Why do placebos work? Scientists identify key brain pathway

Study finds opposite impacts on brainstem of placebo and “nocebo” effects

The placebo effect can bring powerful relief—but what does that look like in your brain? A new study finds fake therapies and fake side effects have a real impact on your brainstem, a hub of pain processing, affecting it in opposite ways. The work could help scientists develop better treatments for chronic pain. 

It’s “a major rigorous contribution to the field,” says Ted Kaptchuk, a biomedical scientist at Harvard Medical School who was not involved with the study. Still, he cautions that more work is needed to see whether this laboratory-based study translates to the real world.

Scientists have known about the placebo effect for more than 400 years. In 1572, a French philosopher wrote that “there are men on whom the mere sight of medicine is operative.” Yet researchers have struggled to understand why patients given a nonactive therapy such as a sugar pill still feel relief. They’ve also been confounded by the opposite phenomenon: When patients are told a placebo has harmful side effects, they often feel bad afterward—the so-called “nocebo” effect.

To find the signature of these two effects in brain, researchers brought 27 participants—13 men and 14 women with an average age of 23—into their laboratory at the University of Melbourne. The scientists strapped a device called a thermode to their arm, which heated up to a moderately painful temperature. Afterward, the researchers told the participants they were applying one of three creams to the affected area: a pain reliever, a pain inducer (which would make the heat feel worse), and a control cream with no effect. In reality, all three substances were petroleum jelly. 

All the while, the team scanned the volunteers with a high-resolution functional magnetic resonance imaging (fMRI) machine to detect which parts of their brain were most active. Most participants in the study experienced either the placebo or nocebo effect. About one-third reported lower levels of pain when the “pain reliever” was applied, whereas slightly more than half reported more pain when the “pain inducer” was applied. 

The fMRI results reflected these responses. Both the placebo and nocebo effects influenced activity in the brainstem, the researchers report this week in The Journal of Neuroscience. The placebo effect increased activity in an area called the rostral ventromedial medulla, which relays pain information, and decreased activity in the periaqueductal gray, which helps the body suppress pain. The nocebo effect induced the opposite change. (The findings may seem counterintuitive, but multiple areas of the brainstem act in complex ways when it comes to creating the sensation of pain, the authors say.) 

The approach is excellent, says Tor Wager, a neuroscientist who studies the placebo effect at Dartmouth College. “It was done at ultra–high resolution, which makes it much better for identifying [parts of] the brainstem that play key roles in pain control.” Though other studies have shown brain activity in response to both the placebo and nocebo effects, he and other experts say the new work offers the most detailed view yet of how the brain responds to these phenomena. 

The results may offer a route for future treatments of chronic pain, says Lewis Crawford, a neuroscientist at the University of Sydney School of Medical Sciences and the study’s lead author. 

Doctors have applied electrical impulses to the brainstem—an approach known as deep brain stimulation—to treat burning “neuropathic” pain, which can be caused by nerve damage, as well as carpal tunnel syndrome, and cancer-related pain (such as that resulting from nervous system tumor invasion or radiation-induced nerve damage) with only mixed success for decades, he notes.

Part of the problem was an inability to identify exactly which parts of the brainstem are responsible for controlling the modulation of pain, Crawford says. By localizing placebo- and nocebo-induced sensations to more precise brain areas, the new study could help narrow down targets for stimulation, he says. 

Placebo or not, that’s a valuable dose of good news. 

doi: 10.1126/science.acx9483

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