The Placebo Effect: Is it Really Mind Over Matter?

What is the placebo effect?

In both medical practice and research, a placebo is considered an inert substance, or medical dose that is identical in odor, appearance, and taste to an active drug.  Clinically, a placebo is defined a substance with no known medical effect that is administered as a control in an experiment to determine the effectiveness of a medical drug. Many times, a placebo simply is a sugar pill. Professionals across several fields are aware that placebos of this definition can cause what is know as the placebo effect. This effect is essentially clinical patients reported the effective treatment of the active drug when a placebo is used. A basic explanation of the idea of a placebo can be found in this video: The Strange Powers of the Placebo Effect. While this effect was originally thought to only be a perspective to the easily tricked human mind, this article from WebMD describes how placebos actually cause physical changes. Many studies can now prove how the expectation of pain relief or other desirable outcomes can actually cause physical changes to how the brain responds to perceived pain and other ailments. PopSci offers this article which explains how functional MRI (fMRI) scans are used to locate the placebo effect’s neural activity in the spinal cord. In the fMRI scans, light patterns are able to depict the specific cells and areas that are responsible for a placebo’s ability to decrease pain. The relief is caused by chemical changes and electrical impulses in the prefrontal cortex. This area of the brain can essentially desensitize or reduce the activity of pain-sensing areas of the brain. While most of this information is well known, much debate comes into play when discussing how, at a very minute level, this effect works.

How does it work?

For the longest time, the placebo effect was labeled to be a psychological phenomenon with no neurological support. This has now since changed. In fact, with various techniques of detecting brain activity, researchers have been able to pinpoint the neurological circuit that is activated during the placebo effect: the reward response and motivated behavior. Specifically, detailed by Archives of General Psychiatry the anterior cingulate (top left), orbitofrontal and insular cortices (top right), the nucleus accumbens, the amygdala (bottom left), and the periaqueductal gray matter (bottom right) are areas that are stimulated.

This stimulation is due to endogenous opioid neurotransmission and dopaminergic activation. During this time, the µ-opioid receptor binding potential decrease 10%-26%, reducing the pain experienced. Let’s take a closer look at the opioid neurotransmission mechanism.

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An agonist binds to a guanosine nucleotide-binding protein-coupled receptor (A), which activates the G protein by switching the GDP to GTP (B). G subunits will stimulate effectors within the receptor, which have effects that include the activation of K+ channels to make neurons less active (C-E). Phosphorylation will occur at the C-terminal of the receptor, which incites the regulating signal transduction proteins to bind to these ends (F). A phosphorylation of dynamin that occurred earlier (D) results in an endocytotic vesicle closing (H). The receptor dephosphorylates (I) and it is reinserted into the neuron (J). Thus, this entire process is one of many that occurs during the placebo effect, which accounts for an effective treatment without medication. Check out the review article Brain for more information.

As for the dopaminergic activation mechanism, it is similar to both the above cycle and the previous blog on midazolam. Dopamine binds to dopamine receptors on a neuron, which activates many other reactions. Some of these include increased ATP production, regulation of ion gates in the neurons, and increased cognitive capability, which amalgamate with other factors to create the placebo effect. However, if you want a more detailed explanation, you can read a book by Dr. Natarajan that is solely dedicated to the dopamine-mediated activation.

Why does it work from an evolutionary standpoint?

It is possible to trace back various stages of the use of placebos throughout history. Beginning examples most often include the idea of spiritual healing. At this time, it was not understood how exactly placebos worked. However, it is and would have been possible to understand why they work. Considering that the function of placebos releases natural chemicals in the body, this process could have changed slightly from year to year. Like many other characteristics, the effective use and response to placebos can be traced as an evolutionary trait. This video by The Royal Institutiondoes an excellent job explaining why the effect works: essentially for survival. It would make more sense for the body to naturally alleviate pain, without a placebo. This does not happen. In order to understand why the body works the way it does, it is much easier to view the situation as a cost benefit analysis. When the benefit of self pain relief outweighs the negative ones. For example, if a body finds it more beneficial to express the sensation of pain (to prevent further injury), than to continue forward (relief pain so the body can function), then the placebo effect may not work as well. Following this logic, the idea of the placebo effect, or self alleviation, should work better when the pain being experienced puts and individual at a greater threat than the pain itself.

Examples In Practice

Research conducted at the University of Michigan and to be published in the Journal of Neuroscience was based off of a controlled experiment conducted on 14 men ages 20-30 years. The men were caused pain via salt injection, then injected with a “pain-killing” placebo. Brain scans showed the release of natural pain relieving endorphins after the placebo was administered. USA Today offers more information on the study.

Ted Kaptchuk  of Harvard conducted a study in which patients with severe arm pains were given two different treatments, pain relieving pills and acupuncture. The results of this research, in which bothtreatments administered are placebos, is astounding. Harvard magazinecovered the story in this article.

Is it ethical?

When the ethics of the placebo are discussed, it is usually in the context of research purposes. However, the much more interesting perspective to argue is whether or not it is ethical to use the placebo effect in clinical cases, given the current understanding of placebo effects. Unlike in the cases of research, in clinical cases, doctor use or “prescribe” a placebo in hopes of positive results. The question that arises then is, in what situations is it ethical to use, or to not use a placebo in place of an active drug during clinical practice? Most arguments for or against the use of placebos in clinical trial focus on whether or not a given placebo is effective. However, given the nature of the placebo, this is a difficult argument to make. While previous knowledge gaps have prevented the use of placebos in practice, it now proves imperative in many clinical situations and should not be denied a place in medical treatments. The Journal of Medical Ethics offers interesting insight into situations in which placebo treatment could be a legitimate therapeutic option, and also when it could be essentially considered a required treatment. In addition to providing example cases, the journal offers practical guidelines to be followed with the use of a placebo in clinical practice. These guidelines include:

  1. The intentions of the physician must be benevolent: her only concern the well being of the patient. No economical, professional, or emotional interest should interfere with her decision.

  2. The placebo, when offered, must be given in the spirit of assuaging the patient’s suffering, and not merely mollifying him, silencing him, or otherwise failing to address his distress.

  3. When proven ineffective the placebo should be immediately withdrawn. In these circumstances, not only is the placebo useless, but it also undermines the subsequent effectiveness of medication by undoing the patient’s conditioned response and expectation of being helped.

  4. The placebo cannot be given in place of another medication that the physician reasonably expects to be more effective. Administration of placebo should be considered when a patient is refractory to standard treatment, suffers from its side effects, or is in a situation where standard treatment does not exist.

  5. The physician should not hesitate to respond honestly when asked about the nature and anticipated effects of the placebo treatment he is offering.

  6. If the patient is helped by the placebo, discontinuing the placebo, in absence of a more effective treatment, would be unethical.

Other questionable ethics that come into play are charging patients for a treatments with no known medical effect, or the possibility of a placebo not working on a test subject who is injured, ill, or in pain. Additional arguments on the ethics of placebos can be found in discussion


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