Once dismissed as a curiosity, the placebo effect is now recognized as the key to the brain’s “inner pharmacy.” If only doctors knew how to open the medicine cabinet.
Sarah Lidstone has a long history with the medical world. A ballet dancer from the age of 3, she developed acute scoliosis and wore a back brace throughout much of her teens. “I spent a lot of my childhood in doctors’ offices,” she says with a wide Cheshire grin. “I loved carrying my X-rays around when I was 10.”
The brace gradually coaxed Lidstone’s body to straighten itself out, but her experience left her with an enduring fascination for medicine and a desire to ease the suffering of others. In college she gravitated to brain science, and particularly to Parkinson’s disease, a crippling condition caused by chronically low dopamine levels in the brain. Dopamine, in addition to moderating mood, controls brain regions crucial to movement. Lidstone was fascinated by the brain’s dopamine systems and by these patients, who were trapped in bodies that wouldn’t respond properly.
After starting her doctorate work in neurology in 2003 at the University of British Columbia, Lidstone led a rather odd brain-imaging experiment. She brought 40 patients with mild Parkinson’s into the lab for a simple drug therapy and explained that some would get their usual dose of Parkinson’s medication, which boosts the brain’s dopamine levels. The others, she said, would get a placebo — an inactive pill that looked just like their usual drug. Then they would lie in a high-resolution positron emission tomography (PET) scanner for a grueling 90 minutes while the machine took pictures in 2-millimeter increments of their nucleus accumbens, a region deep in the brain that (among other things) controls reward and motivation.
When Lidstone’s patients emerged from the scanner, many of them moved easily, as one would expect after a dose of their medication. One older patient with a tall, stooped frame arrived in a wheelchair. He took the pill, sat through the scan, and then walked out past the wheelchair and up a flight of stairs to the debriefing room. There, Lidstone dropped a bomb on him: There was no drug. Everyone in the trial got the same thing — a simple placebo pill.
“When I told him he actually got a placebo, he laughed at me,” Lidstone says. “He was like, ‘Are you serious? I can’t believe I was able to do this on my own without my medication.’ ”
Whether he improved “on his own” is open to interpretation. Parkinson’s patients are especially susceptible to the placebo effect — a phenomenon by which a condition improves solely because the patient believes treatment has occurred. When Lidstone’s team analyzed the patients’ brain activity, the PET images showed dopamine flooding the synapses in the crucial motor control region of their brains, just as surely as from a dose of medication. It was the first time placebo responses in Parkinson’s disease had been definitively linked to a natural burst of dopamine.
“Perhaps it was because I’ve been a patient myself, I don’t know. I think the idea of patients being able to heal themselves is very powerful,” says Lidstone, a gregarious woman who still moves with the grace of a dancer.
Some practitioners dismiss placebo effects as irrelevant. Others blame such effects on neurosis. But scientists are increasingly recognizing the placebo response as an authentic neurochemical reaction in the brain. In the past decade, imaging studies have opened up the possibility that scientists will soon understand the mysterious phenomenon and even harness it in clinical practice — unleashing the power of, well, nothing.
The new evidence has established that placebos trigger the brain’s “inner pharmacy” — in essence, a warehouse perpetually stocked to deliver active drugs to itself. In addition to improving Parkinson’s symptoms, that same inner pharmacy can affect conditions like pain, depression, irritable bowel syndrome, anxiety, schizophrenia and more. As the placebo effect emerges from a long history in the shadows, the new question is: How can we use this age-old brain trick to our advantage?
The Brain on Placebo
For as long as medicine has existed, the placebo effect has been quietly playing a role in treatment. Benjamin Franklin formally demonstrated placebos in 1784, using them to show that magnets can’t cure disease. But it wasn’t until after World War II that they became the milepost against which all drugs would be measured. The change came about after a massive scandal surrounding the drug thalidomide, which in the 1950s was widely prescribed to pregnant women to alleviate morning sickness. The drug, untested in pregnant women, caused severe birth defects in thousands of infants, and the FDA scrambled to improve drug testing. The use of placebos, though it would not have prevented the thalidomide disaster, was one such improvement. Beginning in 1962, drug trials had to include a patient group getting bogus treatment. Today, every drug must outperform a placebo before being sold in the U.S.
