Medical mystery: why are placebos becoming more effective?

There’s a drug that can make you run faster, feel less depressed and experience reduced pain. Don’t believe me? You shouldn’t. That’s because this miracle drug isn’t a drug at all — it’s a placebo.
The “placebo effect,” or an inert substance’s ability to improve a patient’s symptoms, has been documented in everything from pain due to molar extractions to irritable bowel syndrome to Parkinson’s disease to bipolar disorder. And this phenomenon is not static.
Researchers have found a sizable surge in the placebo affect in Americans when studying anti-depressants, anti-psychotics and pain medications. In 1990, for example, patients reported that opiate drugs relieved their pain symptoms 27 percent more than a placebo.
In 2013, this difference dropped to 9 percent, while the drug response remained constant. This noticeable drop, it should be noted, was only demonstrated in Americans — not Europeans or Asians.
This is only one of the many discoveries that makes placebos such a fascinating area of research — and what makes science journalist Jo Marchant’s new book “Cure: A Journey into the Science of Mind Over Body” such a well-researched page-turner.
Marchant devotes several chapters to the burgeoning field of placebo studies. She reveals that though placebos are “fake,” the body’s response to them are anything but. “[Many of the] same biological changes that are happening when you take a drug are also happening when you take a placebo,” Marchant says. “They’re not imaginary. They’re real, biological changes.”
All of this raises questions about the role of culture, environment and neurochemistry in our responses to treatment — and may very well lead to widespread changes in the ways we practice medicine.
Though placebo effects have been around as long as people have been selling snake oil, philosopher Michel de Montaigne is credited as being one of the first to describe the phenomenon when in 1572 he wrote: “There are men on whom the mere sight of medicine is operative.”
It earned its place in the medical literature when T.C. Graves described “the placebo effect” in a paper published in The Lancet in 1920. Forty years later, the effect was embraced officially when placebo-controlled clinical trials became de rigueur.
Even so, placebos had developed a negative reputation. Popular medical opinion held that the effect was primarily illegitimate reactions made by “suggestible and neurotic” patients. The notion of the “natural history effect,” in which many patients recovery over time without intervention, accounted for much of its power, and ethical issues involved in actively deceiving a patient made certain that placebos would not be seriously studied as a curative in mainstream medicine. These notions, though, were upended thanks to emerging neurobiological studies of how the brain responds to placebos. In 1978, scientists at the University of California administered placebo saline injections to patients recovering from oral surgery. The majority of patients reported symptom relief, until researcher Jon Levine injected the patients with naloxone, a drug that blocks the effects of endorphins in the brain. The patients’ pain returned. “This was the first evidence of biochemical pathways behind the placebo effect,” writes Marchant. “It isn’t trickery, wishful thinking or all in the mind. It is a physical mechanism, as concrete as the effects of any drug.”
With the advent of more sophisticated brain imaging, like fMRI and positron emission tomography scans, researchers revealed that some of the brain’s neurotransmitters, endorphins, dopamine and cannabinoids, are involved in the placebo effect. In other words, mere suggestion can set off an elaborate dance of neurochemicals. Other studies followed. In one, a group of Parkinson’s patients who believed they were getting a dopamine agonist drug but instead received saline injections, experienced “dopamine levels [that] tripled, equivalent to a dose of amphetamine in a healthy person,” writes Marchant. These were incredible findings — testaments to the power of the mind to cure the body with mere suggestion. It is important to note the limits of these placebos, however. They show the greatest effect on conscious symptoms — like pain, nausea and fatigue. Believing you are receiving chemotherapy, for example, will not shrink a tumor. Specific areas in our brain appear to be activated by the placebo response, says Ted Kaptchuk, the director of Harvard’s program of placebo studies. These areas include the prefrontal cortex, involved in planning and expectation, and the anterior cingulate gyrus, which (among other things) monitors blood pressure and heart rate.
