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It's MORNING EDITION from NPR News. I'm Steve Inskeep. Today in Your Health, we're going to look more closely at one of the building blocks of the good science: placebos. You probably know them as sugar pills. For decades, placebos have played a major role in medical experiments and tests. But as NPR's Alix Spiegel reports, it looks like our response to placebos is changing over time.

ALIX SPIEGEL: A long time ago, when they were still young, Annette Doeschner and her husband George decided to go for a walk in the park. It was a beautiful day, the sun was shining, everything was perfect - or anyway, everything except for George's arm.

Ms. ANNETTE DOESCHNER: When we were in the park, his left arm wasn't moving. And he was walking and one arm just wouldn't move. You know, when you usually walk. So anyway, I noticed and I said, why isn't your arm working? And he said, I don't know, but my little pinky here is twitching, and I don't understand what that is.

SPIEGEL: Annette encouraged George to see a doctor about his pinky, and so he did. But the doctor had bad news. George had Parkinson's.

Ms. DOESCHNER: And I said, no, it can't be. He was crying. I was crying. It felt like the end of the world. It felt like a death sentence.

SPIEGEL: At that point, George was 40 years old, the father of four young children. It was horrible. Annette Doeschner says that there was only one very small ray of hope: science.

Ms. DOESCHNER: They told him it's a very, very slow progressing disease. It gives you time for scientists to come up with better cures - a treatment, actually, better treatments, perhaps one day a cure.

SPIEGEL: And so Annette and George waited for one day. Then, several years later, one day seemed to come. There was an experimental study. A doctor in Colorado was injecting fetal tissue into the brains of people with Parkinson's.

The experiment was relatively safe, but there was one catch: 40 people would be accepted into the study, but only 20 would get the real operation. Twenty would get a placebo operation. They'd go through everything that the real patients went through without getting the fetal tissue.

Why go through the trouble? Because the doctor knew that even fake surgery -placebo surgery - will often give people relief. So to find out what the real operation might do for his patients, he felt he needed to compare the effect of the real operation with a fake one. George agreed, and flew to Colorado for an elaborate surgery.

Ms. DOESCHNER: They put a crown on your head, screw it into your skull, because your head has to be real still.

SPIEGEL: And so then how many holes did they drill?

Ms. DOESCHNER: Four holes. Four holes was drilled into his skull.

SPIEGEL: Now, eventually, George Doeschner found out that he did not have the real operation. He got the placebo. And you might think that once told, he'd be a little put out about the four holes in his head. But his wife Annette Doeschner says no. She says she and her husband understand just how important placebos are.

Ms. DOESCHNER: This is science. How they ever do it, I don't know, but this is the way science works.

SPIEGEL: It's true. Over the last four decades, placebos have come to play this huge role in the medical research. And to understand more about that role, I called a researcher at Harvard University named Arthur Barsky. I needed Barsky to explain why it is that placebos, the proverbial sugar pill, the fake operation, why these things seemed to make people better when there's absolutely nothing to them. Barsky told me that one big reason is conditioning.

Dr. ARTHUR BARSKY (Professor of Psychiatry,�Harvard University): You've learned over the course of your lifetime that going to the doctor, being examined, having him write out a prescription, waiting in the line at the pharmacy, taking a pill, that that's generally followed by some benefit. So you've kind of learned a pattern of reacting that seems to be pretty powerful.

SPIEGEL: So the mere fact of participating in these activities often makes you feel better. Now, this is incredibly important when it comes to drug trials -studies that try to figure out whether or not a drug is working. Researchers feel that because of this placebo effect, they can't just give their drug to patients then ask them how they feel.

Dr. BARSKY: The question really is: Is your new medication more effective than a sugar pill.

SPIEGEL: Which is whey when there's a drug study in this country, much of the time the drug is compared to a placebo. But, says Barsky, this whole system is premised on some pretty big assumptions about�the ways that placebos work. You see, we really think of placebos as stable.

