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We know the placebo effect is biological. Is it also genetic?

Observed since the start of medical practice in ancient history, the placebo effect refers to the response people have to being treated — even though the ‘treatment’ in the placebo sense is a sham (in most cases dummy tablets, capsules, and the like made to look like an actual drug therapy).

It was first formally identified in 1955, in an article by Henry Beecher, “The Powerful Placebo”, in the Journal of the American Medical Association. According to an article by medical writer Susan Perry:

While treating wounded American soldiers during World War II, Henry Beecher ran out of pain-killing morphine. Desperate, he decided to continue telling the soldiers that he was giving them morphine, although he was actually infusing them with a saline solution. Amazingly, 40 percent of the soldiers reported that the saline treatment eased their pain.

What’s been incredibly interesting in clinical trials over the last several years and captured in excellent and groundbreaking works by Irving Kirsch and Ted Kaptchuk, is that the placebo effect has appeared to get ‘stronger,’ meaning that the magnitude of its effect has increased. What this looks like in practice is that the response of the group of subjects in a clinical trial which receives the placebo compared to the actual drug looks remarkably similar to the treatment group (getting the actual drug). This makes it very difficult in some cases to advance new drug therapies, because if the placebo ‘arm’ of the clinical trial performs so well, then the actual drug therapy has a harder time meeting the criteria for statistical significance in doing better than the placebo—which is a requirement for approval to market the drug.

As Perry explains it, the placebo effect appears to depend on a combination of verbal suggestions, observational cues and conditioning which together create expectations that activate the brain’s reward system. When people believe that a placebo is a real drug, brains produce more dopamine, a -Miracle_Cure!-_Health_Fraud_Scams_(8528312890)brain chemical strongly associated with reward and pleasure. So the biological effects of a placebo are similar to those of other pleasurable experiences, such as eating when hungry or drinking when thirsty.

Some new research shows an association that at least part suggests the placebo effect has a basis in human genetics as well as human biology. The researchers looked at different gene variants of a gene called ‘COMT’ which regulates the level of dopamine in the brain. They found a correlation between higher-dopamine variants of the gene and likelihood to report a placebo response. The trial groups were split in the following way:

Trial group 1: No treatment; The subjects were told that they couldn’t get treated anytime soon and were put on a waiting list

Trial group 2: Fake acupuncture was administered by an unfriendly participant

Trials group 3: Fake acupuncture was administered by a compassionate participant

The design of clinical trials is such that a drug treatment is measured against a placebo, or sometimes a comparator drug. But the placebo effect itself is very powerful–the placebo group in a trial isn’t receiving ‘no treatment,’ it’s receiving a ‘placebo treatment.’placebo-effect-one-a-day

Related article:  Could studies on gene differences lead teachers to unfairly favor 'more educatable' students?

By the very etymology of the word, placebo means ‘I shall please’ in Latin. The treatment is itself the
administration of care, of listening, of the so-called ‘bedside manner’ in some cases. What clinical trials aren’t robustly measuring is the effect of drug and sham (dummy treatment) against a third baseline: no treatment. The assumption is that placebo represents the lack of treatment, but the placebo group is still receiving treatment, sham pills, check-ups, observation, etc. All of this creates something of an observer effect that changes behavior and expectancy of symptom resolution. Additionally, and not of minor importance, are the ethical practice considerations surrounding placebo and sham treatments.

This is hardly an open-and-shut topic, as finding a few genetic correlates does not tell us about the underlying causal mechanism or if the detected effect works in the same way via the same gene for any drug (though this does continue the discussion about progressing genetic screening to identify differential drug effects, placebo response, and overall better personalized medicine). Also, many tests of the power of placebo are run in non-standard ways and with ‘no treatment’ groups, and comparing results meta-analytically against actual drug clinical trials is very difficult to do–at least to draw reliable conclusions from.

To add additional gravity to the topic, it should also be mentioned that the placebo effect isn’t necessarily ‘just in the mind’; A review of arthroscopic partial meniscectomy (knee surgery) vs. sham surgery in the New England Journal of Medicine concluded that “The outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure.”

Ben Locwin is a behavioral neuroscientist and astrophysicist with a masters in business, and a researcher on the genetics of human disease. BIO. Follow him on Twitter @BenLocwin.

5 thoughts on “We know the placebo effect is biological. Is it also genetic?”

  1. Understanding better how much genetics plays a role in our ability to mount a placebo response will be helpful for Precision Medicine. We’ll have more options for care available to fine tune and deliver most appropriate treatment for each person. This is especially important if we want to put First Do No Harm into action and try to minimize potential side effects from active ingredients. What are our options right now? In safe situations, we can just try out openly if a placebo works for us. For some people placebos work even when they know they are taking a placebo. There might be a gene for that as well. I speculate it has to do with our ability to trust in ourselves and to create a strong link between mind and body. I would not use a placebo to replace medical treatment. Yet, in addition to treatment it is a safe way to learn more about your own placebo-response ability. Used like this, taking-a-placebo is similar to meditation. I am fascinated by this topic and created a branded placebo and called it Zeebo Effect. I even made an app for it so you can keep track of your response. And after you try a placebo you still might want to consider meditation.

    • I agree with you that we cannot achieve the gold standard of personalized medicine or precision medicine without understanding how genes affect: a) the disease state and causal mechanisms, b) the response rate of treatments, b) the adverse events (which are different for different people), and c) how the placebo and nocebo effects arise for different genetic profiles.
      In fact, ‘primum non nocere’ will be at its most effective when there are more personalized treatments available which are designed to more precisely target diseases, reduce adverse events, and can take into account differential response rates and the influence of placebo and nocebo effects.

      • Would be great to better understand c). I am going to build out my self-tracking apps (TracknShare) into a platform that could capture such outcomes and factors. Looking for collaborators in research and patient groups. Too bad 23andMe is limited to Ancestry Research for now.

  2. “The outcomes after arthroscopic partial menisectomy were no better than those after a sham surgical procedure.” This doesn’t mean the placebo effect isn’t all in the mind; it just means that arthroscopic partial menisectomy is ineffective itself, at least in some instances.

  3. I am sure that in 20 years there will be a “PILL” for age regression, that means i will be able to grow back to the way i was as a 25 year old. Since by then i will be able to trade in my houseboat “Raumship One” in Sausalito for a place on a “Spaceship” at the Lagrangian libration point 5 (L5), and continue evolving to Homo immortalis omnipotent.
    Remember, the only limit is our imagination. The placebo effect will play a part in this undertaking.

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