Placebos have helped to ease symptoms of illness for centuries, despite their lack of active ingredients. They have also been a fundamental component of clinical research to test new drug therapies for more than 70 years. But why some people respond to placebos and others do not remains under debate.

With the advent of genomic sequencing, researchers are learning that placebo responses may be modified by a person’s genetics, a discovery that raises important new questions regarding the role of the placebo in patient care and in drug development: How many genetic biomarkers exist? Can the medical field harness the placebo response to enhance personalized medical treatment? What might be the impact of placebo-drug interactions? And what will this new information mean for randomized clinical trials, which depend on placebo controls to test the efficacy of new drug candidates? Should a “no treatment” control be added to future trials?

Harvard Medical School researchers from the Program in Placebo Studies (PiPS) at Beth Israel Deaconess Medical Center and from the Department of Medicine at Brigham and Women’s Hospital explore these provocative issues in a review of evidence from placebo studies and randomized clinical trials. Published online today in Trends in Molecular Medicine, the article introduces the concept of “the placebome” and identifies a network of genes that could influence medicine and clinical trial design.

“Genomics is revealing that the placebo response is, in fact, a complex phenotype with an unfolding physiology,” said corresponding author Kathryn Hall, a PiPS Research Fellow in the Division of General Medicine and Primary Care at Beth Israel Deaconess and Harvard Medical School. “The study of genomic effects on the placebo response—what we call ‘the placebome’—is in its infancy, but there is already ample evidence that genetic variations in the brain’s neurotransmitter pathways modify placebo effects. As a result, placebo responses are emerging as a legitimate series of biological reactions that must be rigorously characterized for efficient pharmaceutical development and optimal patient care.”

The article focuses on several key concepts for future research and discussion regarding the role of the placebome in health care.

The placebo effect occurs when patients show improvement from treatments that contain no active ingredients. Scientists initially used behavioral instruments, such as personality measures, to predict which patients would respond to placebos, but over the past decade, the development of sophisticated neuroimaging technologies illuminated the activation of the brain’s neurotransmitter pathways in response to placebos.

“Because they are the chemical messengers that either excite or inhibit nerve function in the brain, many neurotransmitters play key roles in reward and pain,” explained Hall. “We hypothesized that genetic variation in the genes that encode the proteins in these neurotransmitter pathways might also modify placebo responses.”

In 2012, Hall identified the first placebo biomarker, the catechol-O-methyltransferase (COMT) gene, reporting that genetic variations in COMT—which influence the brain’s levels of the neurotransmitter dopamine—also determined the extent of an individual’s placebo response.

A review of the scientific literature over the last 10 years provided evidence for genetic variation in other neurotransmitter pathways that modify placebo response. These include the opioid, endocannabinoid and serotonin pathways— suggesting the potential existence of a placebome or network of genes.

But what if placebo responses and drug responses share the same brain pathways?

“We’re discovering that the placebo is not the only component in the placebo effect,” explained the paper’s coauthor Ted Kaptchuk, director of the PiPS at Beth Israel Deaconess and professor of medicine at HMS. “These neurotransmitter pathways, which are modified by genetics, are pathways that both drugs and the placebo act on. This now suggests that a drug could change a placebo response and a placebo response could modify a drug response.”

This adds to the complexity of the placebome and underscores the importance of understanding how it fits into larger more complex networks.

“The possibility that there could be a placebo-drug interaction as a result of genetic variation in placebo pathway genes suggests that we need to refine and recalibrate the assumptions of placebo controls in randomized clinical trials,” the authors wrote. “An important next step in describing the placebome would be to include a no-treatment control in placebo-controlled randomized clinical trials. This approach might be cost effective and allow for a broad view of placebo response genes and other molecules across varying conditions and treatments.”

As the gold standard for pharmaceutical research, randomized clinical trials include a placebo arm, which is designed to control for the nonspecific, nonpharmacological effects that are part of the administration and receipt of clinical treatment (i.e., the way a doctor is dressed, the way he or she describes what to expect from a drug, even the physical appearance of the doctor’s office). But in order to properly study the placebo response, the authors propose that a no-treatment control arm needs to be incorporated into the trials.

“The best control for a drug is a placebo, but if you want to study placebos you need a no-treatment control,” said Hall. “This is one of the major limitations in the scientific literature, but we believe that this could be addressed prospectively by including such an arm in future clinical trials.

“Knowledge of the placebome has the potential to guide development of novel strategies for both identifying placebo responders and clinical trial design,” she added.

The authors are supported by the following grants from the National Center for Complementary and Alternative Medicine and the National Institutes of Health: T32AT000051; 2K24 AT004095; R01 AT005280; R01 AT004662; P01 AT006663.

Adapted from a Beth Israel Deaconess news release.