by Jo Marchant
Or to put it another way, can a simple belief—that we are about to get better—have the power to heal?
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ROSANNA CONSONNI hunches over the desk, gripping its edge with her left hand. In front of her is a gray, rectangular trackpad, and she tentatively places her right index finger on a green circle at its center. Every few seconds, a red circle lights up at varying positions around the edge of the pad. When that happens, Rosanna has to trace her finger from green to red as quickly as she can.
It’s a task that most people would find easy. But the 74-year-old’s brow is furrowed in concentration, and she looks like a child struggling to write. She’s willing her hand to move but her finger drags slowly, as if it’s not really hers. “Breathe,” advises a young, white-coated neuroscientist, Elisa Frisaldi. Each time Rosanna arrives successfully on red, her time pops up as a blue bar on a graph on Frisaldi’s computer screen.
This is the neuroscience department of the Molinette Hospital in Turin, Italy. It is early in the morning and outside the spring sun is shining. A stone’s throw away, joggers and dog walkers pass up and down the towpath by the wide, glossy river Po. Blossoms are falling and there are lizards in the grass. But we’re squeezed into a windowless basement room packed with computers, lab equipment and a blue couch.
Frisaldi is part of a team headed by one of the pioneers of placebo research, neuroscientist Fabrizio Benedetti. The problem with clinical trials like those of vertebroplasty and secretin is that they are not designed to measure the placebo effect, only to eliminate it. Any changes seen in a placebo group can be due to a range of causes, including random chance, so it’s never certain how much improvement, if any, is a result of the placebo itself. Benedetti and Frisaldi, on the other hand, are using carefully controlled laboratory experiments to probe exactly how and when beliefs can ease our symptoms.
Today’s volunteer, Rosanna, was 50 when she first noticed that her right hand was trembling. After two years of denial and uncertainty, she finally received a diagnosis: Parkinson’s disease. The condition affects about 1 in 500 people; more than half a million in the U.S. alone. It’s a degenerative disease in which brain cells that make a chemical messenger called dopamine gradually die. As levels of dopamine in the brain drop, patients experience steadily worsening symptoms that include stiff muscles, sluggish movement and tremors.
The condition is generally treated with levodopa, a chemical building block that the body converts into dopamine. Rosanna hasn’t taken her drug since last night, however, so that her Parkinson’s is in full flow for Frisaldi’s experiment. She arrives clutching her husband’s arm, taking shaky, shuffling steps. Even when she sits, she is in constant motion. She sways as she’s speaking, her silver earrings wobbling and her hands waving to and fro. Her chin and throat tremble as if she’s chewing. She’s wearing kneepads under her gray trousers because she so often falls.
But her spirit appears not to match her frail physical appearance. She is fiercely independent and jokingly refers to her husband, Domenico, as badente, or nursemaid. After her initial diagnosis, Rosanna tells me, she didn’t want to know anything about her disease. She took her pills, but otherwise “I didn’t read about it. I didn’t want to know my future.”15 For 20 years after her diagnosis, that strategy seemed to work. “I could drive. I was a good mother. My life didn’t change so much.” She enjoyed cycling trips, and snorkeling at the beaches of Versilia, about 150 miles south of Turin.
But in 2008, her symptoms started getting worse. Her body stiffened and her limbs resisted her will to move. One day she went to the supermarket alone, against her doctor’s advice, and when a woman in the checkout line bumped into her she was unable to step to regain her balance. She clattered to the ground and broke her arm. “I was afraid,” she says. “I felt something changing in my life.”
Rosanna’s doctor recommended surgical intervention, and she now wears a black shoulder strap, attached to a pouch that looks like a small camera bag. It contains a portable infusion pump that delivers her drug continuously, through a plastic tube that dives through her abdomen and into her small intestine. She hates the implant—“It makes me feel as if I have a handicap,” she says—but it allows her to keep some measure of independence.
