Why you could be genetically programmed to respond to placebos

placebo
Image credit: Javier Zarracina/Vox

Sugar pills might just be the most used medication in medical research. They’re necessary so scientists can measure the effect of the treatment they’re studying against any of the other, inadvertent aspects of the situation that could have an effect. It may be, for example, that a doctor’s soothing voice and excellent bedside manner put patients at ease and improve conditions. So when she gives a patient a pill, they feel better whether it contained medication or was just a dummy.

But there’s a problem. Patients have been responding better to placebos, at least in the US, according to Jo Marchant writing at Nature. And this is a problem for researchers who are trying to develop new antidepressants, antipsychotics and pain drugs:

This effect would explain why drug companies have trouble getting new painkillers through trials, notes neuroscientist Fabrizio Benedetti, who studies placebo responses at the University of Turin, Italy. Over the past ten years, he says, more than 90% of potential drugs for treatment of neuropathic and cancer pain have failed at advanced phases of clinical trials.

When a placebo effect is increased, it’s harder to prove that the study drug works. And when you can’t prove a drug works better than a sugar pill, the FDA won’t approve a therapy. On one hand, this is further evidence that pharmaceutical companies need to be developing more drugs and better ones. On the other hand, it’s important to know if some change in the American population is causing the effect.

In May 2015, researchers from Harvard Medical School described a set of variants in 11 genes that they say are linked to the placebo effect and called it the ‘placebome.’ Scientists have known for quite some time that some people are more prone to experiencing the effect than others. And early investigations implicated the body’s natural pain control systems, including the opioid-like chemicals made and released in our own brains.

The placebome study compared the genetics of people who had been in clinical trials. They found that high-responders share genetic variation in the metabolic pathways for the pleasure-inducing neurotransmitter dopamine, serotonin and opiods and edocannabinoids. Those correspond to our bodies’ own pain management and mood regulation systems. The variants change the pathway in different manners. A person with two copies of the rare variant of COMT has increased dopamine in the pre-frontal cortex of their brain. That gene combination is also correlated to high placebo responders. Alcoholics with a different dopamine-promoting variant of the DBH gene implicated in the study did better staying sober when they took a placebo than when taking the anti-craving drug naltrexone.

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But these genes couldn’t explain all of the people who had a large placebo effect. And all these gene variants don’t necessarily come together as a package. High responders often differed in which systems their variants affected. You might have a high-response variant in either your dopamine or your serotonin system or both, the scientists wrote:

Consider, for instance, an individual who is dopaminergic dominant and tends to be more responsive to placebo in pain studies: their placebo response in a depression trial might differ significantly depending on whether they were serotonergic dominant or recessive.

This distinction is important because it could determine which clinical trials these high responders would be more likely to throw off. But this begs a larger question: Now that we know there may be some underlying genetic determination of placebo responders, should we eliminate them from trials? That may allow for more efficient, effective and cheaper clinical trials, the study authors note. Although eliminating whole swaths of patients before trials because you expect a bad result is a controversial idea, it’s done all the time. Often, for example, patients with well-controlled chronic diseases like diabetes are too healthy to join new drug studies because their response to medication may not be large enough.

And what about the potential benefit for a patient? If a physician knew a patient was a high responder, could she decide to prescribe a smaller dose of medication or a placebo to reduce cost and chance of side effects? Likely not now writes Cari Romm reporting for the Atlantic:

Another issue is who should own that information in the first place. Out of necessity, a doctor—as the one to facilitate the genetic testing—would be the knowledge gatekeeper when it came to a patient’s placebo sensitivity. Bioethical standards, though, dictate that if doctors use placebos on their patients, then the patients have to be fully informed every step of the way—even if it might lessen the effects.

The healthcare industry has largely and loudly embraced the move towards precision medicine. If we can maximize research and offer patients safer, cheaper therapies based on their placebome, shouldn’t we?

A version of this article originally appeared on October 10, 2016.

Meredith Knight is a freelance science and health writer in Austin, Texas. Follow her on Twitter @meremereknight

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