For a long time, scientists believed that the placebo effect has nothing to do with the treatment of the disease, that it is the result of the patient’s desire to please the doctor, natural recovery, cycles of decline and increase of symptoms of the disease, as well as the bias of the doctor in statistical data processing. However, the data from clinical trials in which some patients received placebo and some did not receive any treatment, with an objective measurement of the condition of patients, force us to reconsider our attitude to placebo.

The first placebo studies related to objective control appeared back in 1981. Then John David Levine, professor of medicine and maxillofacial surgery and neuroscience at the University of California (San Francisco) He found that the placebo effect of pain relief disappears if patients are injected with naloxone, a drug that blocks opioid receptors. To test whether placebo is associated with the release of endorphins, a team of scientists from the University of Michigan used radiolabeled carfentanyl, a substance that selectively binds to mu-opioid receptors. The more opiates the body releases, the fewer places there are for the radioactive label. It turned out that taking a placebo painkiller leads to the release of endogenous opiates in the dorsolateral prefrontal cortex, anterior cingulate gyrus, nucleus accumbens and amygdala. John Car-Zabieta, a scientist at the Department of Psychiatry at the University of Michigan, has shown that a mutation in the OPRM1 gene, which encodes the mu-opioid receptor, leads to a change in the strength of the placebo effect, not only subjectively, but also objectively (dopamine release in the nucleus accumbens). However, further studies involving the untreated group are needed to separate the placebo effect from other factors.

Soon, Professor David J. Scott from the University of Michigan was able to show that the effectiveness of placebo is also associated with the release of dopamine in the basal nuclei and the nucleus accumbens. Moreover, the greater the dopamine response to the monetary reward, the higher the dopamine response to the placebo and placebo effect. The author of the study suggested that this result may be due to the fact that the effectiveness of the placebo is related to the effectiveness of the reward system in humans. Finnish scientists from the Faculty of Pharmacology at the University of Helsinki have shown that replacing just one rs4680 nucleotide in the COMT gene leads to an increase in the placebo effect with analgesia, This is also observed in schizophrenia, heart disease, irritable bowel syndrome. This enzyme is responsible for the breakdown of dopamine, adrenaline and norepinephrine. The rs4680 mutation leads to a three- to four-fold decrease in the enzyme’s effectiveness, resulting in an increase in dopamine concentration. Similar results were obtained by Canadian scientists from the Neuroscience Department of the Center for Mental Health and Addictions in Ontario for mutation of another protein involved in the utilization of dopamine monoamine oxidase-A (MAOA). Gene variants where this protein is less active and, consequently, the baseline dopamine level is higher show a higher level of placebo effect and vice versa.

In a 2011 study, Fabrizio Benedetti of the University of Turin showed that the analgesic effect of placebo is also associated with the production of endocannabinoids, a group of neurotransmitters that play a role in regulating mood, appetite, memory, and pain. For example, an endocannabinoid blocker eliminated the placebo effect when subjects were told that a non-opioid analgesic was being tested, but had no effect if they were told that an opioid analgesic was being tested. John Kar-Zabieta has shown that a mutation in the FAAH gene, involved in the destruction of endocannabinoids after they have already entered the synaptic cleft, affects the strength of the placebo effect.

After the placebo neural pathways were established, a new challenge arose — to determine which genes and molecules influence the placebo effect. Scientists from Harvard Medical University in Boston have identified 28 genes associated with the placebo effect. Analysis of the interactome, the interactions of proteins, revealed 54 more proteins that are closely related to others that synthesize candidate genes. Interestingly, 26 of the 28 candidate genes and 40 of the 54 protein genes closely related to the former were targeted by drugs of various groups, including painkillers, appetite suppressants, and antidepressants. Thus, recent studies reveal the mechanisms of the placebo.