Now, with the pump switched off, Frisaldi runs Rosanna through a series of tasks to assess the severity of her symptoms without any drugs. In addition to the track test, she has to circle her arms, walk in a straight line and repeatedly touch her nose. Once the baseline assessment is complete, it’s time to open the pouch and activate the pump to begin Rosanna’s daily drug infusion. It whirs and beeps; the moment she has been waiting for. “As soon as I take the drug, I can control my movements better,” she says. “I feel my hands relaxing, the rigidity in my legs disappearing.” After 45 minutes, I can see what she means. She sits more upright. Her chin is almost still. She moves with more confidence. And her time on the track test is halved.
But how much of this transformation is due to the drug itself, and how much to her expectation of the relief that she is about to feel? This is the type of question that most clinical trials are ill-equipped to address, but that Frisaldi is hoping to answer. Today, Rosanna is getting a full dose of her drug, but on other days she and her fellow volunteers will get a range of different doses, and sometimes they’ll know what they’re getting and sometimes not (for ethical reasons, Frisaldi isn’t allowed to give them no drug at all).
It seems amazing to me that symptoms as severe as Rosanna’s—caused by a degenerative neurological disease—might be eased by mere suggestion. But this is what studies of Parkinson’s have repeatedly shown. For example, a series of trials carried out by Jon Stoessl, a neurologist at the University of British Columbia in Vancouver, Canada, showed a strong placebo effect when Parkinson’s patients were given fake pills.16 One of them was a keen mountain biker named Paul Pattison. He duly took his capsule and waited for the drug to kick in. “Boom!” he told the makers of a BBC documentary about the placebo effect.17 “My body becomes erect, my shoulders go back.” When he found out he had actually taken a placebo, “I was in a state of shock. There are physical things that change in me when I take my meds so how could a blank thing, a nothing, create those same feelings?”
Stoessl’s experiments answered that question. Using brain scans, he showed that after taking a placebo, the participants’ brains were flooded with dopamine, just as when they take their real drug. And it wasn’t a small effect—dopamine levels tripled, equivalent to a dose of amphetamine in a healthy person—all from simply thinking they had taken their medication.
That finding was followed up by Benedetti, here in Turin. He was carrying out surgery on Parkinson’s patients for a therapy called deep brain stimulation. This involves implanting electrodes deep into the brain, in an area called the subthalamic nucleus, which helps to control movement. The neurons in this region are usually kept in check by dopamine, but in Parkinson’s patients these cells fire out of control, causing freezing and tremors. Once implanted, the electrodes stimulate these regions and calm the neurons down.
The surgery is done while patients are awake, and Benedetti saw the perfect opportunity to watch the placebo effect in action. The electrode would allow him to monitor activity deep inside the brain as someone takes a placebo—something that isn’t usually possible with human volunteers. So he carried out a series of trials: once the electrode was in place, he gave patients a saline injection, and told them it was a powerful anti-Parkinson’s drug called apomorphine.
As we wait for Rosanna’s drug to kick in, Frisaldi pulls up a series of slides on her computer screen. First, she shows me brain activity that Benedetti recorded before the saline injection. It’s a black-and-white line graph, showing the behavior of a single neuron from the subthalamic nucleus of one of the patients in the study. Each time the neuron fires, the line jumps in a sharp peak. Overall the graph looks like a barcode, a dense forest of spikes that’s almost completely black—this i
s a neuron firing out of control. Then she shows me the activity of the same neuron just after the placebo injection. There’s virtual silence; an overwhelmingly white space broken only by the odd, lone spike.
“It’s incredible,” says Frisaldi. “I think it’s one of the most impressive studies that Benedetti has done.” Benedetti had chased a belief right down to an individual cell—demonstrating that in Parkinson’s patients, motor neurons fire more slowly after injection of a placebo, exactly as they do in response to a real drug.18
Between them, what Stoessl and Benedetti showed was remarkable. Although placebo effects had been noted in Parkinson’s patients, it never occurred to anyone that placebos might actually mimic the biological effect of treatment. But here was proof that patients weren’t imagining their response, or compensating for their symptoms in some other way. The effect was measurable. Real. And physiologically identical to that of the actual drug.
