The Power of the Mind and Other Cutting-Edge Research on the Placebo Effect

Every month, we get into a different health topic and explore the research. This month, we’re looking into how something as simple as a sugar pill has mystified scientists—and we’re summarizing the most interesting findings.

Inert pills, or placebos, are the gold standard for drug trials: The Food and Drug Administration requires that prospective new drugs outperform placebos in clinical studies to prove their effectiveness before they are approved for market. A placebo is designed to have no therapeutic properties; however, patients given a placebo may show improvements in their symptoms, possibly due to expectations that they will get better. This is called the placebo effect. And it’s getting stronger.

A study published in 2015 by researchers at McGill University in Canada analyzed clinical trials of neuropathic pain medications (drugs that relieve nerve pain) to determine whether placebo response has changed over time. Across the eighty studies included, the magnitude of the placebo response was significantly stronger in more recent trials than in the ones that took place longer ago.

The effect of neuropathic drugs over placebos also decreased over time: In 1996, neuropathic drugs produced 27.3 percent more analgesia (pain relief) than a placebo, but by 2013, neuropathic drugs beat out a placebo by only 8.9 percent (which represents less than one point of improvement on an eleven-point pain scale). The researchers then analyzed clinical trials by geographic location, finding that this increase in the strength of the placebo effect was driven solely by clinical trials in the United States. For some reason, the placebo effect isn’t increasing elsewhere.

A similar increase in the strength of the placebo effect has also been found with antidepressants and antipsychotic medications. The issue with this is that drugs have to be more and more effective to outperform placebos, which can limit the number of drugs for a particular condition that pharmaceutical companies are able to put on the market. While we don’t quite understand the mechanisms yet, the strength of the placebo effect speaks to a powerful mind-body connection and our body’s innate ability to heal itself.

Typically, clinical trials are double-blind, meaning that neither the investigator nor the study participants know what treatment each participant receives (the active one or the placebo), which helps prevent bias. But what if participants knew they were given a placebo pill—would there still be a placebo effect?

Surprisingly, yes. In a 2010 study, researcher Ted Kaptchuk showed that even when researchers told patients with irritable bowel syndrome that they’d been given a placebo pill, they still showed improvements in symptoms. This is called an open-label placebo, and since then, other studies have replicated the same results.

In a study published in 2018, researchers at the University of Alabama at Birmingham partnered with Kaptchuk to enroll cancer survivors in an open-label placebo trial to study cancer-related fatigue. First the seventy-four participants met with the lead study investigator, who explained the potential power of the placebo effect and the mechanisms by which it may work. Then participants were given an envelope that assigned them to either two placebo pills a day or treatment as usual (continuation of whatever their existing health regimen was) for the twenty-one days of the study.

At the end of the study, the placebo group reported significantly more improvement in their fatigue symptoms than the treatment-as-usual group. A whopping 73.6 percent of the participants in the placebo group had an improvement in symptoms that was greater than the average improvement in the treatment-as-usual group. Overall, the placebo group showed a 29 percent improvement in the severity of their fatigue and a 39 percent improvement in their quality of life related to fatigue. And three weeks after the end of the study, the open-label placebo participants did not show any significant worsening in their fatigue symptoms.

In 2018, researchers at Northwestern University studied eighty-two people with chronic lower back pain, randomly assigning them to either no treatment, active treatment with an analgesic, or a placebo for eight weeks. Throughout the study, participants underwent four neuroimaging sessions using both fMRI and MRI, responded to a series of questionnaires assessing their personality and psychological state, and also rated their pain symptoms twice daily on a mobile app. Participants who were assigned the placebo showed significantly more improvement than participants who were assigned no treatment. Those who scored high on measures of emotional awareness and not distracting themselves from pain exhibited larger reductions in pain.

The researchers did not find an association between participants’ expectations and pain reduction from placebo, which is different from the findings of numerous other studies. Upon analyzing brain scan results, the researchers found that participants who had a thinner cortex in certain areas of the brain related to chronic pain had a greater placebo response. They also found functional differences in brain connectivity between the patients who responded to the placebo and the patients who did not.

This study highlights the unique mechanisms by which the placebo effect works and which may vary from person to person depending on psychological and neurological characteristics. It also poses a new question for pain researchers: Should clinical trials of pain medications address the dimensions of pain response that can affect the strength of the placebo effect?

One of the most mind-boggling studies on placebo to date was published in 2015 by researchers in Italy studying high-altitude headache from acute mountain sickness. They recruited thirty-five healthy volunteers from colleges in Turin and took them to a research station on the Italian-Swiss border for the three days of the study. The station has an altitude of 3,500 meters (almost 11,500 feet), at which a person’s blood oxygen saturation is between 83 and 90 percent. Participants exercised on a stair-stepper machine while wearing a monitor that provided EKG, blood oxygen saturation, and temperature measurements to the researchers via a tablet. The participants also wore a mask that provided them with oxygen, as well as a tube that took saliva samples.

The study participants spent a thirty-six-hour period at the research station, during which three test sessions were conducted—the first at 8 a.m. on day two, the second at 2 p.m. on day two, and the third at 8 a.m. on day three. The participants were randomly divided into five groups: no treatment (control), 100 percent oxygen during the last test, fake oxygen in the last test (placebo), 100 percent oxygen for first two tests and fake oxygen for the third test (placebo and conditioning), and 100 percent oxygen for first two tests and no treatment for the third test (conditioning control). The no-treatment group was used to determine the natural course of high-altitude headache. The 100 percent oxygen group was used to assess the effects of regular oxygen treatment. The placebo group was used to test the effects of fake-oxygen placebo. The placebo-and-conditioning group was used to test whether previous exposure to oxygen affected the placebo response on test three. And the conditioning group was used to test whether conditioning to oxygen in the first two tests affected results on the third test.

As expected, the administration of oxygen at high altitude increased blood oxygen saturation and decreased pre- and postexercise headache, fatigue, and heart rate, while also reducing blood levels of prostaglandin, the chemical compound responsible for inducing headaches.

Participants who were given fake-oxygen placebo showed decreases in levels of fatigue, but their headaches didn’t improve. Interestingly, for participants who were first given two rounds of real oxygen followed by the fake-oxygen placebo in the third test, their postexercise headaches went away, their heart rate was reduced, and their blood levels of prostaglandin also decreased.

This suggests that the placebo effect is influenced by conditioning. Participants began to associate the sound of the oxygen tank turning on with not just reductions in the symptoms of high-altitude sickness but also real reductions in psychological measures of headaches in their blood, illustrating the power of the mind-body connection.

This article is for informational purposes only. It is not, nor is it intended to be, a substitute for professional medical advice, diagnosis, or treatment and should never be relied upon for specific medical advice. To the extent that this article features the advice of physicians or medical practitioners, the views expressed are the views of the cited expert and do not necessarily represent the views of goop.