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Placebo and Nocebo Effects and COMT gene alleles.

The power of positive thinking may not just be more peaceful, it may also be healing - the placebo effect. While the power of negative thinking may be able to increase risk of negative symptoms or an earlier death even - the nocebo effect.

  • The placebo effect is a term used in medical research to describe how many people can seem to gain symptom relief from something as simple as a sugar pill - when it is given with the suggestion that it is a real pill that may help the symptom. Just eating a piece of candy knowing it was candy would not cause a placebo effect. Research studies have been designed around the premise that a treatment or medication is only considered effective if found to provide more symptom relief, or change a survey result, or lab test value, than a placebo. The placebo effect on average is not insignificant - as many as 40% of people may report feeling symptom relief from the sugar pill given as a 'treatment' for the symptom.

  • The nocebo effect is less studied but may be why how a diagnosis is told to a patient can matter to their health. Suggesting that a condition is quite dangerous with a short time remaining until it becomes severe, may lead to that short time, while suggesting that the condition can become a major problem for some patients but that others get better might help promote the patient's getting better.

The rs4680 genes encode a group of enzymes (COMT and COMT1) which are involved in the breakdown of catecholamines. Having less COMT would tend to mean a person would have a higher level of dopamine, a brain neurotransmitter, and other catecholamines such as epinephrine. Whether someone has a more active COMT producing allele of the rs4680 gene may be involved in who is more likely to have a stronger placebo or nocebo effect, based on the actions or phrasing used by their healthcare provider. Someone with more COMT might have less dopamine, and less of a placebo response in comparison to someone with a low level of COMT and a larger amount of dopamine on average.

Placebo: "low-COMT, high-interaction patients fared best of all,"...

Nocebo: " ...but the low-COMT subjects who were placed in the no-treatment group did worse than other genotypes in that group. They were...more sensitive to the impact of the relationship with the healer." (1)

One of the researchers, Kathryn Hall, worked with a large data set from a different research study that included the COMT level. (2) Her discovery may mean that placebo based research is flawed. Without screening all participants in a study for their rs4680 gene allele, and COMT level, and the resulting dopamine level - there potentially would not be an equally matched experimental and placebo group.

The other potential risk if the placebo system for research is continued would be to secretly stack the groups - measure the COMT levels and only place people in the experimental or placebo groups based on whether they may be more or less likely to have a significant placebo response. "The industry would be delighted if it were able to identify placebo responders — say, by their genome — and exclude them from clinical trials." (1) The 40% average might not be necessary to achieve with the experimental treatment if there was reason to believe the high-COMT participants were all in the placebo group instead of being some in each group in a matched ratio.

Science isn't easy - the physical response to the actual treatment may also be effected by the COMT level - it is an enzyme that breaks down catecholamines which may mean it also breaks down other pharmaceuticals too, or that the variation in catecholamine level is effecting other aspects of health which effect how well or poorly the experimental treatment might work.

Which equals -> more research is needed. Stay tuned! Science is exciting! . . . and in the meantime thinking positively about your own issues, and speaking to others in a positive manner may help our health as well as our feelings of peacefulness. Developing rituals around your relaxation or other health care strategies may also help maximize your own positive response to positive thinking.

The research study, which included the COMT levels had two experimental groups, one with a less elaborate patter and hand motion 'ritual' based on acupuncture meridians associated with the type of symptom and the other group received an even more elaborate patter and activity by the health care provider. From the earlier quote: the "low-COMT, high-interaction patients fared best of all," in other words the research participants who likely had higher levels of dopamine and who received the most elaborate ritual had the strongest placebo response, and that same group, also seemed to have a stronger nocebo - negative effect when they were in the control group - participants who received no interaction from the health care provider. (1, 2))

To throw a curveball, a thought of my own about the research design and discovery: the premise of the experimental treatment was based on acupuncture, but with no pins placed - no puncture - in the acupressure point, likely with a premise that acupuncture doesn't really do much - it is a practice that is thousands of years old while Western medicine has only been practiced a few hundred years.

The acupunture/acupressure points and pathways have been found to match a vascular system that is formed in the embryo before the blood and lymphatic vessels are formed (Primovascular system). The nodes or points of the acupuncture system were found to be involved in forming stem cells from which organ repair and growth could occur - and the pathways also match electrical fields that also have a circulatory pattern during health. (3) An elaborate 'fake' hand motion based ritual - that the patient believed was real, might really be affecting their electrical fields in a beneficial way. The COMT gene allele placebo study needs to be replicated in my opinion with a sugar pill and a more elaborate sugar pill or something similarly benign, rather than using the study based on the acupuncture meridians of the body that also measured COMT. (2) Money is a big issue in research and it is a very interesting use of the first study's data to find another way to look at the information.

The Primovascular system may be involved in cancer cells and movement of them to other parts of the body, so dismissing the discovery as just a placebo effect or fake, may be dismissing a route towards more effective cancer prevention. (3)

Which equals -> more research is needed. Stay tuned! Science is exciting!

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes. 

Medical professional in a white labcoat with a stethoscope checking blood pressure of another man with a blood pressure cuff on his arm.
Checking blood pressure - are we our numbers? or patients with feelings? or both?

Reference List

  1. Gary Greenberg, What if the Placebo Effect Isn’t a Trick?, Nov. 7, 2018, New York Times,

  2. Hall KT, Loscalzo J, Kaptchuk TJ. Genetics and the placebo effect: the placebome. Trends Mol Med. 2015;21(5):285-294. doi:10.1016/j.molmed.2015.02.009

  3. Chun Yang, Yi-kuan Du, Jian-bin Wu, Jun Wang, Ping Luan, Qin-lao Yang, Lin Yuan, "Fascia and Primo Vascular System", Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 303769, 6pages, 2015.


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