The numbers here are not trivial. In some conditions, such as cancer, few patients respond to placebos; in others, such as pain and depression, more than 50 percent might. But despite the placebo effect’s clear influence on health, it was long consigned to a mysterious realm somewhere between psychology and pharmacology. The placebo effect “was regarded for many, many years as just a nuisance variable, something you had to take into account to find out about something else,” says Harvard University psychologist Irving Kirsch, who has studied placebos and clinical trial design for decades. “And very few people were at all interested in understanding it.”
Interest sparked with the discovery of endorphins — morphine-like molecules, often called opioids, that the body produces during exercise and that have painkilling or euphoric effects on the brain. It wasn’t long before researchers made the connection between opioids and placebos. In 1978, rheumatologist Jon Levine and neurologist Howard Fields, both at the University of California, San Francisco, did a simple experiment with people in pain after dental surgery. Telling patients it was something to ease their pain, Levine and Fields gave patients either a placebo injection or a dose of naloxone, which blocks the brain’s ability to soak up endorphins.
The patients who got naloxone remained miserable; their brains couldn’t use endorphins to temper their pain. In contrast, many who got a placebo felt their pain subside. The study elegantly showed that for pain, placebo effects were not some neurosis but the brain medicating itself.
The paper was hailed as further proof of the need for placebo controls in drug trials. But Fabrizio Benedetti, an Italian neuroscientist, saw wider implications. In the 1990s, he further tested the relationship between opioids and the placebo effect. He was also curious whether a similar process could explain nocebo effects — a parallel phenomenon in which the brain is fooled into perceiving increased pain. He focused on the natural hormone cholecystokinin (CCK), which actually increases pain by counteracting opioids. In one experiment, Benedetti gave patients recovering from minor surgery a drug that he said would increase their pain. Really what he injected was saltwater, yet just as they’d been led to expect, they reported more pain. When Benedetti blocked the release of CCK in his patients, they felt immensely better.
Perhaps, Benedetti thought, CCK is to nocebos what opioids are to placebos: Whereas blocking opioids canceled pain relief, blocking CCK actually supercharged it by allowing opioids to run wild in the brain. It was a fascinating idea, but still mostly inference, as Benedetti and others weren’t able to truly watch either the placebo or the nocebo process unfurl. Scientists needed a tool to allow them to witness the process in action.
Then came two papers that took placebo research into the age of brain imaging. In the first, published in Science in 2002, a team led by neuroscientist Predrag Petrovic at the Karolinska Institute in Stockholm strapped painful, hot metal pads to nine subjects. They injected some subjects with a powerful opioid painkiller and others with a placebo and had them rate their pain. As expected, the placebo worked.
But Petrovic was most interested in how the placebo effect played out in the brain. Subjects completed the experiment while in a PET scanner, allowing Petrovic to track their brain activity as they experienced both pain and pain relief. As hypothesized, the brain activity of those in the placebo group resembled those that got the drug, especially in a region called the anterior cingulate cortex, or ACC. This region in the middle of the brain is important in processing emotion, anticipating rewards and registering pain. Clearly, Petrovic’s findings showed, the ACC also responds to placebos.
Then psychologist Tor Wager, at the time a graduate student at the University of Michigan, took placebo imaging one step further. Raised in Christian Science, Wager had an enduring curiosity about mind-body connections. But he got the impression that many in his field considered that kind of work too “flaky” for a promising young scientist. “When I started grad school, there was this idea that there were certain areas that people should study,” says Wager, now at the University of Colorado at Boulder. The placebo effect was not one of them. “Placebo has a long history of being a word for an effect that can’t possibly be something real, by definition.”
But Wager longed to follow up Benedetti’s work looking at a tangible link between thought and bodily experience. So he set up a side project attempting to map the placebo effect as it was happening. In one experiment, he and colleagues had 24 subjects lie in an fMRI machine, an imaging device that tracks the blood flow and oxygen use that accompany brain activity. While subjects were in the scanner, the researchers administered a series of electric shocks to their wrists, each time warning them (by showing them either a blue or a red cue on a screen) whether the next shock would be mild or intense. After each shock, subjects described their pain.
After a round of shocks, the experimenter rubbed a skin cream on subjects’ wrists, telling some it was an experimental salve and others that it was a placebo cream. In reality it was all placebo cream. A third of subjects who got what they thought was the painkilling cream reported less pain, showing a clear placebo effect.
When Wager analyzed subjects’ brain activity, he found that the people who reported the greatest relief after receiving a placebo also showed the strongest reduction in activity in the ACC, the thalamus and the insula, all evolutionarily primitive brain structures that respond to physical pain.
