(Vox) The weird power of the placebo effect, explained
Yes, the placebo effect is all in your mind. And it’s real.
Over the last several years, doctors noticed a mystifying trend: Fewer and fewer new pain drugs were getting through double-blind placebo control trials, the gold standard for testing a drug’s effectiveness.
In these trials, neither doctors nor patients know who is on the active drug and who is taking an inert pill. At the end of the trial, the two groups are compared. If those who actually took the drug report significantly greater improvement than those on placebo, then it’s worth prescribing.
When researchers started looking closely at pain-drug clinical trials, they found that an average of 27 percent of patients in 1996 reported pain reduction from a new drug compared to placebo. In 2013, it was 9 percent.
What this showed was not that the drugs were getting worse, but that “the placebo response is growing bigger over time,” but only in the US, explains Jeffrey Mogil, the McGill University pain researcher who co-discovered the trend. And it’s not just growing stronger in pain medicine. Placebos are growing in strength in antidepressants and anti-psychotic studies as well.
“The placebo effect is the most interesting phenomenon in all of science,” Mogil says. “It’s at the precise interface of biology and psychology,” and is subject to everything from the drug ads we see to our interactions with health care providers to the length of a clinical trial.
Scientists have been studying this incredibly complex interface in great detail over the past 15 years, and they’re finding that sugar pills are stranger and more useful than we’ve previously imagined. The new science of placebo is bringing new understanding to why alternative treatments — like acupuncture and reiki — help some people. And it could also potentially allow us to one day prescribe smaller doses of pain drugs to help address the opioid crisis currently ravaging America.
Most instructively, the science finds that since we can’t separate a medicine from the placebo effect, shouldn’t we use it to our advantage?
There is no one placebo response. It’s a family of overlapping psychological phenomena.
Belief is the oldest medicine known to man.
For millennia, doctors, caregivers, and healers had known that sham treatments made for happy customers. Thomas Jefferson himself marveled at the genius behind the placebo. “One of the most successful physicians I have ever known has assured me that he used more bread pills, drops of colored water, powders of hickory ashes than of all other medicines put together,” Jefferson wrote in 1807. “It was certainly a pious fraud.”
These days, placebo — Latin for “I shall please” — is much more than a pious fraud.
As Ted Kaptchuk at Harvard, who is regarded as one of the world’s leading experts on placebo, put it to me in a recent interview, the study of the placebo effect is about “finding out what is it that’s usually not paid attention to in medicine — the intangible that we often forget when we rely on good drugs and procedures. The placebo effect is a surrogate marker for everything that surrounds a pill. And that includes rituals, symbols, doctor-patient encounters.”
And it’s not just one thing. “I see the placebo effect as a kind of loose family of different phenomena that are just yoked together by this term,” says Franklin Miller, a retired NIH bioethicist who has edited a volume on the subject. “Sooner or later we’ll get rid of the term,” he says, and talk more specifically about each of its components.
The family of placebo effects ranges from the common sense to some head scratchers. Let’s start off with the simplest.
1) Regression to the mean
When people first go to a doctor or start on a clinical trial, their symptoms might be particularly bad (why else would they have sought treatment?). But in the natural course of an illness, symptoms may get better all on their own. In depression clinical studies, for instance, researchers find around one-third of patients get better without drugs or placebo. In other words, time itself is a kind of placebo that heals.
2) Confirmation bias
A patient may hope to get better when they’re in treatment, so they will change their focus. They’ll pay closer attention to signs that they’re getting better and ignore signs that they’re getting worse. (Relatedly, there’s the Hawthorne effect: We change our behavior when we know we’re being watched.)
But as we’ve seen, the placebo effect is more than just bias. There’s also:
3) Expectations and learning
The placebo response is something we learn via cause and effect. When we take an active drug, we often feel better. That’s a memory we revisit and recreate when on placebo.
Luana Colloca, a physician and researcher at University of Maryland, has conducted a number of studies on this phenomenon. And they typically go like this: She’ll often hook up a study participant to an electroshock machine. For each strong, painful shock, she’ll flash a red light on a screen the participant is looking at. For mild shocks, she’ll flash a green light. By the end of the experiment, when the participants see the green light, they feel less pain, even when the shocks are set to the highest setting.
