Placebos Could Play a Role in Treating Some Conditions, Scientists Say By LILA GUTERMAN
Washington
The placebo effect -- it's all in your head. When you swallow sugar pills instead of powerful medicine and your symptoms disappear, it's all thanks to the power of your mind.
How does the brain perform that parlor trick? In the past, scientists suspected that any apparent health benefits from placebos had little more basis in biology than did sleight of hand. In studies of new drugs, patients might tell their doctors they feel better because they think that is what their doctors want to hear. Or perhaps they would have recovered without any treatment, real or sham.
But researchers now know that the placebo effect is real and grounded in the physiology of the brain. Using techniques to peer inside the skull, they have begun to find regions of the brain that respond to placebos, and they have even watched a single nerve cell react to a sham medicine.
Those studies show that placebos affect the brain in much the same way that actual treatments do, researchers reported here last week at the annual meeting of the Society for Neuroscience. In other words, the power to treat several troublesome disorders may be wrapped up in the three-pound spongy lump of tissue protected by the skull.
The research points to the power of positive thinking -- even at the unconscious level. When the brain expects relief, it can manufacture some on its own. "The things you can change with a positive outlook are profound," said Tor D. Wager, an assistant professor of psychology at Columbia University. "They are deeper physiologically than we have previously appreciated."
None of the researchers who study the mechanism of the placebo effect suggest that doctors should prescribe dummy pills instead of real medicine. But they say that the study of the placebo effect could change how scientists perform clinical trials of new treatments and could even alter how we understand and treat pain, Parkinson's disease, and depression.
By studying placebos, said Christian S. Stohler, dean of the school of dentistry at the University of Maryland at Baltimore, "you crack into disease mechanisms that might be very important for improving the lives of many pain patients."
Fooling the Patient
Researchers gained their first glimpse at the causes of the placebo effect in the late 1970s, when scientists discovered that under certain conditions they could cancel the effect. In a study of pain relievers, a drug called naloxone prevented patients on placebo pills from experiencing the usual benefit. Since naloxone blocks the action of painkillers called opioids, researchers figured that placebos must stimulate the brain to produce its own opioids.
In the 1990s, another set of experiments provided more evidence that the placebo effect was a real physiological phenomenon. Fabrizio Benedetti, a professor of neuroscience at the University of Turin, and others studied the effect without using a placebo.
Dr. Benedetti judged that a placebo's effect comes from the patient's psychosocial context: talking to a doctor, observing the treatment, and expecting improved health. So he took away that context by giving study participants real drugs, but on the sly.
Patients were told that they would receive an active drug, a placebo, or nothing through intravenous needles, and consented to get any of the different treatments without knowing when any treatment would be supplied. The scientists compared the results when a doctor overtly gave the patient the drug and when a computer supplied the drug without the patient's knowledge. Bedside manner, it turned out, made a difference: Patients required far more painkiller if they unknowingly received the medicine from a computer.
When the doctor gives a drug in full view, Dr. Benedetti said at the neuroscience conference, "there is an additive effect of the drug and of the placebo, the psychosocial component."
He suggested that his experimental setup could be extended to become part of the testing procedure for new drugs. Clinical trials could then compare covert and overt administration, rather than comparing the active drug to a placebo. That way, none of the volunteers would go through the trouble of participating without receiving the real experimental treatment, and researchers could still demonstrate that the drug was effective by showing that it reduced symptoms when given covertly.
Peering at the Brain
With the recent advent of modern brain-scanning techniques, scientists gained the ability to look directly at the regions of the brain involved in the placebo effect. In 2002 researchers in Finland and Sweden published in Science the first brain images of the effect, using a technique called positron emission tomography, better known as PET.
The researchers pressed a hot surface onto the hands of nine male volunteers, and then a doctor gave them injections of either a painkiller or a placebo. When the researchers performed PET scans on the men, both the drug and the dummy induced high blood flow -- indicating brain activity -- in an area of the brain called the rostral anterior cingulate cortex. That area plays a key role in the painkilling effects of opioid drugs.
Then in 2004, also in Science, Mr. Wager reported using functional magnetic resonance imaging, or fMRI, to show that a placebo that relieved pain also decreased activity in the brain's pain-sensing areas.
Different people felt varying amounts of pain relief from the placebo. The amount of pain reduction a volunteer experienced went hand in hand with the amount of change in activity in the brain.
"Part of the effect of a drug," Mr. Wager said at the conference, "is it changes the way you think about drugs."
