by Jo Marchant
Recent studies in the U.S. and U.K. have induced negative symptoms in volunteers after telling them (falsely) that they were being exposed to powerful wifi radiation, or inhaling environmental toxins.15 And in 2007, U.S. doctors reported the case of a 29-year-old man from Jackson, Mississippi.16 He was taking part in a clinical trial for an antidepressant drug and was responding to it well. After an argument with his girlfriend, however, he overdosed on his remaining capsules and collapsed at his local hospital with a racing heart and worryingly low blood pressure. Medical staff gave him more than a gallon and a half of intravenous fluids over four hours before the message got through from the trial organizers that the patient had been in their placebo group. His symptoms disappeared within 15 minutes.
In fact, most of the side effects we suffer when we take medicines are not due directly to the drugs at all, but to the nocebo effect. In clinical trials for conditions from depression to breast cancer, around a quarter of patients report adverse side effects—most commonly fatigue, headaches and difficulty concentrating—even when they are taking a placebo. In one study that specifically addressed this phenomenon, Italian researchers followed 96 men who had been prescribed the beta-blocker atenolol for cardiovascular disease. Some did not know what drug they were taking, whereas others were told about the drug and that it might cause erectile dysfunction. The percentage of patients in each group who subsequently suffered this side effect was 3.1% and 31.2%, respectively.17 This implies that in normal medical practice, where patients know what drug they are taking and are warned of this side effect, as many as a third of them might suffer from impotence after taking atenolol. But only a tenth of those cases are caused by the drug itself. The rest are triggered by the patients’ minds.
Although the nocebo effect might seem harmful, from an evolutionary point of view it makes very good sense. Nicholas Humphrey, a theoretical psychologist based in Cambridge, U.K. who has written extensively on the evolution of placebo and nocebo effects, argues that if we see other people getting sick around us, or have good reason to believe that we have been poisoned, then to start vomiting is actually a wise strategy.18 If we really have been poisoned, then such early action could be life-saving. If not, then no real harm has been done. Headaches, dizziness and fainting may all serve as warning signals that we should flee a location that could be dangerous, and that we may need medical attention.
From this perspective, the nocebo effect is a biological message that we can’t ignore, triggered by psychological cues in our environment that something is wrong. The more threatening we perceive our surroundings to be, the more sensitive we are to such symptoms. But they can be triggered in anyone if the suggestion is strong enough. It’s a self-preservation mechanism, or as Kaptchuk puts it, it’s what happens “when you’re in a forest that’s full of snakes and you see a stick and your brain sees a snake.”
And this, finally, may also explain why we experience positive placebo effects. If threat, anxiety and negative suggestion can induce symptoms of pain and sickness, then it follows that feeling safe and secure, or believing that we are about to feel better, will have the reverse effect. We let our guards down and suppress negative symptoms such as pain. Placebos, then, tap into ancient, evolved neural pathways. Humphrey argues that receiving any kind of medical attention—whether fake, alternative or conventional—helps to persuade these primitive brain circuits that we are loved, safe and getting well, and that there is no further need to feel sick.
Kaptchuk thinks this may be why Linda Buonanno and other participants in his trials experienced placebo effects even though they knew that the pills they were taking were inert. One possibility is that they consciously expected a placebo to help them. But Kaptchuk thinks it runs deeper than that. When Linda took that bottle of capsules from her doctor, Tony Lembo, “she took Tony home,” he says. “She took home the care, the concern.”
The fact that some people experience bigger placebo effects than others, and that the same person can experience differing placebo effects at different times, suggests that some people may naturally have a higher threshold for negative symptoms than others, but that the threshold can also slide up and down depending on our circumstances. If we perceive ourselves to be in a forest of snakes—like the Afghan schoolgirls surrounded by threats from the Taliban, or Linda looking after her kids and working shifts while fighting a messy divorce—the body becomes much more sensitive to biological warning signals such as pain.
If this idea is correct, you’d expect placebos to help eliminate those nocebo effects, by removing our anxiety and pushing our threshold back up. When Linda participated in the placebo trial, “she was in a forest of concerned people,” says Kaptchuk. “Her body switched something on that reduced her pain. And she stopped paying attention to her pain as much.”
A cunning experiment carried out by Benedetti at Plateau Rosa, published in 2014, supports the idea that in some cases, placebos work by removing pre-existing nocebo effects.19 Of 76 students who visited his snow-coated lab, those who had been warned to expect nasty headaches as a side effect of the high altitude suffered more and worse headaches than those who had no idea that this was a risk. Benedetti found that in both groups, the headaches had a biological cause—they were associated with increased levels of prostaglandins, which cause blood vessels to dilate.
It was a nice demonstration of the nocebo effect. In low-oxygen conditions, the brain produces prostaglandins as part of a self-protection mechanism to carry more oxygen around the body. In the students who were worried about headaches, this mechanism was amplified. Their anxiety caused the brain to be more cautious than it would otherwise have been, and to take extra measures to protect itself.
