More Than Just a Sugar Pill: Why the placebo effect is real

by Benika Pinch
figures by Kaitlyn Choi

If you watched the Rio Olympics, you probably noticed that several athletes, including swimmer Michael Phelps, were covered in bizarre circular marks. These bruises were caused by cupping, a therapy that uses suction to pull skin upwards into a circular cup, with the intent of increasing blood flow and reducing muscle tension. While athletes maintain that they benefited from the therapy, a 2015 study found that patients who received cupping reported the same degree of pain relief as patients who unknowingly received a sham version of the therapy (in which the cups had a hole in them and couldn’t create proper suction). Given that cupping is a therapy with limited scientific support, why does it make people feel better? The answer may lie in a peculiar phenomenon known as the placebo effect.

A placebo is defined as a medically inert substance or technique, which is administered like a drug. As the staple negative control in clinical trials, placebos play a critical role in modern medicine. The placebo effect refers to the well-documented phenomenon in which patients feel better after receiving a placebo. In other words, the mere thought that a treatment has been received causes a beneficial physical response.

Now, to be clear, there is no evidence that a placebo can shrink a tumor or heal a broken bone, but when it comes to ailments grounded in self-awareness, such as pain, the placebo effect can be tremendous. In the 1980’s, neuroscientist Jon Levine conducted what is now considered one of the quintessential analyses of the placebo effect. In this study, postoperative patients received either a secret dose of 6-8 mg of morphine, or an overt dose of a substance described as a powerful painkiller (but was actually saline solution!). The results were remarkable: patients in both groups reported the same degree of pain relief.

If you think that all of this sounds a bit unbelievable, you are not alone. For decades the placebo effect was written off as an illusion, spontaneous remission, or biased reporting. However, recent research reveals that the placebo effect is a real biological response, and illuminates the underlying mechanisms driving this phenomenon.

Placebos elicit biological responses

Contrary to popular belief, patients don’t just imagine placebo responses. Rather, numerous brain-imaging studies have confirmed that placebos cause measurable changes in neurobiological signaling pathways . How can a sugar pill lead to a tangible physical response? The key to understanding the placebo is that it is not just the inert therapy itself, but also the expectation surrounding that therapy.

Figure 1: The expectation of benefit associated with a placebo causes measureable changes in neurobiological signaling pathways, resulting in pain relief. — **Figure 1:** The expectation of benefit associated with a placebo causes measureable changes in neurobiological signaling pathways, resulting in pain relief.

Say you are experiencing pain and spontaneously decide to eat a sugar pill – chances are you won’t feel better. However, if you describe your symptoms to a physician, who then prescribes you the same pill (unbeknownst to you, it’s just sugar), you expect that pill to have a therapeutic benefit. This expectation activates reward pathways in the brain, in turn stimulating the release of substances called endorphins, which are chemically similar to opiates like morphine. Like morphine, these endorphins bind to opioid receptors and cause pain relief. Therefore, in response to positive expectations of treatment, your brain becomes flooded with its own supply of natural painkillers. This effect can be partially negated by a chemical called naloxone, which was developed for patients who overdose on opiates, such as morphine or heroine. Naloxone acts by blocking key opioid receptors in the central nervous system, and partially prevents placebo responses. This means that the placebo effect can be biochemically modulated!

Figure 2: (A) Morphine causes pain relief by binding to opioid receptors in the brain. (B) The reward pathways activated by placebos cause the release of endorphins, which bind to opioid receptors. (C) Naloxone blocks opioid receptors, preventing the binding of endorphins, thereby partially blocking the placebo effect. — **Figure 2:** (A) Morphine causes pain relief by binding to opioid receptors in the brain. (B) The reward pathways activated by placebos cause the release of endorphins, which bind to opioid receptors. (C) Naloxone blocks opioid receptors, preventing the binding of endorphins, thereby partially blocking the placebo effect.

