Historical overview of placebo research from Mesmer to modern neuroscience

could “cure” many ailments. Mesmer became highly sought after in Paris, where he would routinely “mesmerize” his followers—one of whom was Marie Antoinette. The King wasn’t buying it, however, and he asked a commission of the French Academy of Sciences to look into the claims. (The members in- cluded Franklin, the chemist Antoine Lavoisier, and Joseph Guillotin—who invented the device that would eventu- ally separate the King’s head from his body.) The commission replicated some of Mesmer’s sessions, and, in one case, asked a young boy to hug magnetized trees that were presumed to contain the healing powers invoked by Mesmer. He did as directed and responded as ex- pected: he shook, convulsed, and swooned. The trees, though, were not magnetic, and Mesmer was denounced as a fraud. Placebos and lies were inter- twined in the public mind. It was another hundred and fifty years before scientists began to focus on the role that emotions can play in healing. During the Second World War, Lieu- tenant Colonel Henry Beecher—who went on to become the first chairman of the anesthesia department at Massachu- setts General Hospital—attempted to assess the degree to which the severity of a soldier's injuries corresponded to the amount of pain he felt. In Europe, Beecher met with more than two hun- dred soldiers, gravely wounded but still coherent enough to talk; he asked each man if he wanted morphine. Seventy- five per cent declined. Beecher was astounded. He knew from his experience before the war that civilians with similar injuries would have begged for morphine, and he had seen healthy soldiers complain loudly about the pain associated with minor inconve- niences, like receiving vaccinations. He concluded that the difference had to do with expectations; a soldier who survived a terrible attack often had a positive out- look simply because he was still alive. Beecher made a simple but powerful ob- servation: our expectations can have a profound impact on how we heal. Armed with this information, and with his conviction that the placebo effect could be harnessed to help relieve suffering, Beecher returned to the United States and continued his research. In 1955, he published an article called “The 32 THE NEW YORKER, DECEMBER 12, 2011 Powerful Placebo,” in which he wrote that “placebos have a high degree of ther- apeutic effectiveness in treating subjec- tive responses.” The paper has been cited more than a thousand times by other sci- entists, and Beecher’s conclusion—that the placebo effect plays a critical role in almost any medical intervention— influenced much of what has followed in clinical research. His basic supposition was correct: emotions and expectations can affect our perception of pain. Before Beecher’s work, new drugs were tested in a haphazard manner; since then, they have always been compared with a placebo or with another drug. But Beecher’s methodology was deeply flawed. Although he reported that place- bos were effective more than a third of the time, he shrugged off a phenomenon known as “regression to the mean.” Over time, the condition of most patients improves, with or without treatment. A person who enrolls in a clinical study when he is feeling particularly bad is likely to improve solely as a result of the natural course of the illness, not because he was given a placebo. (And people often enroll in such studies when they are sickest.) A patient who knows that he is in a study also may expect a better thera- peutic result than one who doesn’t. Ifyou believe that doctors are particularly atten- tive, you can get better more rapidly, even if they aren't. This is known as the Haw- thorne effect. (There is also a “nocebo effect.” Expecting a placebo to do harm or cause pain makes people sicker, not better. When subjects in one notable study were told that headaches are a side effect of lumbar puncture, the number of headaches they reported after the study was finished increased sharply.) For years, researchers could do little but guess at the complex biology of the placebo response. A meaningful picture began to emerge only in the nineteen- seventies, with the discovery of endor- phins: substances secreted in the brain that are chemically similar to opiates like morphine and heroin. The discovery led to the novel idea that, in effect, the brain produces its own pharmacy. In 1978, three scientists from the University of California at San Francisco—Jon Levine, Newton Gordon, and Howard Fields— decided to investigate whether endor- phins might explain why patients who received placebos often reported a significant reduction in pain. People re- covering from dental surgery were told that they were about to receive a dose of morphine, saline, or a drug that might increase their pain. By then, researchers had learned not only about the nocebo effect but that a suggestion of relief will often trigger the production of endor- phins, so they were not surprised that pa- tients receiving saline reported reduced pain. What came next, however, funda- mentally reshaped the field. The re- searchers dismissed the subjects who re- ceived morphine and then divided the remaining participants into those who responded to the placebo and those who didn’t. Then they introduced Naloxone into patients’ 1.V. drips. Naloxone was developed to counteract overdoses of heroin and morphine. It works essen- tially by latching onto, and thus locking up, key opioid receptors in the central nervous system. The endorphins that we secrete attach themselves to the same re- ceptors in the same way, so Naloxone blocks them, too. The researchers theo- rized that, if endorphins had caused the placebo effect, Naloxone would negate their impact, and it did. The Naloxone caused those who responded positively to the placebos to experience a sharp in- crease in pain; the drug had no effect on the people who did not respond to the placebo. The study was the first to pro- vide solid evidence that the chemistry be- hind the placebo effect could be under- stood—and altered. “Tt was one of those studies that make the scales fall from your eyes,” Kaptchuk told me. “T had just started to think about the placebo eftect—scientifically and his- torically. And here comes this paper that says that, even if it’s all in your head, there is still a biological mechanism driving these reactions. It was very exciting.” aptchuk assumed that the results would add legitimacy to the field. He was wrong. “Things are better than they were,” he said. “But even now, you know, people at Harvard talk about pla- cebos the way the Popes used to talk about medicine. They declared that Jews were not allowed to treat Christians— not because they were not good doctors but because it would have been ethically wrong. These are ethical judgments mas- querading as science. Because from the HOUSE_OVERSIGHT_029927