Paolo Rossi Castelli 18 March 2021 6 min read

The placebo effect? Real, strong and still mysterious

A study published in the journal Nature Communications sheds new light on the complex way that the brain manages and processes pain. 600 patients were studied.


How real is the placebo effect, which is achieved by administering inactive drugs (sometimes even just sugar pills) instead of genuine ones, without the patient knowing (especially during trials for new therapies), achieving a positive and tangible effect, sometimes even greater than that of the real drugs?

It has been known for a long time that the power of autosuggestion can be very strong, but the details of the brain mechanisms that lead to these results had never been revealed.

Now, a study published in the scientific journal Nature Communications by neurologists from Dartmouth University in Hanover (USA) and several European universities, members of the Placebo Imaging Consortium, has shed some light on the placebo effect against pain.

Different brain areas involved

The researchers pooled data from 20 studies of more than 600 people (in what is defined as a meta-analysis) and used advanced imaging techniques (functional magnetic resonance imaging and others) in order to gain a more precise understanding of what happens in the brain when people believe they are receiving pain-relief treatment.

The tests carried out in the 20 studies led to several significant understandings. First, it was seen that different areas of the brain are involved, with the activation of many neurons. In particular, the thalamus, which is an important gateway for sensory stimuli, plays a role. The researchers showed that the painful stimulus is then processed by other areas of the brain, in ways that differ from person to person, in a kind of mental construction, which can vary considerably. The placebo effect intervenes in this “pain system” by reducing the activity of areas involved in the early signalling of pain itself and/or its processing, including the memory of previous pain.

Moreover, there are many testimonies that point in this direction. It has been seen, for example, in the context of other studies, that the administration of a large, red-coloured pain-relieving pill produces a greater effect on average than a small, faded-coloured pill, because it is unconsciously considered to be more effective (obviously a more conspicuous pill reduces the nervous stimuli of the “pain system” from the outset). In the same way, if the same amount of morphine is administered to cancer patients, the results are more effective if the doctor or nurse warns the patient that they will be receiving the drug.

Tor Wager, co-author of the study published in Nature Communications, states, “We are still learning how the brain constructs pain experiences, but we know it’s a mix of brain areas that process input from the body and those involved in motivation and decision-making.”

Great variability

The question, with the placebo effect in mind, is: does the drug believed to be a painkiller, even if it is not (or, in any case, the drug believed to be more effective), change the way stimuli reach the brain, or the way these stimuli are processed?

From the data obtained from the imaging, the answer that emerges is probably both, because from time to time several areas referable to the two types of effects are activated. The one that is dominant depends very much on the context, the predisposition of the individual, the type of experience, and various other factors.

All of this confirms the existence and complexity of the placebo effect, and above all provides new clues for possible applications both in the therapeutic field and, for example, in anaesthesia during surgery.


Paolo Rossi Castelli

Journalist since 1983, Paolo has been dealing with scientific divulgation for years, especially in the fields of medicine and biology. He is the creator of Sportello Cancro, the site created by on oncology in collaboration with the Umberto Veronesi Foundation. He collaborated with the pages of the Science of Corriere della Sera for several years. He is the founder and director of PRC-Comunicare la scienza.