An hour or so later, Rosanna’s drug has worn off and the experiment is over. She tells me that she still plans to swim in Versilia this summer, even with her implant, and that she doesn’t waste time worrying about how her disease might progress. “I’m always thinking about the present moment, I don’t want to project into the future,” she says. “That’s how I am generally, and the disease hasn’t changed that.” She takes out her phone and proudly shows me a picture: 150 pounds of lemons from her garden. When she stands to leave, she’s tiny and still swaying; she looks like a frail plant being buffeted by the wind.
After learning about the research with Parkinson’s patients, I’m impressed by the effect that placebos can have, but I’m left with more questions. If a belief can have the same effect as a drug, why do we need drugs at all? Do placebos work for all conditions, or just some? How does a mere suggestion create a biological effect? To find out, I decide to visit Benedetti himself. Although this is his lab, he’s not here. To track him down I have to travel 75 miles north from Turin—and nearly 12,000 feet up.
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I’M STANDING on the edge of a cliff, looking down on alpine crows swooping black against the blinding white snow, and across a crinkled blanket of mountain peaks that stretches to the horizon. Sounds are muffled in the thin air, and at –10°C, it’s biting cold. Behind me is a huge expanse of ice: the Plateau Rosa glacier. This is 11,500 feet above sea level, on the border between what scientists describe as “high altitude” and “very high altitude.” In the Alps, this is almost as high as you can get. From here, only the iconic peak of the Matterhorn rises another half mile, cutting its crooked triangle out of the azure blue sky.
It is early in the morning, and the plateau is deserted. Then a huge cable car arrives and tips out its load of brightly clad skiers. They pour past me, heading for the shallow slope of the glacier and barely noticing what looks like a metal shed perched on the mountainside. It’s half buried in snow and covered in scaffolding.
Inside the shed is Benedetti. He’s tall and welcoming, dressed in black ski trousers and a fleece. This is his high-altitude laboratory, packed with equipment and lined with pine slats like a sauna. He shows me around, pointing out the leaking roof—“It’s terrible in summer,” he says—and letting me peek at a ten-foot infrared telescope with which he shares this accommodation.
Telescope aside, Benedetti has equipped this space out himself, arranging for all the supplies to be brought in by helicopter. There’s a basic living area and kitchen, as well as two bedrooms with bunks, sleep-monitoring equipment and a breathtaking view. The international border runs right through the hut, so we step from the living area, which is in Italy, to the lab, which is in Switzerland.
This turns out to be two adjoining rooms, equipped with a mess of machinery and monitors, blinking lights and switches, and bookcases stuffed with files. Wires run across the ceiling and big, green gas canisters lean against the wall. I’m struck by the noise: hums and buzzes, clicks of different frequencies, a periodic hiss. And the thump-thump-thump of an exercise stepper. Working out on the stepper is Benedetti’s guinea pig for the day: a stout, young engineer named Davide.
Benedetti is here because the thin air is perfect for studying the placebo effect in another ailment: altitude sickness. Instead of working with ill patients, he can induce symptoms in healthy volunteers simply by bringing them here. Then he plays with their beliefs and expectations, and monitors the physiological effects.
Altitude sickness is caused by a lack of oxygen. As we travel higher above sea level, the percentage of oxygen in the air stays the same, but that air becomes less dense, meaning that there’s less oxygen in each lungful that we breathe. Here, above 11,000 feet, the oxygen density is only two thirds what it would be at sea level. That can cause symptoms including dizziness, nausea and headaches. The advice to skiers traveling to Plateau Rosa is to allow time to acclimatize by staggering the journey here overnight. To maximize the effects of the altitude for Benedetti’s experiment, however, Davide has traveled here in just three hours from sea-level Turin.
With ski poles and a focused expression, Davide looks like an explorer. He’s wearing a black neoprene cap fitted with wireless electrodes to monitor his brain activity. Meanwhile various sensors attached to a harness around his chest measure nervous system activity, body and skin temperature, heart activity and the oxygen saturation in his blood. The data are beamed wirelessly from a black recorder, the size of a stopwatch. It’s the same 15,000-euro system that the skydiver Felix Baumgartner used on his record-breaking jump from space,19 says Benedetti. “Only we’re at 4 kilometers rather than 40 kilometers.”