“We have the beginning of a neurobiology of the placebo,” says Kaptchuk. “The medical world is becoming more comfortable with its legitimacy.” Kaptchuk also points to emerging evidence that there is a dopamine-regulating gene that might make some of us more susceptible to the placebo response. That might mean that our placebo response is written into our DNA. But there’s more to the story than our genes, explains Kaptchuk. “Ultimately placebo is about culture,” he says. “The sugar, the cellulose in that pill does nothing. It’s because of the context that surrounds the pill. That’s cultural, psycho-social.”
Everything from what country we live in to our favorite soccer team to our personality plays a role in how we respond to placebos. Blue pills are often marketed as sleeping pills because of the color’s association with calmness. But this is not so with Italian men, who associate the color with their national soccer team. The form that the placebo takes also makes a difference in response. Sham surgeries fare far better in most countries, except those in Europe, where pills are perceived as more effective. In the US, fake pills work better for sleep, but sham acupuncture is better for pain relief.
A meta-analysis that compared placebo responses around the globe found that Brazilians had the lowest placebo effects — 7 percent healing rate — while the world’s average is 36 percent. Germany ranks the highest with a 59 percent response rate, which is three times its neighboring countries, Denmark and the Netherlands. Placebo responses even vary within countries. Though Germans had the highest responses overall, they reported higher placebo effects in ulcer studies than hypertension ones, which were below the global average.
Your perspective on the world — if you see the cup half empty or half full — plays a role, too. Take, for example, the traditional view that placebo-responders are more gullible and neurotic than non-responders. “In fact, the opposite is true. Engaged, optimistic people are most likely to experience the placebo effect. People who are negative, angry, hostile are least likely to experience [it],” Marchant says. Price is also a factor. A 2008 study out of the University of Cincinnati eyed 12 patients with Parkinson’s. One group was given an “injectable dopamine agonist” (really saline solution) that cost $100 per dose; another group was given the same injection but were told it cost $1,500. Sixty-seven percent showed a marked improvement with the more expensive treatment, while 58 percent showed an improvement with the cheaper placebo. Even giving a person a choice between two fake options improves outcomes, according to a study published this month in the Annals of Behavioral Medicine.
When groups were able to choose between what they thought were two name-brand beta-blockers they reported less side effects (or nocebos, placebos’ evil twin) and greater positive outcomes. So, what are the practical implications for clinical care? Marchant cites the study comparing placebo reactions to pain medications as a clue to what can be done on a larger level in medicine. In this study, Americans — unlike Europeans or Asians — showed a marked increase in the placebo response since 1990. This rise in response, she says, can be partially credited to the studies themselves, which tend to be larger, longer and of a higher quality than typical US patient care, which in turn create higher expectations and larger placebo effects. “It suggests that regardless of what drugs are prescribed, simply improving the quality of care might have significant benefits for patients in chronic pain,” Marchant says. This is supported by placebo research.
Studies suggest that a doctor’s body language and whether or not doctors actually believe that a drug will help a patient can influence the patient’s response to treatment. The amount of time a doctor spends with his patient can also alter placebo responses: In a study of acid-reflux sufferers, the group that had a 42 minute consultation with a doctor did twice as well as one that only had 18 minutes. Another study of people with irritable bowel syndrome used the same placebo but had a cold but efficient doctor administer it to one group and a warm and empathetic one administer it to the other. The response rates jumped nearly 20 percent with the warmer doctor, despite using the same “treatment.”
How you present the drug also making a difference. Using a phrase like “I believe this will help you,” instead of “This might work,” makes a difference in treatment response, studies show. There’s also evidence that you don’t need to be sick to reap the benefits of a placebo response. The University of Glasgow tested this assumption on 15 recreational runners, whose race times increased by 1.5 percent when they believed they were receiving powerful doping drugs but were only getting saline injections. And then there are the studies testing the use of placebo without deception. Though the research is young, Kaptchuk is enthusiastic.
These “open label” placebos have worked on patients with IBS, depression and migraine — even when explicitly presented as “like a sugar pill.” “It’s still very preliminary, and we’re very excited,” he says of his research. “It’s a new frontier in the placebo world.” In the mean time, doctors can harness the strength of the mind and the power of care when treating patients, says Marchant ( via ).

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