The placebo effect, where treatments with no active ingredients help to alleviate symptoms in some patients and not others, has been a mystery to medical science for the last 70 years. Now for the first time, researchers in the US reporting in PLoS ONE this week, describe how they found clues that might explain why the placebo effect works for some people and not others: it's in their genes, they suggest.

The research team, led by investigators from Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), believe their findings have important implications for patient care, and will also help researchers design and carry out more cost-effective clinical drug trials.

Placebo Effect is Costly

The placebo effect poses a huge challenge to trial investigators: how can you effectively test a new drug against a "dummy pill", if some of the participants are going to have a response to the dummy? One way, which is expensive, is to recruit a lot more participants, in order to collect enough data for the analysis to be statistically significant.

Current estimates put the cost of dealing with the placebo effect in conducting clinical trials to satisfy the requirements of regulators like the US Food and Drug Administration (FDA) upwards of $1 billion.

Dopamine in Brain Varies with Genes

The study shows how the extent of people's placebo responses may be explained by genetic differences that vary the amount of dopamine in their brains.

First author Kathryn Hall, of BIDMC's Division of General Medicine and Primary Care and member of the Program in Placebo Studies and Therapeutic Encounter (PiPS), says in a statement:

"There has been increasing evidence that the neurotransmitter dopamine is activated when people anticipate and respond to placebos."

"With this new research, we may now be able to use a person's genetic makeup to predict whether or not they will respond to a placebo," she explains.

The researchers set out to find a genetic marker for placebo and chose to focus on the dopamine pathway because it is involved in both reward and pain.

Their attention was soon drawn to a gene called catechol-O-methyltransferase (COMT), as Hall explains:

"COMT made for an excellent candidate because it's been implicated in the cause and treatment of many conditions, including pain and Parkinson's disease."

The gene also features in genetic models of behavior to do with "reward responsiveness and confirmation bias, the tendency to confirm new information based on your beliefs," she adds.

COMT Variants and Dopamine Levels

The way gene variants for COMT work is that a person can have two copies of a variant called the methionine (met) allele, two copies of another variant called the valine (val) allele, or one of each. Thus a person can have either a met/met, a met/val or a val/val version of the COMT gene.

Hall says they found compared to people with the val/val variant, people with the met/met variant appear to have three to four times more dopamine available in their prefrontal cortex, an area of the brain that is linked to cognition, personality expression, decision making, and social behavior.

She and her colleagues then proposed: if dopamine is also involved in the placebo response, then people should show different responses to treatment with placebo depending on whether they are val/val, met/val, or met/met COMT carriers, with the latter showing the strongest response.

COMT Variants and Placebo Effect

They tested this proposal by taking a fresh look at a 2008 clinical trial that investigated the placebo effect in patients with irritable bowel syndrome (IBS).

That trial was led by senior author of the new study Ted Kaptchuk, director of PiPs and Associate Professor of Medicine at HMS, who says:

"In our original work, IBS patients were assigned to one of three treatment arms and we explored the placebo response in relation to the patient-provider experience and the clinical environment in which the placebo is administered."

The participants in that trial had been either assigned to a waiting list during which time they received no treatment, assigned to placebo acupuncture treatment delivered in a business-like clinical manner, or assigned to placebo acupuncture treatment delivered by a warm and supportive health care professional.

Patients' treatment responses had all been assessed using the IBS-Symptom Severity Scale and Adequate Relief.

From patients' blood samples, Hall and colleagues were able to find their genotypes, which they analyzed in relation to the responses for the three treatment arms.

They found that as the copies of met in the COMT gene increased, so did the placebo response ("presumably because more dopamine was available", says Hall).

Their results showed that in the patients assigned to the waiting list there was no difference in treatment response among the met/met, val/val and met/val COMT carriers.

But, among those in the arm that received a placebo treatment in a business-like manner, the met/met carriers showed a small improvement in symptoms compared to their val/val and met/val peers.

However, there were striking differences in placebo response in the group that had received placebo treatment in a warm and supportive manner, with the met/met COMT carriers showing a six-fold improvement in IBS symptoms compared to the val/val carriers.

Genetic Marker for Placebo Response

Hall says their results suggest "met/met is a genetic marker for the placebo response and val/val is a marker for non-response".

Plus, the findings also highlight differences in placebo response depending on how the patient experiences the clinical environment.

For the met/met COMT carriers, having a positive relationship with the health care provider made a big difference.

"Conversely, our findings suggest that the val/val patients are less influenced by placebo treatment and this sheds light on a clinical challenge faced by many health care providers, whose empathic care helps some people, but makes no difference to others," says Hall.

Implications

Hall and colleagues point out this was only a small study and urge others to replicate these findings with larger studies. But nevertheless it takes an important first step in helping to tackle the expensive business of the placebo effect in clinical trials.

Gunther Winkler, Principal of ASPB Consulting, LLC, and consultant to the pharmaceutical industry, says the study is an important step forward on a path leading to "revolutionary changes" in the way new medicines are developed:

"Being able to predict a genetic predisposition for heightened placebo response could potentially have a major impact in reducing the size, cost and duration of clinical trials," he adds.

Kaptchuk says the study opens a new avenue of investigation into the biological underpinnings of the placebo response:

"Just as some people find attending church or synagogue to be transforming and others just fall asleep, there are people who are enticed and deeply influenced by the rituals and symbols of medicine, and now we recognize that there may be a genetic explanation for some of this ," he explains.

Grants from the National Institutes of Health helped fund the research.

Written by Catharine Paddock PhD