Jon-Kar Zubieta, an associate professor of psychiatry and radiology at the University of Michigan at Ann Arbor, and several colleagues, including Dr. Stohler, of the University of Maryland, peered deeper into the brain's workings by finding out where the brain produces opioids in response to placebo treatment.
They used PET scans along with a stain that marks opioid activity in the brain. When the researchers gave male volunteers a painful injection of saline solution into their jaw muscles, the scans showed an increase of opioids in the brain. Most of the regions where the brain produced painkillers coincided with the ones that Mr. Wager identified as important.
"Expectation releases substances, molecules, in your brain that ultimately change your experience," said Dr. Stohler. "Our brain is on drugs. It's on our own drugs."
Relief for Parkinson's
The placebo effect helps not only people in pain but also patients with diseases. In fact, scientists got their most detailed look at the placebo effect by studying how single neurons responded to sham drugs given to Parkinson's patients.
Parkinson's disease is a motor disorder caused by the loss of brain cells that produce dopamine. Some patients experience temporary relief of symptoms from a placebo, and a previous study showed that the relief occurred because the brain produced dopamine in response.
Patients who have Parkinson's disease sometimes receive surgery to implant electrodes deep within the brain. The electrodes can stimulate a neuron or record its activity. Dr. Benedetti, of the University of Turin, and his colleagues enrolled 11 patients who underwent surgery for that type of treatment. They gave the patients a placebo injection, telling them it was a powerful drug that should improve their motor control. The researchers then compared the activity of a single neuron before and after injection of the placebo.
In the six patients who responded to the placebo -- who demonstrated less arm rigidity and said they felt better -- the rate of firing of the neuron went down. (Nerve cells "fire," or generate electrical impulses, in order to send signals to neighboring neurons.) The neurons' firing rate did not change for people who experienced no placebo effect.
Another disorder that shows clinical improvement with placebos is depression. Depressed patients' moods often lift when they take a placebo, although the effect does not last, and they normally need to seek real treatment, according to Helen S. Mayberg, a professor of neurology and of psychiatry and behavioral sciences at Emory University.
Dr. Mayberg became immersed in placebo research a few years ago, when she did a PET study of the brain's response to an antidepressant and to a placebo.
In her study of 15 depressed men, four who had taken Prozac and four who had received a placebo experienced a remission of their symptoms. At the end of six weeks, after allowing the drug sufficient time to take effect, Dr. Mayberg took PET scans. For patients whose symptoms improved, the regions where the brain activity increased after a patient took a placebo formed a subset of the regions that increased after a patient took the true drug.
"Drug is placebo plus," she said at the conference.
In patients whose symptoms did not improve, whether they were on Prozac or on the placebo, the brain activity did not increase in those regions.
She published the results of that study in 2002, but at the conference she reported a new analysis of her data. In the study, she had also collected brain scans one week after patients had begun receiving their treatments, even though the drug had not yet taken its full effect.
Still, people whose symptoms later improved, whether they took the placebo or Prozac, again had increased brain activity in similar areas. One week into treatment, she said, the men's state of mind could be interpreted as a "heightened state of expectation" since they were anticipating clinical improvements. Nonresponders did not show those patterns, so such expectation could be key to whether a depressed patient will recover.
Raising Expectations
Dr. Mayberg would like to find ways to help those who do not respond to antidepressant drugs, and she surmises that expectation could make the difference. Such patients, she said, perhaps should imagine themselves getting well. "What is expectation?" she asked. "How do you cultivate it?"
Those are questions that all of the scientists involved in this research would like to answer. Patients with chronic pain, said Dr. Zubieta, of Michigan, perhaps have lost the ability to produce the brain's natural painkillers. "If you are able to recruit mechanisms that help you cope with stress or pain, that's a good thing," he said, "The question is, How do things like this, or meditation, or biofeedback, work? We don't know."
Dr. Stohler, of Maryland, agrees. "Getting a person to boost their own machinery to improve health -- that's something that medicine needs to know," he said.
It may be especially urgent for patients with dementia, according to Dr. Benedetti. At the conference, he reported preliminary results that patients with Alzheimer's disease may not experience placebo effects at all. He found that Alzheimer's patients felt no difference between overt and hidden administration of painkillers. To Dr. Benedetti, that suggests that the psychological components of treatments -- the expectation of health improvements, and the circuits that such expectations create in the brain -- are absent.
Perhaps, he said at the conference, doctors need to take that loss into account when prescribing any drug for Alzheimer's patients. Those patients may need higher doses of many drugs, such as painkillers, if their brain has stopped aiding the drug's action.
The mind, it seems, may play a critical role in treating diseases. And its services come free of charge, with no co-payments or deductibles.