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The Neurobiological Basis of the Placebo Effect and Potential Therapeutic
Applications
Celeste Acosta

 Two patients, Patient A and B, are diagnosed with the same
chronic pain condition after a catastrophic car accident. Both
patients experience the same type of chronic pain around
their neck and lower back. Both patients receive the same
prescription from the same doctor, except one bottle of pills
does not contain any active drug. Both patients experience
pain relief from their symptoms in a few weeks and improve
their condition drastically with the treatment. How is this
possible if only one of the patients received an active drug
compound? The placebo (pla-see-boh) effect, or placebo
response, can be described as the “improvement of
symptoms” in an individual after receiving a substance under
a certain context that is supposed to have no real
therapeutic effect (Ortega et al., 2022). But what does this
really mean? Is there a neurobiological basis to the placebo
effect? Is there an opportunity for the usage of placebo
treatments in a clinical setting? In the United States, a
country largely influenced by big pharmaceutical companies,
delving deeper into the biological basis and further
therapeutic application might be seen as a potential threat
but nevertheless, a necessary effort to make. 

The brain can, in fact, produce its own natural opioids called
endogenous opioids, and they provide the same level of
pain relief as exogenous opioids! From here the brain is
releasing feel good chemicals and the placebo effect is in
full speed. It can cause even greater changes in the
immune system and hormone system (Ortega et al., 2022) 

Favorita1987/Shutterstock

 Let’s delve a little deeper into how a placebo effect works in
the big complex blob that is the human brain. One of the
most important factors for a placebo to work is context and
setting (Cai and He, 2019). For example, it’s more likely for
someone to trust the words of a confident doctor in a white
coat than your average joe in a sketchy alley. When you're
in the appropriate setting, neurons in your dorsolateral
prefrontal cortex begin to fire (Ortega et al., 2022). This area
of the brain, located right behind your forehead, is basically
like the quality check controller of the brain. If the
dorsolateral prefrontal cortex finds good quality information,
that likely means it’s important! So this information gets sent
off to other areas in the brain, specifically the areas
responsible for releasing dopamine and self made opioids
(Bennedetti et al., 2005).

Figure 1. The context in which a placebo treatment is
administered is crucial for the corresponding signals to
activate the pathways starting from the prefrontal cortex

(BrainFacts/SfN).

But if all it takes is to activate that prefrontal cortex, why
don’t all placebo treatments work? Well, that answer is a bit
more complex but has a lot to do with the context the
placebo is received in and the internal beliefs of the person
receiving the placebo. Belief also has a major influence on
the placebo effect being successful. In fact, the main area of
the brain that stores mental representations of the world in
order to create our own internal beliefs is the prefrontal
cortex (Sathyanarayana Rao et al., 2009). The prefrontal
cortex is the area that starts to bring meaning to the signals
and stimuli around us, something with meaning can be
stored as an internal belief. A “stronger” belief can be
correlated to more neurons firing in the prefrontal cortex, and
when activated in the right setting, can produce the benefits
of the placebo. The more we practice the same connection
over and over, the stronger its effects (Sathyanarayana Rao
et al., 2009). Similarly, if the belief is negative, and those
connections are strengthened, then there won’t be a
perceived change overall (“This doesn’t work!”). So, in
reality, we really do become what we think. 

Benedetti, F., Mayberg, H. S., Wager, T. D., Stohler, C.
S., & Zubieta, J.-K. (2005). Neurobiological mechanisms
of the placebo effect. The Journal of Neuroscience,
25(45),.10390–10402.
https://doi.org/10.1523/jneurosci.3458-05.2005

References
1.

34Brain Matters Volume VI



Brain Matters Volume VI

Cai, L., & He, L. (2019). Placebo effects and the
molecular biological components involved. General
Psychiatry, 32(5). https://doi.org/10.1136/gpsych-2019-
100089
Ortega, Á., Salazar, J., Galban, N., Rojas, M., Ariza, D.,
Chávez-Castillo, M., Nava, M., Riaño-Garzón, M. E.,
Díaz-Camargo, E. A., Medina-Ortiz, O., & Bermúdez, V.
(2022). Psycho-neuro-endocrine-immunological basis of
the placebo effect: Potential applications beyond pain
therapy. International Journal of Molecular Sciences,
23(8), 4196. https://doi.org/10.3390/ijms23084196
Sathyanarayana Rao, T. S., Asha, M. R., Jagannatha
Rao, K. S., & Vasudevaraju, P. (2009). The biochemistry
of belief. Indian journal of psychiatry, 51(4), 239–241.
https://doi.org/10.4103/0019-5545.58285

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