Suddenly, it was clear that when a patient improved on placebo, it wasn’t just some delusion or an effort to please a person in a lab coat. It was a measurable brain event and reflected an actual reduction in the experience of pain.
Even more interestingly, Wager and his colleagues saw that when their subjects were anticipating pain relief, activity spiked in the more evolutionarily advanced prefrontal cortex, a region in the front of the brain that is central to generating expectations, and in a section of the midbrain that is key to the release of opioids. The more a subject’s prefrontal cortex ramped up with anticipated pain relief, the more activity Wager’s group saw in the midbrain.
Wager’s findings implied that the physiological stream of events involved in placebo responses might be the reverse of what happens during the experience of pain. Normally, pain signals begin somewhere in the body and work their way to the thalamus, deep in the brain, and then to the prefrontal cortex, producing conscious perception of pain. By contrast, Wager’s work, published in Science in 2004, suggested that the placebo effect starts in the evolutionarily newer parts of the brain related to expectations and works its way backward toward more primitive areas that release opioids. It’s as though the brain goes out of its way to ensure reality matches expectations.
Placebo in Practice
Like many in the field of placebo research, neurologist Luana Colloca has a practiced calmness about her. Her bedside manner is a sort of bashful nerdiness punctuated by sudden mischievous smiles. That manner, coupled with a level gaze and warm eyes behind glasses that slip down her nose, inspires both comfort and confidence.
Perhaps that is how she persuaded me one cold, clear January day to strap a painful electrode to my left hand for half an hour. Colloca’s laboratory is tucked into a small corner of the sprawling National Institutes of Health complex in Bethesda, Md. Her lab is tidy, containing her electric chair, in which I will be shocked, and a few odd little instruments, like a bike helmet that blows air on your face to make you anxious.
Soon an assistant is sticking sensors below my eye, on my chest and on my hand to measure my reactions — sweating, flinching, heartbeat. But it’s the electrodes on the back of my hand that have my attention. That’s where Colloca will repeatedly zap me, sometimes mildly and sometimes not so mildly. A computer screen, she explains, will warn me which shock I am to receive — a green screen for a mild zip and a red one for a blast I’ve ranked on a pain scale as six out of 10. I’ll then rate the pain of each shock as I go.
Alone in the room, I quickly learn to hate the red screen. It’s not technically torture, but it really hurts — my foot twitches with each shock — and I find myself fretfully counting seconds between the red screen and the jolt. We go three rounds of 18 shocks each. In the third round, I notice that the diminished “green” shock has gotten slightly worse, mounting from a 1 to a 2 on my pain scale. I worry momentarily that I’ve somehow short-circuited my hand.
Finally, the session is done and Colloca returns. As before, she wears a long lab coat and a deadpan expression. She starts by telling me that I have a decent tolerance to pain, which is deeply gratifying. But a sheet of paper in her hand says the “red” shock represented about 101 milliamps — not even enough to power a light bulb. Less gratifying. Colloca’s results also show that for the first two rounds of shocks, the difference between what I rated as light and strong pain was about 40 milliamps.
Then Colloca points to the results of the third round and says something that nearly topples me out of my chair. For that one, she fired every shock at full blast. Yet the shocks that came after a green screen felt far less painful — barely a 2 on my pain scale. Colloca flashes a mischievous smile.
Essentially, in the first two rounds of shocks my brain tied “less pain” with “green screen.” So in the third, when a green screen was paired with harder shocks, my brain released opioids rapid-fire to dampen the increased pain. A high tolerance to pain, but it seems I’m kind of gullible.
Colloca smiles at this. She says not to think of myself as gullible, but rather as a good learner. In two rounds of shocks, my brain learned to activate complex pathways — starting in my prefrontal cortex and trickling through to more primitive parts — every time I saw a green screen.
In 2006, Colloca found that this kind of limited placebo “learning” stays with a person for days. Theoretically, with lots more time in her terrible chair, the effect could be cemented in my brain for years.
The Mind’s Medicine Cabinet
Until recently, most scientists thought the placebo effect was all about tricking gullible patients into responding to fake drugs. But studies such as Petrovic’s and Wager’s linking placebo effects to real neurobiological processes have painted a more nuanced picture.
Today, placebos are widely recognized not as a psychological mirage, but as a potent inner pharmacy that we might someday even harness.
