For years, experts have known that placebos - fake injections and pills with no real medication - can improve the health of patients with pain, asthma, high blood pressure and angina.
Now they've learned that raising the price of a fake pill makes it work even better.
A report this week in The Journal of the American Medical Association shows that expectations - shaped by factors that include the price of a medication - play a key role in how we respond to pain relievers and our response to therapies for depression, cancer, stroke or heart attack.
The new report adds to a store of knowledge about placebos, a subject that has long fascinated scientists. Understanding placebos could unravel mysteries about the body's ability to heal itself, they say.
Experts do know one reason placebos work: They raise our expectations. Make someone believe that a tablet will make a headache disappear and it often does - even if it turns out to be a sugar pill.
"Expectations create a different reality for us, which we don't really appreciate," said Dan Ariely, a behavioral economist at Duke University.
Researchers typically use placebos as controls in clinical trials of medicines and other therapies. Some volunteers get the real drug, while others get identical-looking placebos. It's not unusual for placebos to work almost as well as, and in some cases better than, the drugs being tested.
In the latest study, Ariely applied electric shocks to the wrists of 80 volunteers before and after giving each one a placebo painkiller. He told half that the pills cost $2.50 each, and told the other half that they cost 10 cents apiece.
Bottom line: about 60 percent of the 10-cent group reported pain reduction from the placebo, compared with 85 percent of the "higher-priced" group. None of the test subjects, who received $30 for their trouble, actually received a painkiller.
"It says something about our expectations and how they shape reality," Ariely said. "Price is just one of the things we use to make inferences."
Experts say the results also show the importance of boosting the hopes of patients treated for a wide variety of ailments.
"Our response to any intervention is partly the result of the power of the intervention, and partly the result of our expectations going in," said Alan Bellack, a professor of psychiatry at the University of Maryland School of Medicine.
Placebos have improved outcomes in studies of chronic pain, anxiety, high blood pressure, angina, asthma, ulcers, Parkinson's disease and rheumatoid arthritis, said Irving Kirsch, a psychologist who studies placebos at the University of Hull in England.
Kirsch reviewed 35 clinical trials of antidepressants, submitted by drug companies to the FDA, and found that placebos did just as well as the real drug with moderately depressed patients.
The review, published last month in The Public Library of Science, also found only a small, "clinically insignificant difference" between placebos and the real drugs among patients who were severely depressed. Even so, Kirsch said that patients on antidepressants should talk to their doctors before stopping them.
So, how do placebos work their magic? Researchers have known for years that they trigger a biochemical response in the brain, releasing neurotransmitters such as dopamine that act as natural painkillers. They also know that packaging can enhance the effect.
If researchers wear white lab coats, talk in a soothing voice or somehow instill confidence in volunteers, the placebo is usually more effective, said Dr. Donald Price, a neuroscientist at the University of Florida who has studied the subject for 30 years.
Coloring a tablet red makes it work better than a white pill, he said. Showing volunteers the placebo as they receive it enhances its effect compared with telling a volunteer he will get it through an intravenous feed at some indeterminate future time, he said.
"Little things can make a big difference in terms of any benefit that accrues to the patient," Price said.
But Ariely's study is the first to show that a higher price might enhance a placebo's effect.
"This applies in a very broad way to human beings in a variety of settings," Price said. "It doesn't just apply to medicine. It's sort of a ubiquitous principle."
The pricing effect might also explain the reaction of 20 students at the California Institute of Technology who had their brains scanned while sipping wine they were told cost either $90 a bottle or $5 a bottle.
When they thought they were sipping the expensive stuff, the scans showed increased activation of the brain's pleasure center- even when they were actually sipping from the $5 vino.
"A lower price creates an expectation of inferiority," said Hilke Plassmann, the neuroeconomics researcher at Caltech who led the study. "The expectation is a crucial part of an outcome."
That might also be why optimists usually do better than pessimists in many studies of patient recovery rates, experts say.
Researchers at McGill University in Montreal who tracked 100 patients with head or neck cancer found that optimists had a greater chance of surviving a year after diagnosis, regardless of how advanced the illness was when diagnosed.
Another team at Carnegie Mellon University spent a year tracking 300 patients who had coronary bypass operations in the 1990s. Patients with a positive attitude - measured by a simple personality survey - were significantly less likely to be rehospitalized within a year .
"It's not just that optimistic people feel better, they actually do better," said Michael Scheier, who is head of the psychology department at Carnegie Mellon.
One explanation: Optimists might have better coping strategies, seeking advice from doctors and support from friends rather than becoming fatalistic.
"Expectations do influence behaviors. They influence how you think about stroke and how you respond to it," said Lynn Grattan, a neurology professor who has studied stroke recovery rates at the University of Maryland School of Medicine.
To find out whether you're an optimist (and a good candidate for placebo therapy) visit The Sun's Maryland Med Blog at weblogs.baltimoresun.com/maryland/doctor/blog.