interesting laboratory
findings into medicine is never simple,
however, particularly when those findings
involve fake pills and sham injections.
Some people clearly respond
better to placebos than others, though
we don’t know why; some illnesses and
afflictions are more amenable to suggestion
than others; and many of the most
intriguing findings are tenuous. Even so,
the recent research is difficult to dismiss.
Through conditioning techniques, for
example, our brain can “learn” different
kinds of placebo effects: people first given
morphine and then a placebo have one
neurochemical response, while people
who take ibuprofen followed by a placebo
have another. Different “doses”
cause different reactions, and studies
have demonstrated that people who
suffer from headaches and consume aspirin
regularly can associate the shape,
the color, and even the taste of a pill with
a decrease in pain. The value of treatments
like those—which have none of
the side effects of drugs—would be immense,
but placebos are not pharmaceuticals,
and no reputable researcher has
suggested that they will soon be for sale
at your local pharmacy.
Kaptchuk acknowledges that placebos
are not magic potions. “Placebos
don’t shrink tumors,” he said. “They
don’t make blind people see. If you are
paralyzed, they won’t help you walk.” He
deplores the grandiose claims of alternative
medicine and prefers to rely on data.
“Ultimately, I am not a zealot or even a
true believer,” he said. “I am sure that I do
not understand the placebo effect. I ask
questions, hopefully valuable questions,
and we will see where the research lands.”
Kaptchuk practiced acupuncture for
half his adult life. But he stopped twenty
years ago. Despite the popularity of acupuncture,
clinical studies continually fail
to demonstrate its effectiveness—a fact
that Kaptchuk doesn’t dispute. I asked
him how a person who talks about the
primacy of data and disdains what he
calls the “squishiness” of alternative medicine
could rely so heavily on a therapy
with no proven value. Kaptchuk smiled
broadly. “Because I am a damn good
healer,” he said. “That is the difficult
truth. If you needed help and you came
to me, you would get better. Thousands
of people have. Because, in the end, it
isn’t really about the needles. It’s about
the man.”
For most of human history, placebos
were a fundamental tool in any physician’s
armamentarium—sometimes the
only tool. When there was nothing else
to offer, placebos were a salve. The word
itself comes from the Latin for “I will
please.” In medieval times, hired mourners
participating in Vespers for the Dead
often chanted the ninth line of Psalm
116: “I shall please the dead in the land
of the living.” Because the mourners were
hired, their emotions were considered insincere.
People called them “placebos.”
The word has always carried mixed
connotations. Thomas Jefferson wrote
approvingly of what he called a “pious
fraud,” and noted that “one of the most
successful physicians I have ever known
has assured me that he used more bread
pills, drops of coloured water, and powders
of hickory ashes, than of all other
medicines put together.” But, as increasingly
specific knowledge about human
anatomy emerged, people began to demand
scientific answers to medical questions.
Knowledge displaced faith, and
human health improved rapidly. Antibiotics
are real; placebos are not.
The first publicly acknowledged placebo-controlled
trial—and still among
the most remarkable—took place at the
request of King Louis XVI, in 1784,
under the direction of Benjamin Franklin,
then the American Ambassador to
France. The German physician Franz
Anton Mesmer had become famous in
Vienna for a new treatment he called
“animal magnetism,” and he claimed to
have discovered a healing fluid that
THE NEW YORKER, DECEMBER 12, 2011 31
could “cure” many ailments. Mesmer
became highly sought after in Paris,
where he would routinely “mesmerize”
his followers—one of whom was Marie
Antoinette. The King wasn’t buying it,
however, and he asked a commission of
the French Academy of Sciences to
look into the claims. (The members included
Franklin, the chemist Antoine
Lavoisier, and Joseph Guillotin—who
invented the device that would eventually
separate the King’s head from his
body.) The commission replicated some
of Mesmer’s sessions, and, in one case,
asked a young boy to hug magnetized
trees that were presumed to contain the
healing powers invoked by Mesmer. He
did as directed and responded as expected:
he shook, convulsed, and
swooned. The trees, though, were not
magnetic, and Mesmer was denounced
as a fraud. Placebos and lies were intertwined
in the public mind.