In practice, though, unlocking that inner pharmacy presents an ethical challenge. Sparking a placebo response usually requires doctors to dupe patients, withholding treatment while giving them the false expectation that they’re getting the real thing.
It may be possible to sidestep that ethical roadblock, however. In a 2010 study, Harvard medical researcher Ted Kaptchuk showed that some patients with irritable bowel syndrome improved even when they knew the treatment they were being given was a sham, suggesting that deception could, at least in some cases, be unnecessary. And Harvard University neuroscientist and placebo researcher Karin Jensen has found a way to elicit a placebo response without giving patients any conscious expectation at all.
Jensen got hooked on studying placebos while researching fibromyalgia, a condition involving muscle and joint pain without any observable injury, at the Karolinska Institute in the mid-2000s. She had learned that fibromyalgia patients struggled to access certain opioid-related brain regions, including the ACC — the center of emotion, reward and pain that Petrovic had found played a role in placebos.
Petrovic happened to sit in the chair next to Jensen. When she realized they were focused on the same brain region, she wondered: What if fibromyalgia came down to a problem with the brain’s ability to medicate itself? To study this question, Jensen decided to separate placebos from deception and expectation. To do this, she needed to create a placebo that subjects would not consciously detect.
Jensen used a setup similar to Wager’s — pairing images on a computer screen with different levels of pain (in this case, painful heat). But instead of tying the pain stimuli to blue or red cues, she used images of two similar-looking men. Then she added a major wrinkle to the procedure, flashing the faces on the screen for just 12 milliseconds, too fast for subjects to tell which was which.
But the human brain excels at recognizing faces — and hates pain. So Jensen was betting that some part of subjects’ subconscious minds would catch subtle differences between the faces and pair each one with either high or low pain. If so, their brains should learn to mount a placebo response without subjects’ conscious awareness.
And that’s exactly what happened. After learning to unconsciously associate particular faces with different levels of pain, subjects continued to report more pain when presented with the high-pain face and less pain when presented with the low-pain face, regardless of how high the heat was set. Not only could their brains unconsciously spot the different faces, they instantly doled out painkillers accordingly.
The findings could have tantalizing implications for doctors. “Everything that has to do with the elaborate ritual of delivering care could be a target to enhance the placebo effect,” Jensen says. Our brains may be spotting any number of potential cues — the way a doctor is dressed, the words she chooses to describe a drug, the size of the needle she uses, or even the painting on her wall, which the patient fixates on as the needle goes in.
Medicating Minus the Medicine
Exploiting the placebo effect in the clinic setting will be hard, though. As powerful as they can be, the biochemical processes underlying placebo effects don’t seem to unfold the same way in every brain. Perhaps more than anything else, this problem haunts placebo research: In any study, there are some people who respond to placebos with a special zeal. And when people respond well to placebos, they show stronger activation in brain circuits that control pain compared with those who are less susceptible to the placebo response. Could there be something physiologically distinctive that makes some people especially prone to the placebo effect? Do some people harbor a sort of permanent medical optimism that makes them hyperprone to placebos? If so, such people would not only benefit from all kinds of placebo treatment, they also could be excluded from clinical drug trials. That would mean that many drugs that couldn’t beat a controlled trial because of overzealous placebo responders might get another chance.
The placebo community, however, is divided over whether true “placebo responders” even exist. In drug trials, some people respond better to placebo injections than to placebo pills; or better to placebos for nausea than to those for pain; or even to one color pill than to another. But they are not always the same people. A person might respond well to one doctor and poorly to the next, or well in one phase of a drug trial and not at all in a different phase of the same trial just a month later.
To sort it all out, we need a clear distinction between those who respond to placebos and those who don’t (and maybe some sense of why). Kathryn Hall, a molecular geneticist in Kaptchuk’s research group at Harvard, and her colleagues think they’ve caught the scent of an answer to both questions.
Hall reasoned that if some people are indeed placebo-prone, their ability must be genetically related to brain function. She also saw that the conditions most susceptible to placebos — pain, depression and Parkinson’s disease — share one thing in common: dopamine.
A neurochemical messenger involved in the brain’s processing of reward, dopamine moderates all manner of experiences, from the perception of happiness to sexual ecstasy to the enjoyment of chocolate. But dopamine’s importance goes beyond hedonism. Parkinson’s disease is often treated by giving patients more dopamine, while people with higher levels of dopamine might be more susceptible to pain and possibly, according to Hall, depression.