When the students took aspirin, this reduced prostaglandin levels and eased the headaches in both groups. But the most interesting result occurred when they took placebo aspirin. This worked too, but it had a smaller effect than the real aspirin and it only worked in the nocebo group. Benedetti concludes that the placebo was only effective at removing the extra nocebo component of the headaches. It worked by relieving anxiety, which caused the brain to ease off on prostaglandin production.
Benedetti doesn’t yet know if this principle will hold for any other types of placebo response. But if it does, this could prove to be “a new way of looking at placebo,” he says. Such placebo effects may not influence underlying disease processes. But they do provide a way to maximize our quality of life, whatever our physical state, and demonstrate that we don’t always have to believe the symptoms we feel.
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“I TALK to my pills,” anthropologist Dan Moerman confesses cheerfully. “I say, ‘Hey guys, I know you’re going to do a terrific job.’ ”20 He tells me that he has a painful left knee, and that he uses this technique to boost the effect of his painkillers and get the relief he needs from one pill rather than two.
How we take our drugs, he argues, may be just as important as what they look like. Although there’s little research in this area, he and other experts suggest that anything we can do that helps us to attach more significance to a treatment—active or placebo—may boost any beneficial effects that we feel.
In other words, don’t throw a pill down your throat absentmindedly as you’re racing for the bus. Instead, create a ritual around it. Harald Walach,21 a psychologist and philosopher of science from Viadrina European University in Frankfurt, Germany, suggests taking a drug at the same time each day—after a morning bath, in a special room, or with a prayer or silent meditation.22 Alternatively, Irving Kirsch, a psychologist at the University of Hull, U.K., who collaborated with Kaptchuk on his IBS study, suggests using visual imagery. To do this, be as specific as you can about the effect that you would like a particular drug or placebo to have. “Imagine the improvement,” he tells me.23
Or you could ask someone else to dispense a chosen treatment. There’s little research on this, but experts including Humphrey and Moerman argue that receiving medical help from others i
s likely to trigger larger placebo responses than taking care of ourselves, because it creates stronger feelings of safety and security. “While I think it’s a really good thing for me to talk to my pills, it would be much better if my wife did it with me,” says Moerman.
Children are particularly amenable to this type of placebo effect. As any parent knows, kissing a child better, drawing a heart around a skinned knee, rubbing cream on a rash, or calming a cough with a spoonful of honey can have a dramatic impact on pain and other forms of discomfort, even if they contain little or no active medical component.
But it seems to work on adults too. In 2008, Kaptchuk published a trial of 262 patients with IBS.24 It involved no active treatments, just placebo. One group received no treatment, whereas a second group got fake acupuncture from a polite but cold practitioner who didn’t engage in conversation. A third group got the placebo acupuncture from a warm, caring practitioner who sat with them for 45 minutes, listening to their concerns and providing reassurance. Kaptchuk wanted to know how much improvement would be a result of the acupuncture itself, and how much would be due to the extra-supportive bedside care.
In the no treatment group, 28% of patients said they got “adequate relief” from their symptoms just from being in the trial. Of those who got placebo acupuncture alone, 44% got adequate relief. In the group that received both acupuncture and empathic care, that figure jumped to 62%—as big an effect as has ever been found for any drug tested for IBS.
For Kaptchuk, this and similar studies highlight what is perhaps the most fundamental lesson from research on placebos: the importance of the doctor-patient encounter. If an empathic healer makes us feel cared for and secure, rather than under threat, this alone can trigger significant biological changes that ease our symptoms. Here was the answer to what was happening in his acupuncture practice, years earlier. When his patients improved before they had even received any treatment, it was their interaction with him that made the difference.
Unfortunately, due to budget and time constraints, as well as an emphasis on drugs and physical treatments, there is increasingly little room for the doctor-patient relationship in Western medicine. Doctors might have less than ten minutes with a patient, with the production of a prescription note seen by both sides as more important than having a lengthy, reassuring chat. It’s a shift that Kaptchuk blames, ironically, on the introduction of placebo-controlled trials in medicine in the 1950s. “Before that, doctors knew that care was important for their patients, and that they were an active ingredient,” he says. Now, it’s all about the data, and the drugs.
Modern medicine’s focus on physical data and objective test measurements has undoubtedly allowed huge advances, but Kaptchuk argues that it has also led to an obsession with molecules and biochemical pathways to the exclusion of how we actually feel. “The only reason people pay attention to placebo [now] is because we’ve found some neurotransmitters that are involved, and because my team and a lot of other teams are finding great things with neuroimaging,” he says. “As if patients’ experiences are not important.”
Alternative medicine has filled the gap. Therapies such as homeopathy and reiki contain no active ingredient and show no benefit in rigorous clinical trials. They are based on principles that from a scientific point of view are nonsensical—almost certainly they do not work in the way that practitioners claim they do. But with long, personal consultations and empathic care, they are perfectly honed to maximize placebo responses. For that reason they probably do provide real relief, particularly for chronic ailments that conventional medicine is not well equipped to treat.
So even if prescribing honest placebos doesn’t catch on, Kaptchuk hopes that his work will trigger a wider debate about the importance of reinstating in Western medicine the doctor’s role as a healer, so that we can benefit from both personal care and scientifically proven treatments, not just one or the other. We need to ask, “How can we administer drugs so that we make them more effective, and make the side effects less prevalent?” he says.
