The placebo response—mind over matter, plus the mind does matter

For many years, the placebo response both in medicine and in clinical studies was the beneficial physiological response to an inherently inert medical treatment. Science recognized it as a statistical fluke attributed to some individuals with a stronger psychosomatic, mind-body connection—a response that created feelings of well-being through the power of belief and a positive frame of mind with the expectation of positive results.  It was a baseline patient response in clinical studies to outperform.  But in the past few decades, it has become notorious for performing equal to drugs in clinical trials of antidepressants.

Placebo researcher, Fabrizio Benedetii, at the University of Turin, has connected many biochemical reactions responsible for the placebo response. He began by finding an old study done by US scientists that showed the drug naloxone could block the pain-relieving power of the placebo response. The brain produces opioids, natural painkillers, and placebos elicit these same opioids in addition to neurotransmitters like dopamine, helping to relieve pain and sense of well-being.  Furthermore, he showed that Alzheimer's patients with impaired cognitive functioning that were unable to formulate ideas about the future, i.e., creating a sense of positive expectations, were not able to experience any pain relief from a placebo treatment. The neurophysiological bases for many mental illnesses, like social anxiety, chronic pain, and depression are not well-understood, and these are the same conditions that have beneficial responses to placebo treatments. 

Last month, clinical neuroscience researchers at Northwestern University published a new discovery backed by strong experimental design and statistics showing that the placebo response of a patient is quantifiable and reversely they can predict with 95% accuracy the placebo response of a patient based on the patient’s brain functional connectivity prior to starting the study. They utilized resting-state functional magnetic resonance imaging, rs-fMRI, specifically blood-oxygen-level dependent (BOLD) rs-fMRI.  In this form of MRI, the well-accepted assumption that blood oxygenation levels in the brain fluctuate depending on neural activity and these metabolic changes in the brain are seen using BOLD fMRI.  The researchers compute the changing metabolic function of a patient’s brain into image intensity and from the culmination of imaging they can depict and derive brain functional connectivity, i.e. brain information sharing. 

The clinical researchers at Northwestern, looked at fMRI-derived brain activity of osteoarthritis sufferers in response to a placebo and the pain medicine duloxetine. In study one, the researchers conducted a single-blind placebo trial.  They found about half the patients responded to the placebo and the other half didn't. The placebo responders showed greater brain functional connectivity when compared with placebo nonresponders in a brain region called the right midfrontal gyrus, r-MFG. 

In study two, the researchers used the brain functional connectivity measure of the r-MFG to predict patients that would respond to a placebo with 95% accuracy. 

In the final study three, they looked at patients that only responded to duloxetine and discovered the fMRI-derived functional connectivity of another brain region (the right parahippocampus gyrus, r-PHG) as predictive of the analgesic response to duloxetine. The last finding being consistent with the known pharmacological action of duloxetine in the brain. 

Finally, they generalized their findings of r-PHG functional connectivity to predict the duloxetine response in the entire group of patients and then corrected for a predicted analgesic response to placebo. They found that duloxetine both enhanced and diminished the placebo response. This leads to a never before observed side-effect of an active drug diminishing the placebo response. The mechanism of interplay between r-PHG and r-MFG remains to be determined.  


The placebo response is no longer just a statistical confound resulting from psychosocial factors in clinical studies or a regression to mean phenomena. Instead, it's a significant measurable effect seen as differing patient brain functional connectivity that furthermore is predisposed in some individuals based on yet unknown genetic factors. This latter study of genomic effects on placebo is termed the placebome.

Often, people push the expression "mind over matter," in hopes of toughening up their friends on the premise of the placebo's power. Change the way you think, and you will change the way you feel, they say. 

But as we have seen, people who have physically altered brains from illnesses like Alzheimer's or chronic severe depression, are unable to tap into their endogenous opioid “happy chemicals” to relieve their anxiety, pain or melancholy.  These individuals are only able to receive improvements in their health through drug treatment. Thus, being mindful of your ability to switch between a positive and negative frame of mind could keep you from developing depression.

In the future, would new antidepressants work by eliciting and increasing the placebo response in everyone? Could researchers find the brain region responsible for the nocebo, the opposite of placebo, viz., a negative frame of mind in which one expects no improvements or only side-effects? And if so, would targeting these regions prove the most efficacious in chronic pain or depression?  What are, if any, mental illnesses that have no placebo or nocebo responses? 

Perhaps true innovation for mental illnesses will only come from understanding the placebome and altering genetic mutations that predispose for chronic pain and depression. How do natural methods and the placebo relate, because activities like socializing, meditation, and yoga, have all been shown to improve depression by repeatedly exercising brain regions related to our natural positive well-being machinery.  There is a lot left to discover. And more research could lead the way to the future of patient-specific, personalized medical treatment.  

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