Researchers are beginning to explore whether the genetics of patients who experience a placebo effect are different from those of patients who don't. It's well known that people can feel better if they believe they are receiving treatment, but the biological pathways involved are relatively unexplored. In a new review, publishing April 13 in Trends in Molecular Medicine, scientists at Beth Israel Deaconess Medical Center discuss what we know as well as possible ethical issues related to conducting genetic tests to determine whether a patient is a placebo responder.

"Understanding the placebome--the collection of genes related to placebo responses--opens possibilities to improving patients' responses to clinical care and pharmaceuticals and to refining research designs for detecting drug-placebo differences," says lead author Kathryn Hall, PhD, a member of Beth Israel Deaconess Medical Center's Program in Placebo Studies.

Past studies have revealed that certain signaling pathways in the brain--especially the dopamine, opioid, endocannabinoid, and serotonin pathways--help mediate the placebo effect. Hall and her colleagues examined evidence that genetic variations in these pathways can modify the placebo effect; their findings raise the possibility of using genetic screens to identify placebo responders. Such information could lead to better patient selection for clinical trials--for example by pointing to those who should be excluded because they are likely to experience a benefit no matter what treatment they receive or by ensuring that potential placebo responders are evenly allocated across treatment arms.

Hall notes that if the placebo response is influenced by certain brain signaling pathways, then it might also affect patients' responses to drugs that target those same pathways, and the magnitude of the drug effect might differ from one patient to another as a result of their genotype.

"These are novel hypotheses that, to our knowledge, have not yet been discussed in the scientific literature," she says. "This broader conception that points to more personalized medicine calls for additional research." Her group proposes including no-treatment controls in addition to placebo controls in some future clinical trials. "Our proposal to incorporate a formal placebo study into future clinical trials is innovative and could represent significant cost savings, leading to rapid access to knowledge of mechanisms involved in the placebo response across a wide variety of disease and drug regimens," Hall says.

A number of ethical issues must be considered if genetic profiles of placebo responders can be established. If high placebo responders are not included in clinical trials, this raises several important questions. For example, how will the drugs be labeled, and which patients will be approved for treatment in light of the fact that the drugs will have only been tested in placebo non-responders? Should physicians test for genetic placebo-response propensities and should patients be allowed to refuse permission to be tested? Should patients be told about their propensity to respond to placebos, and could patients refuse to know or refuse to have this designation in their medical records? Would physicians be able to ethically use this information and, if so, how? And of course, what if knowing one is a placebo responder affects one's placebo response?

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This study was funded by the National Institutes of Health and the National Center for Complementary and Integrative Health.

Trends in Molecular Medicine, Hall et al.: "Genetics and the Placebo Effect: the Placebome" http://dx. doi. org/ 10. 1016/ j. molmed. 2015. 02. 009