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Rebranding placebos

This story was originally published by Knowable Magazine.

In early April, several hundred scientists converged in the
Netherlands for the first-ever meeting of the Society for
Interdisciplinary Placebo Studies. The topic drew psychologists,
psychiatrists, physiologists, ethicists and neuroscientists, all
enthusiastic about focusing a wider lens on a booming area of
study: investigation of how beliefs, expectations and motivations
can shape health. The well-documented, if often incidental, effects
of placebos — drugs with no active ingredients, or other shams
concocted to better measure another therapy’s effect — have
triggered that boom.

But even before the conference date had been set, something was
bothering some prospective attendees, an annoyance that had gnawed
at a few of them for years. It was the word placebo
itself. And though it seems like a small issue — a word choice, a
semantic nuisance — it struck scholars like clinical psychologist
John Kelley of Harvard that the name was having an outsize effect
on doctors’ ability to harness the power of placebos for good.

For starters, the name defies logic. “‘The placebo effect’ in
and of itself is an oxymoron,” Kelley says. “The placebo effect is
the effect of something that has no effect. That can’t be
true.”

“‘The placebo effect’ in and of itself is an oxymoron.”

John Kelley

Even if it were true, the name comes with baggage. Studies have
found that placebos can dampen pain, relieve anxiety and help
headaches. Yet despite its growing resumé, placebo effect
still carries a strong whiff of woo. That name implies a fake, a
sham, an intention to deceive, says neuroscientist Vitaly Napadow
of Massachusetts General Hospital and Harvard Medical School. “The
word placebo has a really bad connotation that’s holding
it back in a way from actually being something we use.”

That bad rap came up again in a musty room tucked away in Leiden
during a small gathering the day before the official placebo
meeting began. Napadow, Kelley and about two dozen other scholars
convened to talk about how placebos might transform clinical
practice. But almost immediately, the conversation turned to
vocabulary as the scientists debated the advantages and
practicalities of a rebranding campaign for the poor, shamefaced
placebo.

Their objection goes beyond PR. The real problem, they argue, is
that the term placebo effect is incorrect. Sugar
pills, pretend surgeries and fake acupuncture needles are supposed
to be inert, existing only so that something else (the “real
medicine”) can shine. For people studying placebos seriously, that
narrow, dismissive way of thinking is limiting. Placebos
fails to capture the deeper essence of how beliefs actually can and
do transform the body.

But if the old term no longer makes
sense, what then to call it?

“Language is a real problem here,” Kelley says. But if the old
term no longer makes sense, what then to call it? Alternatives —
“meaning response,” “expectancy response,” “non-specific effect,”
and “context effect” — come with their own squishiness. Kelley,
ticking through the list of proposed substitutions, admits there’s
still no lexical savior.

The meeting ended with no new name, only an acknowledgment that
the name, and the concept, of placebos remains a substantial
roadblock to incorporating them into everyday medical practice.

Still, research marches on. Today’s growing evidence of placebo
power is built on more sophisticated explanations of just how
beliefs can change the body, as revealed in a bevy of
neuroscientific studies. Scientists are figuring out when thoughts
and expectations can change outcomes, and when they can’t. More
interestingly, these effects aren’t always due to simple learned
associations — take a sugar pill, feel better. Instead, the placebo
effect appears to hook into a much more active and broad-based
neural process, one in which the brain builds its own expectations
from a wide range of clues. And that active construction of reality
may simply be how our brains work in all situations, making guesses
about what will happen next based on past experience and present
cues.

Placebo effectiveness graphic

Researchers looking at how the brain builds the expectations
that fuel the placebo response have recently identified one brain
region — the ventromedial prefrontal cortex — as particularly
important, serving as a neural hub for transforming beliefs into
body responses. This brain network helps place a person in context
relative to the outer world, a situational awareness that then
leads to predictions about, among other things, whether a
treatment, sham or real, might work. Other neural networks are no
doubt involved, too, depending on the situation. The search for a
better name may signal a field coming of age, helping scientists
define the mysterious process by what it is and what it isn’t.