Dr. BARSKY: We have always assumed that it was a pretty constant effect, that the same person would have the same response to a placebo at different points in time. That similar illnesses would respond in a similar way to placebo. It was a constant, predictable, stable and very important phenomenon that you saw in any medical interaction.

SPIEGEL: But it turned out the placebo effect might not be as stable as we've assumed. Barsky recently published a study that found that in 2005, patients who were involved in testing drugs for depression responded to placebos way more than patients did back in the 1980s.

Dr. BARSKY: The placebo response was about twice as powerful than it was in the 1980s.

SPIEGEL: Let me repeat that: Placebos seemed to be twice as effective today as they were 30 years ago.

Dr. BARSKY: That's a pretty significant difference.

SPIEGEL: Now, no one, including Barsky, really knows why the placebo effect appears to be changing. But Ted Kaptchuk, another Harvard professor who studies the placebo effect full-time, says placebo drift, as it's now known, does appear to be real. He says it's shown up in more than just antidepressant trials. And one possible explanation, he says, is that there's been a change in our expectations. He points out that by 2005 for example, our belief in the power of antidepressant drugs was very strong.

Professor TED KAPTCHUK (Harvard Medical School): It was like if you have depression, an antidepressant will make you feel much better. You feel a lot of confidence. And that changed both providers' impression of what happened, and changes presumably, the patient's experience of what could happen.

SPIEGEL: But also, says Kaptchuk, it could be that because drug companies mostly pay for drug experiments, doctors who do the research have a subtle incentive to say the drugs are working. And since doctors don't know who's really taking the pills and who's not, the fact that they tend to see improvement in test subjects would also mean that those on the placebo would look better.

Then there's another possible explanation.

Prof. KAPTCHUK: Researchers, especially in pharmaceutical industry-sponsored trials, get paid for every patient they recruit.

SPIEGEL: But often, says Kaptchuk, it's just really hard to find people, so doctors will sometimes admit patients to trials who are not quite as sick as the trial requires, who simply aren't that depressed. And people who aren't that depressed are much more susceptible to the placebo effect.

Prof. KAPTCHUK: It's really hard to recruit people. And, you know, if it's borderline, put them in. And those people who aren't the borderline at the end, get a lower - got more - they are better in the placebo group.

SPIEGEL: Whatever the cause, placebo drift is something that has the potential to cause real mischief in medical trials.

As Barsky points out...

Prof. BARSKY: If the placebo response - that baseline is shifting all the time, then it really confuses the issue of whether the drug is effective or not.

SPIEGEL: The truth is that the process of science is just incredible messy -messier than most people know.

As for Annette and George Doeschner, their experience with science has also been messy.

What did you do today? Anything special?

Mr. DOESCHNER: I watched a movie on TV.

SPIEGEL: George and Annette are older now, in their 60s. They live in Long Island, New York. Years ago, after learning that George had had the placebo operation, they decided to go back and get the real thing. And at first, Annette says, it worked great: the tremors went away.

Ms. DOESCHNER: And next thing, before you know it, he started getting wild movements, waggling of the arm on the left side or the right side, and we're thinking, what's wrong? The tremor's gone, but now this movement.

SPIEGEL: It got so bad that they went for another new kind of surgery: deep brain stimulation, which has quieted much of the shaking.

Ms. DOESCHNER: And that's what he has today, and he looks just fine. And we're very happy about it. We'd be happier if there was a cure, but we're hoping for that.

SPIEGEL: In fact, says Annette, if there was another potential cure, she thinks she and her husband might consider it.

Ms. DOESCHNER: Where there's life, there's hope. And there's always something coming out, either better medication, treatment, something. I believe in that.

SPIEGEL: Even, Doeschner says, if it involves placebos.

Alix Spiegel, NPR News, Washington.

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INSKEEP: It's MORNING EDITION, from NPR News.

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