by Jo Marchant
But this is just one placebo mechanism. Benedetti also found pain-relieving placebo effects that are not mediated by endorphins and can’t be blocked by naloxone. Then he moved on to studying placebo effects in Parkinson’s, the research I learned about from Frisaldi, which works via yet another mechanism: release of dopamine. Placebo effects have only been studied in a few systems so far, but there are probably many others. Benedetti emphasizes that the placebo effect isn’t a single phenomenon but a “melting pot” of responses, each using different ingredients from the brain’s natural pharmacy.
Up here in the Alps, Benedetti has just started to study how placebos work for altitude sickness. When we’re at altitude, low oxygen levels in the blood trigger the brain to produce chemical messengers called prostaglandins. These neurotransmitters cause a variety of physical changes, such as dilating blood vessels, to help pump more oxygen around the body. They are also thought to induce the headaches, dizziness and nausea of altitude sickness. So can fake oxygen interrupt this pathway and ease the symptoms?
Davide finishes his half-hour exercise stint. The altitude has clearly affected him; he looks woozy, and totters slightly as Benedetti helps him to a chair. But he has put in a solid performance on the stepper, impressive for someone who was at sea level just a few hours ago. Benedetti tells me later, after analyzing the results from Davide and other volunteers, that the fake oxygen did indeed create a biological effect in their brains compared to a control group who weren’t given the placebo. Even though oxygen levels in the blood stayed the same, prostaglandin levels and vasodilation were reduced. When volunteers experience a placebo effect (and not everyone does) their brains respond as if they are breathing real oxygen, reducing their symptoms and allowing them to perform better.
This result illustrates two important points about the limitations of the placebo effect. The first is that any effects caused by belief in a treatment are limited to the natural tools that the body has available. Breathing fake oxygen can cause the brain to respond as if there is more oxygen in the air, but it cannot increase the underlying level of oxygen within the blood. This principle applies to medical conditions too. A placebo might help a patient with cystic fibrosis to breathe a little more easily, but it won’t create the missing protein that their lungs need, any more than an amputee can grow a new leg. For someone with type 1 diabetes, a placebo can’t replace their dose of insulin.
The second point, which is becoming clear from a range of placebo studies, is that effects mediated by expectation tend to be limited to symptoms—things that we are consciously aware of, such as pain, itching, rashes or diarrhea, as well as cognitive function, sleep and the effects of drugs such as caffeine and alcohol. Placebo effects also seem to be particularly strong for psychiatric disorders such as depression, anxiety and addiction.
In fact, they may be the main mode of action for many psychiatric drugs. Irving Kirsch, a psychologist and associate director of the placebo studies program at Harvard University, has used freedom-of-information legislation to force the U.S. Food and Drug Administration (FDA) to share clinical trial data sent to it by drug companies. This revealed what the companies had been hiding: that in most cases (severely ill patients are an exception), antidepressant drugs such as Prozac have little effect over and above placebo.22 Meanwhile Benedetti has found that Valium, which is widely prescribed for anxiety disorders, has no effect unless patients know they are taking it.23 “The more we know about placebos,” he says, “the more we learn that many positive outcomes of clinical trials are attributable to placebo effects.”
Placebos, then, are very good at influencing how we feel. But there’s little evidence that they affect measures we’re not consciously aware of, such as cholesterol or blood sugar levels, and they don’t seem to address the underlying processes or causes of disease. Bonnie Anderson’s fake surgery banished her pain and disability, but it probably didn’t mend her spine. One asthma study found that although patients reported that they could breathe more easily after taking a placebo, objective measurements of their lung function did not change.24 Clinical trials involving cancer patients generally show significant placebo effects for pain and quality of life, but the proportion of patients in placebo groups whose tumors shrink is low (in one analysis of seven trials, it was 2.7%).25
These are crucial limitations. Placebos don’t create an all-powerful protective magic that can keep us well in every circumstance. We’re not going to be able to throw out physical drugs and treatments. But on the other hand, Benedetti’s research shows that the effects of placebos are underpinned by measurable, physical changes in the brain and body. And just because the benefits mediated by placebos are mostly subjective, that doesn’t mean they have no potential value for medicine.
After all, many of the treatments used in medicine target symptoms rather than underlying disease processes, particularly when the underlying disease is hard to diagnose or treat. Tumor growth and survival time are critical for a cancer patient, but pain control and quality of life are important too. Telling a patient with fibromyalgia or irritable bowel syndrome that there’s nothing physically wrong with them will not give them much comfort. A subjective improvement in suicidal thoughts in a patient with depression can mean the difference between life and death.
In lab experiments, placebo effects are often short-lived, but there is evidence that in clinical practice, placebos can keep working for months or years. In a U.S. trial published in 2001, researchers injected neurons from aborted human embryos into the brains of Parkinson’s patients, in the hope that they would thrive there and start producing dopamine.26 The trial was essentially a failure—there was no significant difference between the treatment group and placebo controls. What did make a difference, however, was which group the patients thought they were in. A year later, those who guessed they had received the transplant were doing significantly better (in terms of their own reported scores, and those of blinded medical staff) than those who believed they had received placebo.