This, not that

One scenario where the term placebo effect fails is in
talking about active drugs. Morphine behaves very differently based
on whether people know they’re getting it or not. A powerful opiate
falters when people don’t know they’ve taken it. That’s not a
placebo effect, because there is no placebo. Still, it feels like
it should be one, since it’s based on the user’s expectations,
Kelley says. “It seems to me that it is exactly the same thing.”
Similarly, people can experience negative side effects from a
placebo, if that’s what they are expecting. This phenomenon is
called the nocebo effect (more problematic
vocabulary).

Another example comes from studies in psychologist Alia Crum’s
lab at Stanford. She and her colleagues gave two groups of people
shakes to drink. One group was told the shakes were healthful; the
other was told the shakes were an indulgent treat. The shakes were
identical, but the people’s bodies responded very differently. The
hunger-stimulating hormone ghrelin, produced in the gut, was three
times lower in the people who had the “indulgent” shake, as if they
knew they should feel sated, Crum and colleagues reported in 2011.
In that study, “there’s no doctor, there’s no patient, there’s no
placebo,” Kelley says. “Is this the same phenomenon? Not exactly,
but to me, it’s very similar.”

“The clinical picture that’s emerging is that in many disorders
the placebo response is quite strong.”

Tor Wager

What these studies have in common is that they deal with
psychological adjustments, tweaks to people’s perspectives, beliefs
and expectations. As with some types of psychotherapy, people may
reframe their beliefs to make space to believe something will help
or not (or even hurt them). And these beliefs can have profound
influences on the body.

Pain and such disorders such as depression, anxiety and
Parkinson’s disease seem especially amenable to psychological
manipulations delivered as medicine, research suggests. In a study
of people with Parkinson’s, brain surgery to implant a virus that
enhances dopamine production produced improvements in symptoms for
two years. Those gains should have been exciting, but the trial,
reported in 2015 in Annals of Neurology, failed. That’s
because the same two-year improvements were experienced by the
people who underwent sham surgery — a very potent placebo, it turns
out.

Parkinsons therapy trials graphic

Medically meaningful placebo effects have turned up elsewhere.
“The clinical picture that’s emerging is that in many disorders the
placebo response is quite strong,” says cognitive neuroscientist
Tor Wager of the University of Colorado Boulder. And that response
is shaped by a variety of psychological forces.

Pavlov’s placebo

One of these psychological ingredients may be simple
conditioning, a study from Napadow’s lab makes clear. After
regularly coming into the lab to receive a small injection of an
allergen in their skin, participants learned that the skin prick
made them itch. But after a while, the researchers switched the
allergen for salt water. “They were led to believe that this is the
same allergen they’d been feeling all along,” Napadow says.

And lo, they believed it. Participants
rated the sensation as itchy
, and their brains showed
itch-related activity similar to the traditionally acquired itch,
Napadow and colleagues reported in Allergy in 2015. “You
imagine the itch and you are in fact itching,” he says. “Your
perception becomes your reality.”

placebos itch figure

That type of linking of two events may help explain much of the
placebo effects that have been observed in creatures with very
little psychological baggage: animals and infants, who, it’s been
shown, can learn to expect certain outcomes after taking a drug or
undergoing a procedure. While this type of Pavlovian learning is
certainly part of the placebo spectrum, such conditioning “doesn’t
explain the whole story,” says Katja Wiech, a pain researcher at
the University of Oxford. That’s true particularly when it comes to
pain.

People are very good at remembering something that hurts. After
a back injury, a person knows exactly which movements to avoid. But
“forgetting pain is so much harder,” Wiech says. At the placebo
conference in the Netherlands, she presented data that suggest it
takes about three times as much evidence for people to learn that
the pain is gone.

“It’s not about the experience. It’s about the sense you make
out of your experience.”

Katja Wiech

If perception were as simple as receiving input from the senses,
that difference in learning and unlearning pain might not exist.
People would be keen observers of the sensory cues coming in and
adjust their experiences to fit with them. But incoming sensory
information — a throbbing toe, for instance — is not the only
signal that matters. “Over time, we’ve learned that there’s not a
direct proportional relationship between tissue damage and the
pain,” Wiech says. People can learn to feel pain when they expect
it, whether it’s there or not.