Clearly, the words physicians use to communicate the benefits and side effects of drugs affect how patients respond. (We’ll come back to the importance of language in chapter seven.) But expectations can be passed to patients in much more subtle ways too. In a classic study carried out in 1985, doctors’ beliefs about whether they were prescribing a painkiller or placebo dramatically altered the amount of pain felt by their patients—even though what they told those patients didn’t change.25
Such indirect placebo effects—dependent on the beliefs and attitudes not of patients but their caregivers—are another reason why placebo effects are seen in children (and even animals).26 In Sandler’s secretin study described in chapter one, the parents’ positive expectations may have influenced their own behavior, in turn creating a real improvement in their children’s symptoms. Alternative remedies such as amber bracelets for teething pain may soothe a baby by calming the parents’ anxiety.
In 2012, Kaptchuk induced both placebo and nocebo effects using pictures of faces flashed up so quickly that patients weren’t aware of them27—supporting the idea that our experience of symptoms such as pain is easily influenced by subliminal cues. “Words, gaze, silence, body language, all are important,” says Kaptchuk. Although these aspects of care have often been ignored in medicine, he reckons that placebo studies are now helping to trigger debate about their role.
He’s a persuasive speaker, but before I get too carried away he reminds me that there are lots of things positive expectations cannot achieve. “You’re not going to change the underlying physiology [of disease],” he says. “I don’t see that in any of the research.” I guess he’s right to emphasize those limits. Feeling great isn’t everything. We also want to stay alive, and for many conditions, such as allergies, infections, autoimmune diseases or cancer, that underlying physiology is desperately important.
In cases like these, influencing subjective symptoms isn’t enough. So I decide to travel to Germany, where researchers are using the mind to infiltrate the front line of the body’s physical fight against disease.
Karl-Heinz Wilbers pops open a small plastic case and takes out four foil blister packs of drugs. Myfortic, tacrolimus…these are the names he reads every day, and on which his life now depends. Today there’s an extra pill, a chunky white capsule that smells slightly of fish. Before he takes it, he switches on the CD player and cues up “Help Me,” by Johnny Cash. And he pours himself a glass of a bright green liquid that smells strongly of lavender.
Karl-Heinz is a retired psychiatrist from Essen in northern Germany. He’s an earnest, academic man with a quiet, almost melancholy demeanor and small, wire-rimmed glasses. Sixteen years ago, his kidneys failed. It’s not clear why, he says, although the most common causes are diabetes and high blood pressure. He became one of 80,000 Germans who depend on dialysis, a procedure in which a patient’s blood is regularly fed through a tube into a machine and filtered to remove waste products before being passed back into their body.
He was hooked up to the machine for nine hours at a time, four to five times a week. Karl-Heinz was lucky, he was able to have the dialysis overnight at home. “But you can’t sleep the whole night,” he says. “Alarms go off. You have to check the machine, change fluids. You have two big needles in your arm.” He shows me a large scar on the inside of his forearm, where the needles sat in his flesh night after night.
He was alive. He could still walk his dog and was able to paint. But his dependence on the dialysis machine made it impossible to travel, and his chances of surviving to enjoy retirement with his wife and daughter weren’t good. The average life expectancy for patients on dialysis is just five years.
After 12 years on dialysis, Karl-Heinz was beating the odds. So when he was finally given the chance for a kidney transplant he said, “Yes,” albeit with some trepidation. “After that, my life was very different,” he says. “The freedom you get. Being mobile.” He tells me that in the four years
since the transplant, he and his wife have visited their daughter in the U.K.’s Lake District, something that would have been impossible on dialysis. They have flown to New York twice, and are planning a trip to the south of England.
But he has paid a heavy price. He is no longer tied to the dialysis machine, but to stop his body from rejecting the foreign organ he has to take powerful drugs that will suppress his immune system every day for the rest of his life. They put him at risk of life-threatening infections, and he lives with the constant threat of cancer.1 There are neurological side effects; he gets a painful, burning sensation in his feet. And the toxicity of the drugs puts pressure on his precious kidney. Get the dose too low, and his body could reject it. Too high, and the toxicity could cause the organ to fail.
“Help Me” is one of Karl-Heinz’s favorite songs; he has chosen it because it puts him in a calm, thoughtful frame of mind. As he listens to the lyrics, he swallows the chunky capsule and downs his lavender drink. He knows that unlike the rest of the pills in his plastic case, these contain no active drug. He’s taking them as part of a pioneering trial to investigate whether this ritual—the drink, the pill, the music—has the power to shape his body’s response to his transplant, in this case suppressing it above and beyond the effects of his drugs alone.
The placebos we’ve looked at so far are based on conscious belief or expectation. You think a pill or injection will have a certain effect, and then it does. Although such fake treatments can create biological changes in the body, they mostly influence subjective symptoms such as pain—affecting how we feel, not our underlying disease. But Karl-Heinz is hoping that his mind will trigger another type of mechanism that can influence basic biological functions, including the immune system.
