Dr. Ulrike Bingel, Professor of Clinical Neuroscience, Director of the Center for University Pain Medicine, Essen University Hospital: The classic definition of the placebo effect is a positive mental or physical reaction that occurs after taking dummy medication.

However, we now know that this effect is not caused by the placebo itself, but rather by the positive expectations associated with it. In a broader sense, placebo effects are therefore also understood as the effects of positive expectations, which can also occur even when no placebo is given. For example, it can be shown that a positive expectation of a headache tablet – namely, that it will reduce the headache – relieves the pain faster and better than without it. The placebo effect therefore also occurs with real medications and is by no means linked to placebos, even if it has been described as such historically.

The driving psychological force behind the placebo effect is thus the positive expectation that a therapeutic measure or medication will work. This effect triggers complex processes in the brain and body that are already very well understood in the case of placebo analgesia, i.e., the effect of placebos on pain Perception. This activates the body's own descending pain-modulating system. It is the body's own pain brake, which begins in parts of the Frontal lobe and then involves parts of the Midbrain and Brain stem This system is capable of suppressing nociceptive signals, i.e., pain signals, arriving from the body in the Spinal cord It is thus a pain brake for incoming pain signals at the spinal cord level.

It is also known that complex messenger substances are released in the process. The body's own opioid system plays a role in this, but so does the Dopamine system. Studies also suggest that the body's own cannabinoid system is involved. It is therefore a complex neurochemical, neurobiological process that ensures that pain is reduced when it reaches the brain and is perceived as less intense there.

The nocebo effect, on the other hand, causes symptoms such as pain to worsen or intensify due to fear and negative expectations. In this case, the opioid and dopamine systems mentioned above are inhibited and pain stimuli are transmitted and perceived more intensely in the brain.

In everyday clinical practice, nocebo effects probably play a greater role than placebo effects, as many people have concerns and fears about diagnostic measures or taking medication, for example, after reading the package insert. This leads to undesirable effects (so-called side effects) occurring more frequently. Nocebo effects can also cause medications to not work as well as they could pharmacologically. This has been demonstrated for pain medications, for example.

Much is known about the placebo effect in other physical systems from clinical placebo-controlled studies. In these studies, one group of patients receives the medication and a control group receives the placebo. However, the patients do not know which group they belong to (this is called blinding). These studies have shown that the placebo effect actually exists in all physical systems: not only in pain, depression, and fatigue, but also in very basic physiological systems such as the cardiovascular system, the lungs, or the gastrointestinal tract. The effects are even evident in the immune system, where they can be detected in changes in inflammatory mediators. In fact, there is no system in which the placebo effect does not occur, but its intensity varies and it is triggered by different mechanisms.

The effects are particularly pronounced in subjective symptoms such as pain, mood, fatigue, or sleep quality. Although there are also objectifiable effects in the brain and body, the effects on subjective symptoms are particularly strong. What exactly happens in these other systems during the placebo effect is not yet well understood, and scientists are only beginning to investigate these effects in detail. The question arises as to whether there is a common mechanism in the brain that underlies all types of placebo effects. It is believed that the prefrontal cortex, a part of the cerebral Cortex behind the forehead, plays a role, as it is very important for expectations and learning, but the exact nature of the connections is the subject of current research.

There are also significant inter-individual differences in the placebo effect. Some people show a strong placebo effect, while others show only a weak one. This can also change from situation to situation in a single patient. The reasons for this have not yet been systematically researched. In addition to genetics, personality, and individual brain architecture, situational aspects such as anxiety are also thought to play a role. Diseases such as dementia can also influence placebo effects. Investigating these differences is very important in order to be able to provide personalized medicine that takes advantage of these effects.

Recorded by Stefanie Flunkert