As Davide works out, Benedetti watches the data come in on his iPad. The engineer’s heartbeats are translated into green lines rolling across a black screen, while a digital display shows the oxygen saturation in his blood—at sea level it would normally be around 97–98%, but now it has fallen to just 80%. On a nearby computer screen, a rotating head pulsates with waves of yellow, red and blue—Davide’s brain activity.
He steps for 15 minutes, then puts on an oxygen mask attached to a small white canister on his chest, which Benedetti explains will make his activity easier for the remainder of the test. What Benedetti doesn’t tell him (or me) is that the mask isn’t connected, and the canister is empty. Davide is breathing fake oxygen.
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I FIRST met Benedetti the evening before, over beer and pizza down in the nearest ski resort of Breuil-Cervinia. Dressed in a zigzag woolen sweater, he looked utterly at home in an alpine lodge. Although he’s from the Italian coast, he was always bored on the beach, he tells me. He loves the mountains.
Benedetti sees placebo effects in all aspects of life, from music to sex. He explains that if he gives me a glass of wine and tells me how good it is, that will affect how it tastes to me. Or that if I’m given a hospital room that has a pretty view out of the window, I will recover faster. “We are symbolic animals,” he says. “The psychological component is important everywhere.”20
His interest in how psychological factors affect our physical bodies began in the 1970s, when he was starting his career as a neuroscientist at the University of Turin. He had already noticed that when he ran clinical trials, patients in the placebo group often did as well or better than those who received the active drugs. Then he saw a paper that changed his life, not to mention the world’s understanding of the placebo effect.
Scientists had recently discovered a class of molecules produced in the brain, called endorphins, that act as natural painkillers. Endorphins are opiates, meaning that they belong to the same chemical family as morphine and heroin. The effects that these powerful drugs have on the body were well-known, but the fact that we might make our own versions of such molecules was a revelation. It was the first hint that the brain was capable of producing its own drugs.
A neuroscientist named Jon Levine, at the University of California, San Francisco, wondered if this might help to explain how placebos are able to relieve pain. Scientists had generally assumed that gullib
le patients are somehow tricked into thinking they are in less pain than they actually are. But what if taking a placebo could trigger the release of these natural painkillers? Then the reduction in pain would be real. Levine tested his idea on patients who were in the hospital recovering from oral surgery. Just over a third of them reported significant pain relief after taking a placebo—an intravenous infusion of saline that they thought was a powerful painkiller. Then, without telling them, Levine gave them naloxone, a drug that blocks the effects of endorphins. The patients’ pain returned.21
It was at this moment, says Benedetti, that “the biology of placebo was born.” This was the first evidence of biochemical pathways behind the placebo effect. In other words, if someone takes a placebo and feels their pain melt away, it isn’t trickery, wishful thinking or all in the mind. It is a physical mechanism, as concrete as the effects of any drug. Benedetti wondered if this could also explain why the placebo patients in his trials did so well. “I decided to investigate what was going on in their brains.”
He dedicated his career to lifting the veil of the placebo effect—starting with pain relief. In trials he identified more natural brain chemicals that, triggered by our beliefs, can turn our response to pain up or down. He found that when people take placebo painkillers in place of opioid drugs, these don’t just relieve pain, they also slow breathing and heart rate, just as opiates do. And he discovered that some drugs thought to be potent painkillers have no direct effect on pain at all.
Opioid painkillers are supposed to work by binding to endorphin receptors in the brain. This mechanism isn’t affected by whether we know we’ve taken a particular drug. Benedetti showed that in addition to this mode of action, such drugs also work as placebos—they trigger an expectation that our pain will ease, which in turn causes a release of natural endorphins in the brain. This second pathway does depend on us knowing we have taken a drug (and having a positive expectation for it). Incredibly, Benedetti found that some drugs previously thought to be powerful painkillers only work in this second way. If you don’t know you’ve taken them, they are useless.