It was another hundred and fifty years
before scientists began to focus on the
role that emotions can play in healing.
During the Second World War, Lieutenant
Colonel Henry Beecher—who
went on to become the first chairman of
the anesthesia department at Massachusetts
General Hospital—attempted to
assess the degree to which the severity
of a soldier’s injuries corresponded to
the amount of pain he felt. In Europe,
Beecher met with more than two hundred
soldiers, gravely wounded but still
coherent enough to talk; he asked each
man if he wanted morphine. Seventyfive
per cent declined.
Beecher was astounded. He knew
from his experience before the war that
civilians with similar injuries would have
begged for morphine, and he had seen
healthy soldiers complain loudly about
the pain associated with minor inconveniences,
like receiving vaccinations. He
concluded that the difference had to do
with expectations; a soldier who survived
a terrible attack often had a positive outlook
simply because he was still alive.
Beecher made a simple but powerful observation:
our expectations can have a
profound impact on how we heal.
Armed with this information, and
with his conviction that the placebo
effect could be harnessed to help relieve
suffering, Beecher returned to the United
States and continued his research. In
1955, he published an article called “The
Powerful Placebo,” in which he wrote
that “placebos have a high degree of therapeutic
effectiveness in treating subjective
responses.” The paper has been cited
more than a thousand times by other scientists,
and Beecher’s conclusion—that
the placebo effect plays a critical role
in almost any medical intervention—
influenced much of what has followed in
clinical research. His basic supposition
was correct: emotions and expectations
can affect our perception of pain.
Before Beecher’s work, new drugs
were tested in a haphazard manner; since
then, they have always been compared
with a placebo or with another drug. But
Beecher’s methodology was deeply
flawed. Although he reported that placebos
were effective more than a third of
the time, he shrugged off a phenomenon
known as “regression to the mean.” Over
time, the condition of most patients
improves, with or without treatment.
A person who enrolls in a clinical study
when he is feeling particularly bad is
likely to improve solely as a result of the
natural course of the illness, not because
he was given a placebo. (And people
often enroll in such studies when they are
sickest.) A patient who knows that he is
in a study also may expect a better therapeutic
result than one who doesn’t. If you
believe that doctors are particularly attentive,
you can get better more rapidly, even
if they aren’t. This is known as the Hawthorne
effect. (There is also a “nocebo
effect.” Expecting a placebo to do harm
or cause pain makes people sicker, not
better. When subjects in one notable
study were told that headaches are a side
effect of lumbar puncture, the number of
headaches they reported after the study
was finished increased sharply.)
For years, researchers could do little
but guess at the complex biology of the
placebo response. A meaningful picture
began to emerge only in the nineteenseventies,
with the discovery of endorphins:
substances secreted in the brain
that are chemically similar to opiates like
morphine and heroin. The discovery led
to the novel idea that, in effect, the brain
produces its own pharmacy. In 1978,
three scientists from the University of
California at San Francisco—Jon Levine,
Newton Gordon, and Howard Fields—
decided to investigate whether endorphins
might explain why patients who
received placebos often reported a
significant reduction in pain. People recovering
from dental surgery were told
that they were about to receive a dose of
morphine, saline, or a drug that might
increase their pain. By then, researchers
had learned not only about the nocebo
effect but that a suggestion of relief will
often trigger the production of endorphins,
so they were not surprised that patients
receiving saline reported reduced
pain.
What came next, however, fundamentally
reshaped the field. The researchers
dismissed the subjects who received
morphine and then divided the
remaining participants into those who
responded to the placebo and those who
didn’t. Then they introduced Naloxone
into patients’ I.V. drips. Naloxone was
developed to counteract overdoses of
heroin and morphine. It works essentially
by latching onto, and thus locking
up, key opioid receptors in the central
nervous system. The endorphins that we
secrete attach themselves to the same receptors
in the same way, so Naloxone
blocks them, too. The researchers theorized
that, if endorphins had caused the
placebo effect, Naloxone would negate
their impact, and it did. The Naloxone
caused those who responded positively to
the placebos to experience a sharp increase
in pain; the drug had no effect on
the people who did not respond to the
placebo. The study was the first to provide
solid evidence that the chemistry behind
the placebo effect could be understood—and
altered.