The pain signals that zing from the toe to the brain are but one
piece of evidence the brain uses to build its narrative. Some
information is more powerful than others, and we weigh it
accordingly. “It’s not about the experience,” Wiech says. “It’s
about the sense you make out of your experience.”

Mapping placebos through the brain

No matter what they are called, some placebo effects take hold
of a compelling piece of neural real estate, Wager and colleagues
argue: the ventromedial prefrontal-cortex, or vmPFC. This cortical
patch lies near the very front of the brain, behind the eyes. From
its perch, the vmPFC forms neural connections that enable it to
both help form beliefs and execute their orders. Drawing on
memories, sensory cues and emotional input, the vmPFC evaluates
relationships between things and creates an idea of the self,
positioning a person in the context of her world.

Because of its far-flung connections to the spinal cord, skin,
heart and immune system, the vmPFC and its vast neural networks may
also orchestrate the body’s responses to these beliefs. Scientists
are drawing increasingly detailed maps of the roads that lead from
beliefs in the brain to changes in the body, progress detailed by
Wager and his colleagues in 2017 in the Annual Review of
Neuroscience
.

Placebo effect on brain

PLACEBO HOTSPOTS Over the last decade, scientists have been
tracking placebo effects to specific locales in the brain. Although
many different areas appear important in mediating certain effects
(including the hypothalamus, the amygdala and the periaqueductal
gray), the ventromedial prefrontal cortex (vmPFC) has garnered
recent scientific interest.

CREDIT: TEXTBOOK EXAMPLE (CC BY-ND)

Take pain, for example. Scientists have traced a pathway that
converts neural activity into perception of a throbbing toe, for
instance, and the vmPFC seems to be a key node. Neurons in the
vmPFC send signals directly to a part of the spinal cord called the
periaqueductal gray, a hotbed of pain-detecting and
pain-alleviating neurons. Other signals arrive here from the
amygdala, a structure involved in emotions; the nucleus accumbens,
linked with motivation and addiction; and the hypothalamus, a brain
structure with basic bodily jobs of regulating temperature, hunger
and sleep. These brain structures are all in deep communication
with the vmPFC.

This admixture of signals, which can dial pain up or down, gets
shuffled through several more middlemen before creating the
sensation of back pain, for instance. Neuroimaging studies suggest
that placebos can tweak signals all up and down this pathway. One
of the strongest responders to placebos is the vmPFC, Wager and
others have found.

Those rose-colored assessments mean
that a person might selectively see what she already believes. A
self-fulfilled prophecy is built.

A similar pathway exists for a parallel but distinct part of the
nervous system called the autonomic nervous system. This network
can soothe the body or turn it into a sweaty, heart-thumping lump
of panic. Recent work on Cebus monkeys revealed synaptic fibers
that run from a part of the pre-frontal cortex near the vmPFC and
other cortical areas to a part of the adrenal gland, which can
flood the body with adrenaline. The immune system is within the
vmPFC’s reach, too. Activity in the region is thought to spur the
body to produce inflammatory cytokines and other immune system
signals.

three placebo pathways figure

Placebos’ influences on these pathways remain to be worked out,
but Wager and others suspect that the vmPFC may turn out to be a
key regulator. What’s more, this brain area and its many
collaborators may be involved in triggering a positive experience
that lasts, Wager believes. His talk at the placebo meeting was
about why some placebo effects seem to linger far beyond the time
they’d be expected to fade.

Wager’s idea, and one that recent work from his lab backs up, is
that placebo effects kick off feedback loops of goodness. “Once you
have a positive expectation, you’re biased toward looking for and
learning from things that match those expectations,” he says. “You
value the good stuff and discount the bad stuff.” Those
rose-colored assessments mean that a person might selectively see
what she already believes. A self-fulfilled prophecy is built.

Better living through placebos

But despite the positive results, placebos as treatments haven’t
overcome their stigma to reach doctors’ offices yet. “We have some
pretty good success” with disorders like depression, anxiety and
migraines, Kelley says. “But I don’t think anyone is prescribing
them. It just feels wrong.”