The lesson: We get cues about how we should respond to pain — and medicine — from our environments.
Take morphine, a powerful drug that acts directly on neurochemical receptors in the brain. You can become addicted to it. But its analgesic powers grow when we know we’re taking it, and know a caring professional is giving it to us.
Studies show that post-operative patients whose painkillers are distributed by a hidden robot pump at an undisclosed time need twice as much drug to get the same pain-relieving effect as when the drug is injected by a nurse they could see. So awareness that you’re being given something that’s supposed to relieve pain seems to impact perception of it working.
The research also suggests that fake surgeries — where doctors make some incisions but don’t actually change anything — are an even stronger placebo than pills. A 2014 systematic review of surgery placebos found that the fake surgery led to improvements 75 percent of the time. In the case of surgeries to relieve pain, one meta-review found essentially no difference in outcomes between the real surgeries and the fake ones.
There is such thing as the nocebo effect: where negative expectations make people feel worse. Some researchers think this is what’s fueling the gluten-free diet fad. People have developed a negative expectation that eating gluten will make them feel bad. And so it does, even though they may not have any biological gluten sensitivity.
4) Pharmacological conditioning
This is where things get a little weird.
Colloca has conducted many studies where for several days, a patient will be on a drug to combat pain or deal with the symptoms of Parkinson’s disease. Then one day, she’ll surreptitiously switch the patient over to a placebo. And lo and behold, they still feel healing effects.
On that fifth day, it seems the placebo triggers a similar response in the brain as the real drug. “You can see brain locations associated with chronic pain and chronic psychiatric disease” acting like there are drugs in the system, she says. For instance, Colloca has found that individual neurons in the brains of patients with Parkinson’s disease will still respond to placebos as though they are actual anti-Parkinson’s drugs after such conditioning has taken place.
What’s going on here? Learning. Just like Pavlov’s dogs learned to associate the sound of a bell with food and would start to salivate in anticipation, our brains learn to associate taking a pill with relief, and start to produce the brain chemicals to kick-start that relief.
This pharmacological conditioning only works if the drug is acting on a process that the brain can do naturally. “You can condition pain relief because there are endogenous pain-relieving mechanisms,” Miller says. Painkillers activate the opioid system in the brain. Taking a pill you think is a painkiller can activate that system (to a lesser degree).
And some studies do suggest that the placebo effect’s powers may possibly move beyond the brain.
In a 2012 study, participants were given a sweet drink along with a pill that contained an immune suppressant drug for a few days. Without notice, the drug was swapped with placebo on one of the trial days. And their bodies still showed a decreased immune response. Their bodies had learned to associate the sweet drink with decreased production of interleukin, a key protein in our immune systems, which is produced in many cells outside the brain.
Results like these show “we are talking about a neurobiological phenomenon,” Colloca says.
5) Social learning
When study participants see another patient get relief from a placebo treatment (like in the electroshock experiment described above), they have a greater placebo response when they’re hooked up to the machine.
6) A human connection
Irritable bowel syndrome is an incredibly hard condition to treat. People with it live with debilitating stomach cramps, and there are few effective treatments. And doctors aren’t sure of the underlying biological cause.
It’s the type of ailment that’s sometimes derided as “all in their head,” or a diagnosis given when all others fail. In the early 2000s, Harvard’s Ted Kaptchuk and colleagues conducted an experiment to see if usually intangible traits like warmth and empathy help make patients feel better.
In the experiment, 260 participants were split into three groups. One group received sham acupuncture from a practitioner who took extra time asking the patient about their life and struggles. He or she took pains to say things like, “I can understand how difficult IBS must be for you.” A second group got sham acupuncture from a practitioner who did minimal talking. A third group was just put on a waiting list for treatment.
The warm, friendly acupuncturist was able to produce better relief of symptoms. “These results indicate that such factors as warmth, empathy, duration of interaction, and the communication of positive expectation might indeed significantly affect clinical outcome,” the study concluded.
This may be the least-understood component of placebo: It’s not just about pills. It’s about the environment a pill is taken in. It’s about the person who gave it to you — and the rituals and encounters associated with them.