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Even as scientists discover more and more examples of the placebo effect, they have been stumped by one big mystery: How does it get out of the head and into, say, the immune system?

A study published on Monday takes a step toward answering that question, at least in lab mice.

It is a giant step from mice to people, but the idea is this: in people, the brain’s reward circuitry becomes active when we anticipate, for instance, recovering from depression or banishing pain, as brain imaging has shown. That circuitry then activates neurons that wend their way from the brain to organs, including those of the immune system.


Presto: Expecting to recover from, say, infection or illness triggers an immune response that makes expectation reality. That might explain how, for instance, the placebo effect can slightly reduce how long and how badly someone sniffles and sneezes, as a 2011 study found.

“This is an exciting paper,” said neuroscientist Tor Wager of the University of Colorado and a leading placebo researcher who was not involved in the new study. “It’s a powerful proof of concept regarding functional connections” between the brain and the immune system, and “fills a gap” in science’s understanding of the connections between them.


Until now, research on the placebo response has made more progress explaining its effect on circuits within the brain, such as those involved in perceiving pain or feeling depressed, which are directly connected to the circuits that placebos activate.

But the immune system is controlled by organs like the thymus, spleen, and bone marrow. How do brain signals reach them?

To find out, neuroimmunologist Asya Rolls of Technion-Israel Institute of Technology, and her colleagues infected mice with E. coli bacteria and then activated neurons that make up the reward circuit in the animals’ brains. That seemed to turbocharge the animals’ immune systems. Compared with mice whose reward circuit had not been activated, the manipulated mice unleashed many more immune-system cells to engulf and devour the bacteria.

Those mice also had many fewer bacteria in their liver (where E. coli tend to go) and more anti-E. coli antibodies. Their immune system kept responding this way even when E. coli were injected a month later.

The bridge connecting the activated reward circuitry to the revved-up immune system seemed to be what’s called the sympathetic nervous system, better known as the fight-or-flight system (in general, it responds to emotional events). The neurons that constitute this circuit wend their way from the brain to organs including the spleen and thymus, and when the scientists destroyed them, the reward circuitry had no effect on the immune system. The bridge from brain to immune system had been severed.

Claims about the placebo effect have triggered a backlash from physicians who believe it is credited for too much.

One of those critics, Dr. Harriet Hall, said that in the new study, published in Nature Medicine, “they are looking at surrogate measures, not actual disease outcomes. I suspect this is one of those things where a statistically significant change can be measured but where there is no clinically significant response,” like healthier mice. And Colorado’s Wager warned that the results “do not mean that all things that activate the reward system will change immunity.” Don’t expect winning at poker to keep you from getting the flu.

But if the extra antibodies and immune activity do keep the mice healthier, and if the human reward circuitry works anything like it does in the rodents, it may explain how human brains turn expectations of good health into actual good health, and, therefore, how homeopathic remedies and other sham treatments can sometimes “work.”