Dopamine’s role in all these conditions brought Hall to the enzyme COMT, or catechol-O-methyltransferase. This enzyme roams the brain, devouring dopamine, and comes in several different flavors. Depending on his or her genetics, every person has a COMT recipe that includes some combination of two ingredients: the amino acids valine and methionine. At the extremes, some people (known as “met/mets”) only have methionine and some (“val/vals”) only have valine.
Because val/vals degrade dopamine about four times as fast as met/mets, people’s lifelong dopamine levels, and thus mood and personality, are a reflection, in part, of their COMT recipe. In 2009, Jensen showed that met/mets, flush with dopamine, are also more sensitive to certain types of pain than val/vals. If people’s COMT recipe affects how they perceive pain, Hall reasoned, then it might also affect their response to placebos.
To test this, she turned to the mysterious irritable bowel syndrome. IBS, an uncomfortable and often painful gastrointestinal ailment that affects some 10 percent of American adults, resists both classification and treatment. But studies like Kaptchuk’s show people with IBS often respond well to placebos.
In a 2011 study, Hall analyzed blood samples taken as part of an earlier study of 112 patients with mild IBS, examining each person’s COMT recipe. Patients had been split into three groups for a three-week fake acupuncture treatment, using placebo needles that only appeared to break the skin. One group got the fake needles with an aloof practitioner; another got them with a warm, supportive acupuncturist (Hall calls this “augmented” treatment); and the last group sat on a wait list.
Overwhelmingly, met/met patients responded splendidly to sham treatment, especially when they had a caring acupuncturist. Val/val patients had a dismal response to placebos — even worse than those who got no treatment. People with a mix of valine and methionine fit perfectly in the middle of the spread.
Hall was excited by this discovery of a potential biomarker for placebo responses, especially because it suggests there may be many more. She is under no illusion that the gene for COMT will turn out to be the placebo gene — placebo effects are way too complicated for that. But her results for the first time establish a link between the placebo response and a physiological event with a known genetic cause — namely, the flavor of COMT in a person’s brain.
Hall, who worked for a time in the pharmaceutical industry, says that might be enough to lure big drug companies into investing more in placebo research. “Having a biomarker for placebo is a product — it’s a real asset that the pharmaceutical industry can engage with,” she says.
But the real placebo revolution may be in reshaping clinical practice. Jensen says many doctors cripple their chances of leveraging the placebo effect by acting disinterested or lacking confidence with patients. She would know: When she started out, she had trouble eliciting a placebo effect. It was the doctor, not the patient, who had to change in order to boost the placebo. She learned to exude confidence and crafted a warmer manner, and her patients began to respond.
Lidstone shares Jensen’s resolution to use placebo research to change medical practice. If not, she asks, “Why else are we doing it?”
After finishing her Ph.D., Lidstone made the tough decision to go back to medical school. Four years later, she’s working at a Toronto hospital — just another anonymous neurology resident. But her work with placebos has made its mark on her, and at times she yearns to marshal her lessons from placebo research to help her patients. What doctors need, she says, is a list of indicators of diseases for which placebo treatments might be suited. Not long ago, she treated a young arthritis patient with mysterious, intractable stomach pain. After multiple emergency room visits and fruitless tests — a CT scan, an ultrasound and blood work — nothing about her condition was clearer. The girl’s pain and the resemblance of her symptoms to those of IBS indicated placebo treatment might have been the best option.
“She’s freaking out and at her wit’s end,” Lidstone remembers. “I was like, ‘Look, in the past 24 hours you’ve given her tons of morphine, and it’s not making her feel better at all. She knows it doesn’t work for her.’ ” Lidstone thought the answer might be to use the power of suggestion: to “hang a bag of saline [and] say we have this new pain medication … it’s really effective in situations like this. But I’m not allowed to try that. It’s not considered ethical.”
Tellingly, Lidstone is nervous about even discussing the situation on the record, afraid of seeming irresponsible. Despite all scientists have learned about placebos, even just talking about implementing it is taboo, she says.
Nevertheless, one survey of general practitioners found that about 85 percent had incorporated a placebo into their treatment at least once. And that is key: “incorporate.” Placebos won’t kill Big Pharma or replace pill popping. But they could augment existing treatment rituals. First, though, the placebo effect will have to pass the rigorous tests and analysis of medical researchers — just like any other drug.