Studies Hint at Placebos’ Potential


by Melanie Leitner

January, 2006

Researchers have often viewed the placebo effect as a con-founding factor in clinical trials, and thus have tried to minimize it. Now some are taking the opposite approach and studying how the placebo effect occurs and could be harnessed to help with treatment.

The placebo effect is a beneficial health effect experienced by an individual that appears to occur because of the individual’s beliefs or expectations, rather than by effecting chemical or biological changes. Trust in caregivers and faith in the medical process, for example, can help a patient benefit from a pill or a procedure that should not make a difference on its own.

In the past few years, neuroimaging researchers have identified significant changes in the brain’s activity resulting from placebos. Others, studying the brain’s chemistry, have also begun to unravel the placebo response. At the conference, researchers discussed recent findings regarding what is happening in the brains of individuals experiencing the placebo effect, focusing in particular on studies of placebo responses in Parkinson’s disease, depression, and pain conditions.

Fabrizio Benedetti, a neuroscience professor at the University of Torino Medical School in Italy, presented the results of several studies aimed at dissociating a given treatment’s biological effects from its psychosocial context: the words of a patient’s doctor, the hospital environment, and a patient’s expectations of improvement, for example.

Benedetti and his colleagues showed that in some patients with Parkinson’s disease, merely expecting to benefit from treatment could induce changes down to the firing of a single brain cell, and these changes in firing correlated with improvement in both the patient’s subjective experience of muscle rigidity and a clinician’s assessment of Parkinson’s symptoms. Not all patients responded to the placebo treatment, and those who were placebo nonresponders failed to show changes in either neuronal firing rates or in muscle rigidity.

To further isolate the role psychosocial context plays in mediating therapeutic benefit, Benedetti and his team used computers to administer actual treatments that are known to alleviate symptoms. However, patients were unable to detect when they had received treatment, as there were no obvious indications (no nurse appearing at the bedside to administer an injection, for example).

The researchers found that the hidden therapies were significantly less effective in patients with Parkinson’s or pain than open or expected therapies, even though the actual treatments were the same. These studies indicate that expectation is a major component of therapeutic benefit, even with real drugs, and that placebos may benefit patients for the same reason.

Preliminary research from Benedetti’s team suggests that when expectations are reduced, as occurs in people with dementia, the effects of treatment may also decrease. This finding, if confirmed in larger studies, could hold important implications for treatment approaches in diseases such as Alzheimer’s.

Other researchers have used positron emission tomography scanning to make sense of the role of the placebo effect in treating depression. Helen Mayberg, a professor of psychiatry and neurology at Emory University, found that placebos caused changes in brain activity similar to those observed when patients took antidepressant drugs, and that these changes were very different from the changes that occurred following cognitive-behavioral therapy. Her studies show that antidepressant drugs and cognitive-behavioral therapy, each of which relieves depression in some individuals, appear to operate via different brain circuits.

Mayberg stressed that although there were similarities between placebo- and drug-induced brain changes, the changes in the brains of those who responded well to the drugs were over and above those seen with placebo. “Placebo is not a drug substitute,” Mayberg said. “Relapse rates for depression are higher in patients receiving placebos.”

Imaging studies conducted by Tor Wager, an assistant professor of psychology at Columbia University, have examined the brain circuits involved in placebo-induced alleviation of pain. His group found that areas involved in generating expectations, particularly areas of the prefrontal cortex, showed increased activity following placebo treatment. These findings indicate that changes in subjects’ anticipation of pain are an important part of the placebo effect.

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In someone with Parkinson’s disease who responds to a placebo, arm rigidity and neuron firing decrease after a placebo is administered, as shown at left. The arrow represents the administration of the placebo. In a Parkinson’s patient who does not respond to placebo, right, rigidity levels remain constant and the change in neuron firing is negligible. © 2005 by the Society for Neuroscience

Wager’s team found that treatment with a placebo also lowers activity in brain areas associated with the actual subjective experience of pain, such as the insula. “A placebo treatment can change how your brain processes pain while it’s happening,” Wager said.

Christian Stohler, dean of the school of dentistry at the University of Maryland, and Jon-Kar Zubieta, associate professor of psychiatry and radiology at the University of Michigan, took a different approach. Their research team explored whether expectations of pain relief from placebo treatment caused the brain to release its own antipain chemicals, known as endogenous opioids or endorphins.

Their team found that placebo treatment did indeed appear to cause increases in endorphin release, as detected by positron emission tomography scans. Stohler and Zubieta conclude that placebos exert at least part of their pain-relieving effects by increasing opioid release in the brain. The brain areas where endorphin release was greatest corresponded with the areas Wager’s group found to be active in the functional imaging studies of placebo-mediated reductions in pain.

Major challenges lie ahead in this relatively young field, the researchers agree. Future studies must examine other conditions and identify the differences between placebo responders and nonresponders.

“The meaning ascribed to an event has important health implications,” Wager said. “Your expectations can have profound impacts on your brain and on your body. … We are just beginning to learn how that process works in the brain. We also have much to learn about what kinds of placebo treatments produce neurobiologically meaningful outcomes.”

Placebos’ promise, Zubieta emphasizes, lies in their potential to be used with other drugs—not instead of them. “It is an additive effect, not a substitutive effect, in many ways,” he says.