"Green and White Pill" by Christopher E. Hamrick / CC BY-NC-ND 2.0

The Biology Behind Placebo Effects

February 21, 2019

Common statements heard when discussing placebo effects include “it’s not real; it’s the placebo effect” or “it’s just in your head.” Each of these statements reflects the belief that placebo effects aren’t beneficial or are worthless.

This is an erroneous viewpoint; placebo effects often produce robust psychological and physiological effects that are very real. Placebo-induced effects influence behavior and a variety of experiences.

It can be expected that the benefits obtained from any treatment are at least partially due to placebo effects.

“Subjects typically know they are getting some kind of treatment, and so we may rarely be able to measure the actual effects of a drug by itself.  Instead, we see the effects of treatment plus placebo effects that are shaped by the subjects’ expectations.  We then compare those effects with the effects of placebo alone” (Myers and Hansen 2002).

It is important to avoid explaining the variation in outcome of those receiving placebo as strictly a placebo effect, as other variables may also be involved with the outcome. As an example, consider the common misconception in how the term placebo effect is defined in the context of a standard clinical trial.

Placebo effect is the explanation given for the outcome of those in placebo groups, without considering that a variety of factors are responsible for the reduction of a symptom when taking a placebo (or receiving a placebo-related treatment). The reduction of the symptom could be due to any number of factors: spontaneous remission, regression to the mean, effects of co-intervention, biases (experimenter and participant or patient), or a real placebo response; neurobiological, psychological, and various physiological responses (Benedetti 2009).

In an effort to separate placebo responses from other factors such as those involved with natural history, a control condition (receiving no treatment) is necessary in some cases. However, this type of no treatment condition might not be ethical in particular contexts.

What is a placebo?

The word placebo is derived from a Latin phrase meaning “to please.” The traditional definition—an inert, inactive, non-therapeutic substance or procedure presented as a treatment—has been replaced with a broader definition.

In the past placebos were only mentioned in the context of medicine or discussed by researchers in clinical or experimental studies. Modern definitions and uses of placebos are much wider. With expanding research involving placebo and placebo-related effects comes new scientific concepts. Placebo researchers often refer to a placebo as a substance or procedure that has no inherent or specific power to produce an effect that is sought or expected. Virtually any sort of stimulus may serve as a placebo, even if it is fake, neutral, or isn’t expected to generate specific effects or outcomes. When considering placebo, the entire ritual surrounding the administration of the substance or procedure is considered.

Placebos are context specific. As an example, when you visit a physician, not only are the specific effects of treatment important in determining outcome, so is your perception of the physician. A strong relationship with the physician results in positive expectations, better adherence to protocol, and increased motivation. Benedetti (2011) provides strong evidence for the benefits of a positive physician/patient relationship in his book The Patient’s Brain. Placebos are present in our everyday lives and sometimes have profound impacts on behaviors and experiences.

Placebo effects (or placebo responses) are positive effects induced by placebos. These effects are biopsychological and have been demonstrated in an array of research areas, including pain, motor skills, hormone systems, immunology, food perception, and psychology (to name a few).

One of the earliest studies involving the neurobiology of the placebo effects was conducted by Levine and colleagues (1978). It was shown that placebo analgesia (pain relief) could be blocked by the opioid antagonist naloxone, which indicates an involvement of endogenous opioids, when placebo effects occur. By using this approach with naloxone, several other studies have confirmed and extended this observation: placebo effects involve production of endogenous opioids.

The endogenous opioid system is one of the most studied innate pain-relieving systems. Placebo administration induces the activation of opioid neurotransmission in several brain regions, including the prefrontal cortex, nucleus accumbens (referred to often as the brain’s pleasure center), and the insula (Zubieta et al. 2005). Research also indicates placebo effects involve increased dopamine production, which is relevant to reward/pleasure mechanisms and movement skills. Dopamine is also involved in attention, motivation, memory (a key molecule in molecular signaling pathway of memory in mammals), and learning. Increased dopamine production is a key mechanism involved with placebo improvements regarding Parkinson’s Disease. Positive expectations are associated with increased dopamine activity.

Verbal cues leading to positive expectations can strengthen placebo effects. Vase and colleagues (2003) found that placebo analgesia can be strengthened when a placebo is given along with verbal instructions. They conducted a study in an effort to enhance placebo pain relief in individuals suffering from irritable bowel syndrome. The placebo effect was strengthened when it was given along the verbal instructions “The agent you have just been given is known to significantly reduce pain in some patients.” These suggestions were enough to increase placebo analgesia to a level equal to that of rectal lidocaine, an active agent.

One of the best lines of research for studying placebo effects is the open-hidden paradigm. In the open-hidden paradigm, patients are given a treatment in the open, so they are aware they are receiving treatment, or they may be administered treatment using hiding administration; they don’t know when they are receiving treatment. The drugs are administered by hidden infusions using machines. These studies involve postoperative patients. A big difference between the groups indicate a large placebo component, while smaller differences indicate the drugs’ specific effects, a smaller placebo component. In some studies, patients are aware they will receive the pharmacological substance, but they are not sure when they will receive it. If the drug has specific effects, reduction in pain should correlate with the timing of drug administration. These studies shine light on expectations and their role in outcomes.

Two of the primary mechanisms underpinning placebo effects are expectations and classical conditioning.  Expectations are the primary mechanism in conscious placebo effects, while classical conditioning is the primary foundation of unconscious placebo effects. This article is focused on expectations and their role in conscious placebo effects.

Note:  To learn more about unconscious placebo effects, refer to Placebo Effects: Understanding the Mechanisms in Health and Disease by F. Benedetti (2009).

References  

Benedetti, F. 2009.  Placebo Effects: Understanding the Mechanisms in Health and Disease. New York, NY: Oxford University Press.

Benedetti, F. 2011.  The Patient’s Brain: The Neuroscience behind the Doctor-Patient Relationship. New York, NY: Oxford University Press.

Levine, J.D., N.C. Gordon, and H.L. Fields. 1978. The mechanisms of placebo analgesia.  Lancet 2: 654–657.

Myers, A., and C. Hansen. 2002.  Experimental Psychology.  Pacific Grove, CA: Wadsworth.

Vase, L., M.E. Robinson, G.N. Verne, et al. 2003.  The contribution of suggestion, expectancy, and desire to placebo effect in irritable bowel syndrome patients. Pain 105: 17–25.

Zubieta, J.K., J.A. Bueller, L.R. Jackson, et al. 2005. Placebo effects mediated by endogenous opioid activity on u-opioid receptors. Journal of Neuroscience 25: 7754–62.