Of course, patients who did better might be more likely to guess that they had received the transplant. But the researchers who analyzed the data from this study suggest there was more to the effect than that, concluding that even over the course of a year, “the placebo effect was very strong.”27 Rosanna believes her refusal to see herself as ill might be one reason why her disease was slow to progress for so many years after her initial diagnosis—this study hints that she might be right.
On the face of it, then, placebos might seem to be a magic pill, with wide-ranging benefits, no side effects and essentially zero cost. But there has always been one huge problem, which causes even doctors who acknowledge the power of placebos to reject their use in medicine. It has always been assumed that you have to lie to patients for placebos to be effective—to fool them into thinking that they’re receiving an active treatment when they are not. No matter what the potential benefit of placebos, critics argue, it is not worth jeopardizing the fundamental bond of trust between doctors and patients.
But within the last few years, a handful of scientists have started to suggest that this traditional assumption is wrong. Their results could turn conventional medicine on its head.
Linda Buonanno hugs me as soon as we meet, and shows me upstairs to her small, first-floor apartment in a housing block just off the freeway in Methuen, Massachusetts. Her living space is tidy but densely packed with framed photos, scented candles and an overwhelming preference for the color green. She sits me at the table, in front of a perfectly laid out tea set and a plate of ten macaroons. The 67-year-old is plump with short, auburn hair and a girlish giggle. “Everyone thinks it’s dyed, but it isn’t,” she tells me. She hovers until I try a macaroon, then sits down opposite and tells me about her struggles with irritable bowel syndrome (IBS).
She talks fast. Her symptoms first struck two decades ago, when her marriage of 23 years broke down. Although she dreamed of being a hairdresser, she was working shifts in a factory,
running machinery that made surgical blades, juggling the 60-hour week with a court battle and caring for the two youngest of her four children. “I went through hell,” she says. Within a year of the split, she started suffering from intestinal pains, cramps, diarrhea and bloating.
The condition has affected her ever since, especially at stressful times such as when she was laid off from the factory. Their jobs outsourced to Mexico, the group of women with whom she had worked and bonded was scattered. She retrained as a medical assistant, hoping to find work in a chiropractor’s office, but once she qualified she found that no one was hiring. When she did finally find a part-time job, she had to give it up because of the pain from her IBS.
The condition has destroyed her social life too. When the symptoms are bad, “I can’t even leave the house,” she says. “I’d be keeling over in pain, running to the bathroom all the time.” Even buying groceries requires staying within reach of a bathroom, and she lists the local facilities: one in the Market Basket, one in the post office down the street. “This is 20 years I’ve been doing this,” she says. “It’s a horrible way to live.” Now she has to juggle the condition with looking after her elderly parents—her mother lives alone, while her father, who suffers from dementia, is in a nursing home. Linda’s brother was killed in Vietnam, and her twin sister died of cancer 18 years ago, so she is the only one left to help them.
She brightens. “But I travel,” she says. “I go to England, I do everything. I love it.” I’m thrown by this statement until I realize that she’s talking about Google maps. I ask her to show me, and we move over to her computer, which sits on a desk squeezed between the sofa and the microwave. She fires up the maps program and lands us on top of Buckingham Palace in London.
Suddenly I get a sense of how much time Linda has spent in this flat. She knows the layout of the palace intimately, zooming in to try to peek through the windows, then flying around the back to check out the private gardens. Other favorite destinations include the Caribbean island of Aruba, and the celebrity mansions of Rodeo Drive. Sometimes she looks up the addresses of her old workmates from the factory, friends who when they lost their jobs moved away to Kentucky or California, places that because of her IBS, and the demands of her parents, she can never visit for real.
Over the years, Linda has, like many patients with irritable bowel syndrome, been passed from doctor to doctor. She has been tested for intolerances and allergies, and has tried cutting out everything from gluten and fat to tomatoes. But she found no relief until she took part in a trial led by Ted Kaptchuk, a professor at Harvard Medical School in Boston. It was a trial that would revolutionize the world of placebo research.
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“YOU KNOW I’m deviant?” Ted Kaptchuk looks straight at me and I get the sense that he is rather proud of this fact.1 “Yes,” I answer. It’s hard to read anything about the Harvard professor without coming across his unusual past. In fact it seeps from every corner of our surroundings—the house where he lives and works, on a leafy side street in Cambridge, Massachusetts.
I’m asked to remove my shoes as I enter, and offered a cup of Earl Grey tea. Persian rugs cover the wooden floors, and proudly displayed in the hall is a huge brass tea urn. The décor is elegant, featuring period furniture, modern art and shelves filled with books—rows of hardbound doorstops embossed with gold Chinese lettering next to English volumes, from The Jewish Wardrobe to Honey Hunters of Nepal. Through the window I glimpse the nuanced greens and pinks of a manicured ornamental garden that might be more at home in Japan.
