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Genetics behind placebo effect
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Placebo is any pharmaceutically inert substance or medical procedure applied with the purpose to deceive the recipient. Even without appropriate treatment, patients could feel better simply because they believe that given pill will improve their condition. This phenomenon is called placebo effect. Brain’s effect on physical health is very important and medical researchers are using placebo as control in many experiments. However, using placebo in clinical practice is unethical due to deceiving patients with false information and ineffective treatments.

Placebo is not working with everybody. It’s believed that 35% of people respond to placebo. Effect is individual, such as the reaction to the active drug (some people don’t respond to pharmaceutically active pills). Dark side of the placebo is “nocebo”. If patient don’t believe that treatment could improve his health, nocebo effect will result in deteriorated medical condition. Negative attitude patient has toward the therapy could result in serious worsening of the symptoms. Patient could also feel the “side effects” of the investigated drug while on placebo. Withdrawal symptoms are noted as well. Study on hormone replacement therapy in women in menopause lasted for more than 5 years. When completed, > 40% of the women in placebo group reported same withdrawal symptoms as the women receiving hormone replacement therapy.

Despite all positive and negative effects of placebo, it’s still inevitable part of the clinical trials. Placebo can produce same beneficial effect to the health like the investigated drug during the clinical trial. That’s a problem. Cheap and medically inert substitute of a drug shouldn’t be effective like brand new, billion dollars worth pill (cost of typical drug development process). Reason is high susceptible to placebo. To overcome this problem, researchers are recruiting more people to get statistically significant results. Placebo is necessary, but it is not cost effective. Average study spends more than 1 billion dollars due to placebo.

To address this issue, scientists need to discover biological effect responsible for high placebo susceptibility. For the first time, it looks like that they finally have the right answer.

Genetic variations are responsible for the effect of placebo or drug on human organism. Previous experiments showed that dopamine level in the brain is higher in people responding to placebo (dopamine is associated with both sensation of pain and reward). Latest study focused on dopamine pathway, more specifically on catechol-O-methyltransferase (COMT) gene. COMT can be present in couple of forms. Person bearing two copies of a variant methionine allele will have met/met type of COMT gene, those with two copies of valine allele will have val/val type of a gene or, person can have both types of alleles resulting in met/val type of a gene. People with met/met variant have 3-4 higher level of dopamine in their prefrontal cortex (associated with cognition, decision making, social behavior and personality expression) compared to people bearing val/val variant of a gene. Since elevated dopamine level has already been linked with high placebo response, scientists proposed that people bearing different variant of COMT gene (met/met, val/val or met/val) will show different response to placebo. Study of irritable bowel syndrome conducted in 2008 proved that COMT gene proposed hypothesis was correct. During the study, patients were divided in three control groups: one that was on the waiting list, second that received placebo acupuncture treatment in a cold, business manner and third where placebo acupuncture treatment was delivered in a warm and supportive manner. Using the patient’s blood, genotypes were easily determined. People on the waiting list didn’t show any difference in the response, no matter what type of COMT gene was present. In the second group, where placebo was provided in a cold, business manner – met/met carriers showed slightly higher responding rate compared to val/val and met/val genotypes. Striking difference in the placebo response was noted in the third treatment group where met/met carriers showed exceptional difference in response to the placebo delivered in a warm manner, compared with other two COMT variants. This experiment confirmed that met/met genotype is typical placebo “responder” while val/val is not.

Genetics behind the placebo should be investigated further, but even this discovery could reduce the cost, duration and efficiency of the clinical trials by selecting placebo “non-responding” genotypes for the future experiments.
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