“It was one of those studies that make
the scales fall from your eyes,” Kaptchuk
told me. “I had just started to think about
the placebo effect—scientifically and historically.
And here comes this paper that
says that, even if it’s all in your head, there
is still a biological mechanism driving
these reactions. It was very exciting.”
Kaptchuk assumed that the results
would add legitimacy to the field.
He was wrong. “Things are better than
they were,” he said. “But even now, you
know, people at Harvard talk about placebos
the way the Popes used to talk
about medicine. They declared that Jews
were not allowed to treat Christians—
not because they were not good doctors
but because it would have been ethically
wrong. These are ethical judgments masquerading
as science. Because from the
32 THE NEW YORKER, DECEMBER 12, 2011
beginning I kept having this nagging
thought: what is so bad about getting
better from a placebo?”
That kind of thinking, still hard for
most doctors to accept, was heretical in
1990, when Kaptchuk arrived at Harvard.
“People kept saying, ‘Oh, this is just
the placebo effect.’ You would hear that
every day,” Kaptchuk said. He had spent
years studying Chinese medicine (and
medical history), and this made no sense
to him. “I thought, Ted, step back a
minute. This wasn’t just something that
was a negative. It was something that
needed to be understood.”
Slowly, over the past decade, researchers
have begun to tease out the
strands of the placebo response. The
findings, while difficult to translate into
medicine, have been compelling. In most
cases, the larger the pill, the stronger the
placebo effect. Two pills are better than
one, and brand-name pills trump generics.
Capsules are generally more effective
than pills, and injections produce a more
pronounced effect than either. There is
even evidence to suggest that the color of
medicine influences the way one responds
to it: colored pills are more likely
to relieve pain than white pills; blue pills
help people sleep better than red pills;
and green capsules are the best bet when
it comes to anxiety medication.
Conditioning and expectations matter,
and so does learned behavior. In the
eighties, Levine and Gordon divided a
group of postoperative patients into three
sections: those in the first section received
morphine secretly, those in the
second were told they would receive
morphine (and did), and those in the
third were given a placebo that was described
as a powerful pain reliever. The
results were startling. Patients who were
told that they would receive a painkiller,
whether they actually received it or not,
had the same experience in the trial as
those who secretly received between six
and eight milligrams of morphine—a
significant amount. The covert dose had
to be increased to twelve milligrams to
surpass the effect of the placebo. Over
the past two decades, the Italian neuroscientist
Fabrizio Benedetti (who studied
with Gordon and Levine), and Luana
Colloca, a colleague of Benedetti’s, who
is now based in the United States, at
the National Institutes of Health, have
expanded on these studies. They have
found, for example, that diazepam—
more commonly known as Valium—has
no discernible effect on anxiety unless a
person knows he is taking it. And, increasingly,
studies like those have been
carried out with the help of imaging
techniques—such as PET scans and functional
M.R.I.s—that can track brain
changes as they happen. These advances
in brain imaging, along with an increased
understanding of neurochemicals, have
transformed a vague and mysterious notion
into a tangible effect that scientists
consider worthy of investigation.
“What’s exciting here is that, if we are
to talk about using placebos in a clinical
setting, they would have to have a measurable
effect and a biology we understand,”
Wayne Jonas told me. Jonas is an
interesting hybrid in a world often
sharply divided between conventional
and alternative therapies. In the early
nineties, he served as the director of the
Medical Research Fellowship Program
at the Walter Reed Army Institute of
Research, in Washington, D.C. He went
on to run the Office of Alternative Medicine
at the National Institutes of Health,
from 1995 to 1999. Today, Jonas is the
president of the Samueli Institute, a
Washington research group devoted to
shifting the focus of health care from
treatment to prevention.
“The morphine studies bring us a long
way,” he said. So did a recent investigation
by Kaptchuk, in which participants
“Bore me to sleep, Daddy.”
suffering from irritable-bowel syndrome
were not deceived about their treatment;
in fact, they were told in great detail about
the placebos they received and that they
were often as effective as real medicine.
The pills brought them relief.
For many people in the field, results