The opioid system is not the only pathway at play when it comes to placebos. For example, placebos also increase the release and uptake of dopamine, a neurotransmitter involved in reward-motivated behavior and decreased pain sensitivity. Specifically, in anticipation of benefit when a placebo is administered, dopamine receptors are activated in regions of the brain associated with reward.

As further evidence that the placebo effect is a genuine biological phenomenon, genetics can influence the strength of the effect. Specifically, genetic signatures that alter the opioid and dopamine signaling pathways are predictive of whether a patient is more or less likely to experience a strong placebo effect. For example, patients with opioid receptors that are less active are less likely to be placebo responders. On the other hand, patients with reduced dopamine metabolism, and therefore higher dopamine levels in the brain, are more likely to experience a strong placebo effect.

The placebo as a (not so) negative control

While placebos are grounded in a patient’s psychological reaction to receiving treatment, they can act via the same biological pathways as painkillers. In fact, placebos are so good at causing pain relief that the placebo effect is stealing the spotlight in recent clinical trials for new pain medications.

In order to be approved by the Federal Drug Administration (FDA), new drugs must prove more efficacious than placebos in clinical trials. However, in the pain field this is becoming an increasingly tall order. An analysis of 84 clinical trial results for neuropathic pain conducted since 1996 found that, while the responses to the drugs have remained about the same, the responses to the placebo have increased over the past two decades. Why might the placebo effect be growing stronger? It’s hypothesized that the increasingly showy and large-scale setting of clinical trials, combined with direct-to-consumer advertising by pharmaceutical companies, may raise patients’ expectations of drug efficacy. The result: placebo effects in pain are now so large that pharmaceutical companies have an increasingly hard time proving drug efficacy.

That being said, for most drugs the placebo effect and drug effects should be additive. In other words, a patient’s response to a drug should be equivalent to the drug’s biochemical effects plus the placebo effect. Therefore, if a drug can’t outperform a placebo in a clinical trial, it’s fair to conclude that the drug isn’t good enough to receive approval. However, when it comes to the pain field, distinguishing between placebo and drug effects can be tricky because both activate the same mechanisms, such as the release of endorphins. This means that strong placebo responses could mask drug effects in painkiller trials. Nonetheless, that doesn’t answer the question: why approve and administer a drug, which costs money and has potential side effects, when a sugar pill would have the same effect? At that point, we might as well just prescribe the placebo (or make better drugs)!

Conclusions and future directions

The placebo effect has traditionally been regarded as something negative, as a seemingly unexplained mystery at the heart of modern medicine. However, as we are beginning to understand the biological mechanisms underlying the placebo effect, it is becoming increasingly evident that placebos present a unique opportunity to harness the power of the mind in controlling pain.

The placebo effect highlights the importance of the environment in which treatment is received, and indicates that patients can benefit from language used to boost expectations. But what if there was a role for placebos themselves in medical care – what if they could be prescribed as a treatment?

Of course, this unleashes a Pandora’s box of ethical issues. The assumption is that placebos, by their very definition, must be concealed as a drug in order to work; they require deception. But maybe this doesn’t have to be the case. Doctors could prescribe placebos honestly, a so-called “open-label” placebo. Sounds like an oxymoron, right? Well, it turns out that one discussed application is to administer blister packs of painkillers that contain both the active drug and the placebo, but the patient doesn’t know which pills are which. Such pill packs might achieve the same degree of pain relief, but with less medication – thereby limiting side effects, cost, and problems with drug dependency. The next few years are sure to bring a multitude of studies, and ethical debates, of “honest” placebos.

Let’s briefly return to cupping, a treatment that may not cause a real physical benefit, but makes people feel better. If the placebo effect teaches us anything, it’s that the complex neuropsychological response that results in “feeling better” is not to be discounted. And, with six medals added to his tally, I think it’s safe to say that Michael Phelps was feeling great in Rio.

Benika Pinch is a third year Ph.D. student in the Chemistry and Chemical Biology program at Harvard University.