Placebo effects

images-1In general, the placebo effect is understood as an improvement in the symptoms and/or physiological functions of the organism as a reaction to non-specific and apparently inert factors, such as visual or verbal suggestion, taking pills, and fictitious surgery. Placebo effects are most commonly attributed to the symbolism exerted by the treatment on the positive expectations of the patient.

The placebo effect stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. Brain networks and signaling systems may be involved in the placebo response. The engagement of lateral prefrontal regions associated with the expectation of symptom relief, results in the inhibition of limbic regions (reducing anxiety and arousal) and greater engagement of endogenous pain inhibition systems.

Placebo-induced analgesia: 

images-1Opioid neurons play an important role to reduce painful sensation. Nociceptive messages from the spinal cord to the brain is suppressed by the descending inhibition system. Opioid neurons at the periaqueductal gray (PAG) play an important role of descending inhibition. It is widely accepted that placebo analgesia is partly mediated by the endogenous opioid system. Among the modulating mechanisms of placebo analgesia, it is postulated that the expectation of lessening of pain stimulates production of endogenous opioids (Placebo analgesia 1999).

The prefrontal cortex (PFC) in the brain is responsible for executive function, which relates to abilities to differentiate among conflicting thoughts, determine good and bad, same and different, future consequences of current activities, working toward a defined goal, prediction of outcomes, expectation based on actions, etc.

Placebo analgesia is typically preceded by greater activation of the PFC during anticipation of pain, an effect that predicts reductions in pain perception and activity in pain-related brain regions. It has been suggested that the dorsolateral PFC has a primary role in maintaining and refining internal representations of expectations, then activating the other regions of the brain later. Positive expectations concerning analgesia would stimulate the dorsolateral PFC, which would then simultaneously activate the medial PFC, the orbito-frontal PFC and the opioid system of the brain (periaqueductal gray; PAG) (Placebo analgesia 2011).

Placebo effects in depression: 

In depression, there are clinical evidences that different regions of the brain linked to serotonin (5-HT) are involved in the placebo response for depression. The placebo group manifests a mean therapeutic effect of 30%, while the active group manifested 50%. Similarly, the placebo effect showed a mean therapeutic response of 31 % in the placebo group, compared to 56% in the active group.

imagesWhen any placebo intervention creates a positive expectation of reward, neurons of the PFC are activated by the probability of its occurrence; these cells send excitatory glutamatergic direct impulses and inhibitory GABAergic indirect impulses to the dopaminergic neurons throughout the body, with the combination of these signals being the determinant for their tonic activation. Neurons from the PFC, dorsal striatum and ventral striatum may also show tonic activation during the expectation of reward (Placebo in depression 2002) .

In addition, central OXT seems to be involved in mediating placebo effects. Social interaction stimulates OXT release and that OXT mediates trust, analgesic and anti-depressive effects.It is conceivable that a reliable patient-doctor relationship increases OXT expression in the patients’ brain, resulting in analgesic and anti-depressive effects. It remains unknown, however, whether the hypothalamic OXT stimulation is initiated via the activation of the PFC in response to a reliable patient-doctor relationship.

Effects of emotional impact on brain activity: 

imagesIn general, most doctors dislike the placebo effects, because they think that placebo effects are due non-specific and/or psychological. However, it should be emphasized that such emotional impact (whatever non-specific or psychological) can modulate the brain activity and its networking, resulting in the stimulation ofvarious neurotransmitters and neuropeptides (opioid, OXT, 5-HT, dopamine, GABA, glutamate, etc.), which lead to the beneficial effects.

Placebo Medicine:

CWM developed different kinds of agonists of opioid, OXT, 5-HT, dopamine, GABA, glutamate, etc. and these drugs have been widely used to treat various diseases and symptoms. Future medicine should pay more attention how to activate/upregulate the endogenous substances, rather than exogenous drug-administration. The development how to activate endogenous substances should be one of the most important directions toward our future medicine.