Kaptchuk himself has gold rings, big brown eyes and a sweep of graying hair topped by a black skullcap. He likes to quote from historical manuscripts, and his answers to my questions are accompanied by long pauses and a furrowed brow. I ask him to tell me his own version of the path that brought him here and he says it started when he was a student and he traveled to Asia to study traditional Chinese medicine.
It’s a decision he attributes to “sixties craziness. I wanted to do something anti-imperialist.” He was also interested in Eastern religions and philosophies, and the thinking of the Chinese Communist leader Mao Zedong. “Now I think that was a really bad reason to study Chinese medicine. But I didn’t wanted to be co-opted, I didn’t want to be part of the system.”
After four years in Taiwan and China, he returned to the U.S. with a degree in Chinese medicine and opened a small acupuncture clinic in Cambridge. He saw patients with all sorts of conditions, mostly chronic complaints from pain to digestive, urinary and respiratory problems. Over the years, however, he became more and more uncomfortable with his role as a healer. He was good at what he did—perhaps too good. He would see dramatic cures, sometimes before patients had even received their treatment. “I would have patients who left my office totally different,” he says. “Because they sat and talked to me, and I wrote a prescription. I was petrified that I was psychic. I thought, Shit, this is crazy.”
Ultimately, Kaptchuk concluded that he didn’t have paranormal powers. But equally, he believed that his patients’ striking recoveries didn’t have anything to do with the needles or the herbs he was prescribing. They were because of something else, and he was interested in finding out what that something was.
In 1998, Harvard Medical School, just down the street from Kaptchuk’s clinic, was looking for an expert in Chinese medicine. The U.S. National Institutes of Health (NIH) was opening a center dedicated to funding scientific research into alternative and complementary medicine. Although tiny compared to existing NIH centers investigating cancer, for example, or genetics, it promised to be a useful new source of research dollars for Harvard. “But no one there knew a thing about Chinese medicine or any kind of alternative medicine,” says Kaptchuk. “So they hired me.”
Rather than study Chinese medicine directly, however, he decided to investigate the placebo effect, to find out whether this could explain why his patients did so well. Whereas Benedetti is interested in the molecules and mechanics of the placebo effect, Kaptchuk’s focus is on people. The questions he asks are psychological and philosophical. Why should the expectation of a cure affect us so profoundly? Can the placebo effect be split into different components? Is our response affected by factors such as the type of placebo we take, or the bedside manner of our doctor?
In one of his first trials, Kaptchuk compared the effectiveness of two different kinds of placebo—fake acupuncture and a fake pill—in 270 patients with persistent arm pain.2 It’s a study that makes no sense from a conventional perspective. When comparing two inert treatments—nothing with nothing—you wouldn’t expect to see any difference. Yet Kaptchuk did see a difference. Placebo acupuncture was more effective for reducing the patients’ pain, whereas the placebo pill worked better for helping them to sleep.
This is the problem with placebo effects—in trials they are elusive and ephemeral, rarely disappearing completely but often altering their shape. They change depending on the type of placebo, and they vary in strength between people, conditions and cultures. For example, the percentage of people who responded to placebo in trials of a particular ulcer medication ranged from 59% in Denmark to just 7% in Brazil.3 The same placebo can have positive, zero or negative effects depending on what we’re told about it, and the effects can change over time. Such shifting results have helped to create an aura around the placebo effect as something slightly unscientific if not downright crazy.
But it isn’t crazy. What these results actually show, says Kaptchuk, is that scientists have long gotten their understanding of the placebo effect backwards. When he arrived at Harvard, he says, the experts there told him that the placebo effect “was the effect of an inert substance.” It’s a commonly used description but one that Kaptchuk describes as “complete nonsense.” By definition, he points out, an inert substance does not have any effect.
What does have an effect, of course, is our psychological response to those inert substances. Neither fake acupuncture nor a fake pill is in its
elf capable of doing anything. But patients interpret them in different ways, and that in turn creates different changes in their symptoms.
It’s a perspective championed by Dan Moerman, an anthropologist from the University of Michigan, who studied the herbal remedies used by Native American healers before he became interested in placebos—and who analyzed those ulcer trials. According to Moerman, the active ingredient is meaning—the meaning that is attached to and surrounds any medical treatment, fake or otherwise. (He wants to change the name of the placebo effect to “the meaning response,” but it’s showing no signs of catching on.)
In a phone interview, Moerman refers me to one of Benedetti’s studies, on patients recovering from surgery who were given painkillers via an intravenous drip.4 One group of patients was given the drugs by a doctor who told them what was happening. The other group received their drugs surreptitiously, with the drip controlled by a computer. The only difference between the two groups, says Moerman, was “human interaction and words.”5
The effect of that human interaction was striking. The patients who received their drugs with the doctor present got up to 50% more pain relief. The study included four different drugs, and got the same result for all four. “I don’t see any placebo there at all,” says Moerman. “What I do see is a clinician wearing a uniform of some sort.” Instead of focusing on fake pills, he argues, we should be looking at those trappings of medicine that make us expect to feel better—whether it’s the white coat, stethoscope, and gleaming hospital equipment of a Western physician, or the incense and incantations of a traditional healer.