“Yes, kind of weird, but in a
somewhat mysterious way, empowering,” a top reviewer writes [of
“honest” placebos on Amazon].

People could seek out a placebo prescription. It turns out
that’s not necessary, since commercial, over-the-counter “honest”
placebos exist. You can Amazon Prime yourself 45 Zeebo brand pills
for $24.90. That may seem like a lot to pay for gelatin capsules
clearly labeled as containing “no active ingredient,” but there’s
evidence that more expensive placebos work better than cheap ones.
“Yes, kind of weird, but in a somewhat mysterious way, empowering,”
a top reviewer writes.

More palatable to physicians may be ideas such as, with the
patient’s agreement, slowly tapering a patient’s dosage of an
opioid painkiller or other drug. That way, a patient might get pain
relief without the risk of side effects or addiction.

Still, as the more expansive concepts of mindset and beliefs
imply, patients’ outlooks can be tweaked without pills, creams or
sham surgery. Doctors can take time to sit down, talk through the
rationale of why a certain treatment might work, smile. Some people
believe that those actions, called the “common factors” in the
therapy world, are responsible for much of the improvements that
come with psychotherapy. (The controversial “Dodo Bird Verdict,”
proposed in the 1930s by psychologist Saul Rosenzweig, posits that
most forms of psychotherapy are equally effective, thanks to these
common factors. As the dodo said to Alice and her companions in
Wonderland after a circular race with no start and no stop,
Everybody has won, and all must have prizes.”)

Napadow and colleagues are searching for the neurobiological
markers of what scientists call the “therapeutic alliance” by
measuring brain activity concurrently in doctors and patients. By
creating positive expectations, good rapport might lead to better
outcomes, the researchers suspect.

But even the low-tech approach of smiling and seeming to care
has not yet made it into the clinic in a rigorous way. “The science
of motivation, expectation and decision-making hasn’t percolated
into medical practice,” Wager says. “And that would be such an
exciting thing to see happen. The science we’re doing is preparing
the way for that.”

“I feel pretty good that there are
some people doing placebo research who just really want to know the
answers,” no matter how the results turn out, Wager says. “And we
need that. Desperately.”

Of course, placebos — or more general psychological adjustments
— won’t work for everything, or perhaps even most things. You can’t
think your way out of a brain tumor, Napadow says. “There are
obviously going to be limits to how much our brains can control the
diseases that are ravaging our bodies,” he says.

One telling example of placebos’ shortcomings appeared in the
New England Journal of Medicine in 2011. People with
asthma came into a lab at Harvard and were treated with an
albuterol inhaler, a placebo inhaler or sham acupuncture.
Afterward, the patients reported similar levels of improvement for
all three treatments, but their airways felt the difference: Only
after getting the active drug could people objectively blow more
air out of their lungs. People taking placebos felt better, but
they still couldn’t breathe.

Placebos and asthma

That study illustrates some newfound rigor for the field of
placebo research, which has been plagued by a pro-placebo bent in
some cases, Wager says. “I feel pretty good that there are some
people doing placebo research who just really want to know the
answers,” no matter how the results turn out, he says. “And we need
that. Desperately.”

For now, the questions still outweigh the answers, a point made
by a study Wager and colleagues are conducting now. The researchers
combined data from most of the existing brain imaging studies on
pain and placebos, about 20 studies in all. Overall, placebos’
effect on the pain network in the brain — the one that supposedly
jumps into action when something hurts — seems surprisingly small.
“For me, that opens up the door to say, ‘OK, it might be pretty
rare for placebo manipulation or treatment to have a deep impact on
the things that cause pain,’” Wager says. That said, other brain
circuits, such as those that handle motivation and value, might
have the power to override this pain signal in the brain to make
people feel better, he says.

Untangling the various ingredients that shape our mindsets may
well alter clinical practice one day. “There are principles to how
we come to those beliefs and how we change them,” Wager says. And
now, those principles are beginning to take shape, emerging from
their shady history and asking for proper names.

This story was originally published by Knowable Magazine. Knowable Magazine is an independent journalistic endeavor from Annual Reviews.

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