Patient care and enzyme release appear crucial to placebo effect

Research points to biochemical basis for perplexing but powerful medical treatment

According to my Collins dictionary, a placebo is “an inactive substance or other sham form of therapy administered to a patient usually to compare its effects with those of a real drug or treatment, but sometimes for the psychological benefit to the patient through his/her believing he/she is receiving treatment”. And the placebo effect is defined as “a positive therapeutic effect claimed by a patient after receiving a placebo believed by him/her to be an active drug”.

Placebos can be powerful medical treatments and can work even when the patient knows they are placebos, especially when administered with warmth and attention. Ailments that respond particularly well to placebos include chronic stress-related conditions such as depression, anxiety, migraines, back, neck and shoulder pain, digestive disorders, insomnia, and so on.

There is no full understanding of how placebos work and they are not part of standard medicine. However, studies are now starting to uncover biochemical roots to the placebo effect and when the full picture emerges it may revolutionise medicine. The story of the placebo effect is outlined by Gary Greenberg in an article entitled "What if the placebo effect isn't a trick?" (New York Times Magazine, 7 November 7th, 2018).

The traditional explanation of the placebo effect invokes concepts such as expectancy and conditioning to explain how the mind can cause physical responses in the body, but as yet there is no molecular explanation for this effect. Ted Kaptchuk, head of Harvard medical school's placebo studies programme, describes medical care as a "moral act" in which the patient puts his/her fate in the hands of a trusted healer. Kaptchuk believes the placebo effect results from the complex conscious and unconscious processes embedded in the practitioner-patient relationship.


Functional magnetic resonance imaging shows consistent patterns of activation lighting up in the brains of placebo responders

Kaptchuk carried out a significant study on acupuncture treatment of irritable bowel syndrome (IBS). He divided participants in the study into three groups. One group got acupuncture treatment but using sham needles, the second group got acupuncture treatment with sham needles, but with much doctor-patient interaction and the third group received no treatment. Both sham treatments worked better than no-treatment but the second sham treatment with a high doctor-patient interaction worked best.

Kaptchuk believes science may not be the only way to understand illness and healing and that the placebo effect is a biological response to the act of caring – the rituals involved trigger specific neurobiological pathways that modulate body sensations, symptoms and emotions.

Pharmaceutical companies

In a funny sort of way, medicine takes the placebo effect very seriously while, at the same time, dismissing it. The American Food and Drug Administration (FDA) requires pharmaceutical companies to prove new drugs are effective before approving them for the market. The new drugs must outperform placebos in two independent studies before they are granted FDA approval.

Recent research, described by Greenberg in the aforementioned New York Times article, is starting to discern a biochemical basis for the placebo effect. For example, functional magnetic resonance imaging shows consistent patterns of activation lighting up in the brains of placebo responders. Also, catechol-O-methyltransferase (COMT), an enzyme whose activity affects levels of catecholamines, seems to play an important biochemical role.

If this is true, it will mean that one cornerstone of modern medicine, the placebo controlled double-blind drug trial, is fundamentally flawed

Catecholamines are hormones and neurotransmitters, eg adrenaline and dopamine, associated with stress, reward and feelings of positivity which are secreted by the adrenal gland into the bloodstream when you are physically or emotionally stressed. COMT is widely distributed among the organs but is of particular significance in nerve cells. Low-levels of COMT correlate with high levels of dopamine. COMT levels correlate with Parkinson’s disease, depression, schizophrenia and response to pain – conditions known to respond to the placebo effect. In Kaptchuk’s IBS study described above, patients with the highest levels of COMT showed the lowest placebo response, and vice versa.

Placebo effect researchers are now seriously entertaining the notion that plaebos and drugs do not involve separate processes, one psychological and the other physical, but operate on the same biochemical pathway governed in part by the COMT gene.

If this is true, as Greenberg points out, it will mean that one cornerstone of modern medicine, the placebo controlled double-blind drug trial, is fundamentally flawed because it assumes that placebos and drugs operate via different mechanisms, one psychological and the other physical.

William Reville is an emeritus professor of biochemistry at UCC